Risk Of Cardiovascular Disease In Offspring Research Articles

Placental Pathology and Blood Pressure at Age 7: A Longitudinal Discordant Twin Analysis.

Evidence suggests that the intrauterine environment shapes offspring cardiovascular disease risk. Although placental dysfunction may be an important pathophysiologic pathway, numerous parental and pregnancy characteristics that influence offspring blood pressure are strong confounders of the mechanistic role of the placenta in observational analyses of singletons. Therefore, we leverage twin- and sibling-based comparison designs to determine whether placental pathology is associated with offspring blood pressure at age 7 while mitigating major sources of confounding. Data are from pregnant participants and their offspring in the Collaborative Perinatal Project, a longitudinal pregnancy cohort conducted from 1959 to 1965 in the United States. After delivery, placentas were systematically examined for lesions indicative of maternal vascular malperfusion (MVM) and acute inflammation. Blood pressure was assessed at a follow-up research visit when the offspring were 7 years old. Linear fixed-effects models were used to estimate associations between within-twin or sibling discordance in placental pathology and differences in blood pressure at age 7. Overall, 193 twin pairs were eligible for inclusion, and 23.3% had placentas discordant for MVM. In a fixed-effect analysis, a twin with high-grade MVM had a higher systolic blood pressure Z score by 0.56 SDs than their co-twin without MVM (95% CI, 0.06-1.05) or a 5.7-mm Hg difference (95% CI, 0.6-10.8). Associations were consistent in a sensitivity analysis restricted to dichorionic twins and in a secondary analysis of 759 MVM-discordant sibling pairs. Acute placental inflammation was not associated with blood pressure at age 7. MVM in the placenta is associated with higher offspring blood pressure in mid-childhood, independent of parental and pregnancy characteristics that twins have in common. The findings support the role of the placenta and the intrauterine environment in the developmental origins of cardiovascular health.

Pre-existing maternal cardiovascular disease and the risk of offspring cardiovascular disease from infancy to early adulthood.

A variety of maternal heart conditions are associated with abnormal placentation and reduced foetal growth. However, their impact on offspring's long-term cardiovascular health is poorly studied. This study aims to investigate the association between intrauterine exposure to pre-existing maternal cardiovascular disease (CVD) and offspring CVD occurring from infancy to early adulthood, using paternal CVD as a negative control. This nationwide cohort study used register data of live singletons without major malformations or congenital heart disease born between 1992 and 2019 in Sweden. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for essential maternal characteristics. Paternal CVD served as a negative control for assessment of unmeasured genetic and environmental confounding. Of the 2 597 786 offspring analysed (49.1% female), 26 471 (1.0%) were born to mothers with pre-existing CVD. During a median follow-up of 14 years (range 1-29 years), 17 382 offspring were diagnosed with CVD. Offspring of mothers with CVD had 2.09 times higher adjusted HR of CVD (95% CI 1.83, 2.39) compared with offspring of mothers without CVD. Compared with maternal CVD, paternal CVD showed an association of smaller magnitude (HR 1.49, 95% CI 1.32, 1.68). Increased hazards of offspring CVD were also found when stratifying maternal CVD into maternal arrhythmia (HR 2.94, 95% CI 2.41, 3.58), vascular (HR 1.59, 95% CI 1.21, 2.10), and structural heart diseases (HR 1.48, 95% CI 1.08, 2.02). Maternal CVD was associated with an increased risk of CVD in offspring during childhood and young adulthood. Paternal comparison suggests that genetic or shared familial factors may not fully explain this association.

Cardiovascular health of offspring conceived by assisted reproduction technology: a comprehensive review.

Recently, the use of assisted reproductive technology (ART) has rapidly increased. As a result, an increasing number of people are concerned about the safety of offspring produced through ART. Moreover, emerging evidence suggests an increased risk of cardiovascular disease (CVD) in offspring conceived using ART. In this review, we discuss the epigenetic mechanisms involved in altered DNA methylation, histone modification, and microRNA expression, as well as imprinting disorders. We also summarize studies on cardiovascular changes and other risk factors for cardiovascular disease, such as adverse intrauterine environments, perinatal complications, and altered metabolism following assisted reproductive technology (ART). Finally, we emphasize the epigenetic mechanisms underlying the increased risk of CVD in offspring conceived through ART, which could contribute to the early diagnosis and prevention of CVD in the ART population.

Family History of Modifiable Risk Factors and Association With Future Cardiovascular Disease.

Background A parental history of cardiovascular disease (CVD) confers greater risk of future CVD among offspring. Whether the presence of parental modifiable risk factors contribute to or modify CVD risk in offspring is unclear. Methods and Results We studied 6278 parent-child trios in the multigenerational longitudinal Framingham Heart Study. We assessed parental history of CVD and modifiable risk factors (smoking, hypertension, diabetes, obesity, and hyperlipidemia). Multivariable Cox models were used to evaluate the association of parental history and future CVD among offspring. Among 6278 individuals (mean age 45±11 years), 44% had at least 1 parent with history of CVD. Over a median follow-up of 15 years, 353 major CVD events occurred among offspring. Parental history of CVD conferred 1.7-fold increased hazard of future CVD (hazard ratio[HR], 1.71 [95% CI, 1.33-2.21]). Parental obesity and smoking status were associated with higher hazard of future CVD (obesity: HR, 1.32 [95% CI, 1.06-1.64]; smoking: HR, 1.34 [95% CI, 1.07-1.68], attenuated after adjusting for offspring smoking status). By contrast, parental history of hypertension, diabetes, and hypercholesterolemia were not associated with future CVD in offspring (P>0.05 for all). Furthermore, parental risk factors did not modify the association of parental CVD history on future offspring CVD risk. Conclusions Parental history of obesity and smoking were associated with a higher hazard of future CVD in offspring. By contrast, other parental modifiable risk factors did not alter offspring CVD risk. In addition to parental CVD, the presence of parental obesity should prompt a focus on disease prevention.

Cardiovascular disease risk in offspring of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women at reproductive age. PCOS diagnosis (Rotterdam criteria) is based on the presence of two out of three criteria; clinical and/or biochemical hyperandrogenism, oligo- or an-ovulation and polycystic ovaries. PCOS women suffer from a constellation of reproductive and metabolic abnormalities including obesity and insulin resistance. PCOS women also have increased blood pressure and increased risk of cardiovascular diseases (CVD). In-utero, offspring of PCOS women are exposed to altered maternal hormonal environment and maternal obesity (for most of PCOS women). Offspring of PCOS women could also be subject to genetic susceptibility, the transgenerational transmission of some of the PCOS traits or epigenetic changes. Offspring of PCOS women are commonly reported to have an abnormal birth weight, which is also a risk factor for developing CVD and hypertension later in life. Although studies have focused on the growth pattern, reproductive and metabolic health of children of PCOS women, very limited number of studies have addressed the risk of hypertension and CVD in those offspring particularly as they age. The current narrative review is designed to summarize the available literature (both human studies and experimental animal studies) and highlight the gaps in addressing hypertension and CVD risks in offspring of PCOS women or hyperandrogenemic female animal models.

Maternal obesity causes fetal cardiac hypertrophy and alters adult offspring myocardial metabolism in mice.

Obesity in pregnant women causes fetal cardiac dysfunction and increases offspring cardiovascular disease risk, but its effect on myocardial metabolism is unknown. We hypothesized that maternal obesity alters fetal cardiac expression of metabolism-related genes and shifts offspring myocardial substrate preference from glucose towards lipids. Female mice were fed control or obesogenic diets before and during pregnancy. Fetal hearts were studied in late gestation (embryonic day (E) 18.5; term≈E21), and offspring were studied at 3, 6, 9 or 24months postnatally. Maternal obesity increased heart weight and peroxisome proliferator activated receptor gamma (Pparg) expression in female and male fetuses and caused left ventricular diastolic dysfunction in the adult offspring. Cardiac dysfunction worsened progressively with age in female, but not male, offspring of obese dams, in comparison to age-matched control animals. In 6-month-old offspring, exposure to maternal obesity increased cardiac palmitoyl carnitine-supported mitochondrial respiration in males and reduced myocardial 18 F-fluorodeoxyglucose uptake in females. Cardiac Pparg expression remained higher in adult offspring of obese dams than control dams and was correlated with contractile and metabolic function. Maternal obesity did not affect cardiac palmitoyl carnitine respiration in females or 18 F-fluorodeoxyglucose uptake in males and did not alter cardiac 3 H-oleic acid uptake, pyruvate respiration, lipid content or fatty acid/glucose transporter abundance in offspring of either sex. The results support our hypothesis and show that maternal obesity affects offspring cardiac metabolism in a sex-dependent manner. Persistent upregulation of Pparg expression in response to overnutrition in utero might underpin programmed cardiac impairments mechanistically and contribute to cardiovascular disease risk in children of women with obesity. KEY POINTS: Obesity in pregnant women causes cardiac dysfunction in the fetus and increases lifelong cardiovascular disease risk in the offspring. In this study, we showed that maternal obesity in mice induces hypertrophy of the fetal heart in association with altered expression of genes related to nutrient metabolism. Maternal obesity also alters cardiac metabolism of carbohydrates and lipids in the adult offspring. The results suggest that overnutrition in utero might contribute to increased cardiovascular disease risk in children of women with obesity.

Effect of in-utero polysubstance exposure on adolescent cardiovascular disease risk: Results from the Maternal Lifestyle Study

BackgroundPolysubstance use during pregnancy typically includes use of one or more illicit substances in addition to tobacco and/or alcohol. Rates of polysubstance use during pregnancy range from 5 to 10% and continue to rise. However, to date, there are no studies using longitudinal data exploring cardiovascular disease risk in adolescents exposed to polysubstances in utero. ObjectiveThe objective of this analysis was to discover the possible association between maternal substance use and cardiovascular disease risk (i.e., increased blood pressure) in adolescence. MethodsThe National Institute on Drug Abuse (NIDA)-funded Maternal Lifestyle Study (MLS) cohort was used for this analysis. Briefly, in 1993 MLS enrolled mothers by substance use during pregnancy status (Y/N) at four US locations (Detroit, MI; Miami, FL; Providence, RI; and Memphis, TN) and followed offspring until 2011. Generalized linear modeling assessed cardiovascular disease risk in offspring via systolic blood pressure (mm Hg) at age 16 comparing those prenatally exposed and unexposed to maternal substance use. ResultsThe most prevalent singular substance used during pregnancy in this sample (n = 910) was alcohol (n = 121, 16%), while the most common polysubstance used during pregnancy was a combination of tobacco, alcohol, and cocaine (n = 123, 16%). Those born normal birthweight (≥2500 g) and exposed to tobacco, alcohol, and opioids in utero had 22 mm Hg higher systolic blood pressure at age 16 compared to those not exposed to any substances (β coefficient = 22.44, 95% CI: 10.53–34.35). ConclusionSingularly, tobacco, alcohol, and opioids are among the most used during pregnancy and when used in combination, pose great risk for cardiovascular disease in offspring. Given its recent rise and high prevalence, targeting maternal substance use is critical for cardiovascular disease prevention.

Association of Maternal Hypothyroidism With Cardiovascular Diseases in the Offspring.

BackgroundNo previous study has examined the effect of maternal hypothyroidism on a broad spectrum of cardiovascular disease (CVD) endpoints in the offspring.MethodsA nationwide population-based cohort study based on the linkage of several Danish nationwide registries was conducted to explore whether maternal hypothyroidism is associated with offspring’s CVD. Altogether 1,041,448 singletons born between the 1st of January 1978 and the 31st of December 1998 were investigated from the age of 8 years to the 31st of December 2016. Exposure was maternal diagnosis of hypothyroidism across lifespan and the outcome of interest was a CVD diagnosis in the offspring. Cox regression models were performed to estimate the hazard ratios (HRs) of CVD.ResultsOffspring born to mothers with hypothyroidism had an increased risk of CVD (hazard ratios (HR)=1.23, 95% confidence interval (CI): 1.12-1.35), and of several subcategories of CVD including hypertension, arrhythmia, and acute myocardial infarction in offspring. The magnitude of association was the most pronounced in an exposure occur during pregnancy (HR=1.71, 95% CI: 1.10-2.67), which is consistent across all the subgroup analysis, including sibling analysis.ConclusionsMaternal hypothyroidism is associated with an increased risk of CVD in offspring. Thyroid hormone insufficiency during pregnancy may predominantly contribute to the observed associations; however, the effects of a shared genetic background and a time-stable familial environment/lifestyle factors cannot be excluded.

Programming of a Pro‐Adipogenic Phenotype in Offspring Born to Metabolically Compromised Pregnancies

ObjectivesDetermine the role of adipose tissue dysfunction in programming of cardiovascular disease risk in offspring born to dams with metabolic dysfunction.MethodsThe female mouse heterozygous for leptin receptor deficiency (Hetdb) was used as a model of maternal metabolic dysfunction. These females exhibit higher adiposity, dyslipidemia and hyperinsulinemia during pregnancy. Our data show that this model reproduces programming of early‐onset cardiovascular disease risk reported in human offspring born to obese or diabetic mothers. We sought to test the hypothesis that programming of cardiovascular disease risk is attributable to perturbed adipose tissue development leading to later‐life adipose tissue dysfunction. Wild type (Wt) offspring from both Wt and Hetdb pregnancies were studied as neonates and adults. At 7 weeks of age, offspring were placed on either a control or high fat/sugar (HF/HS) diet. Adipogenic potential was examined in preadipocytes isolated from the stromal vascular fraction (SVF) of inguinal subcutaneous adipose tissue (iSAT) in both neonatal and adult Wt offspring. After induction of differentiation, Oil Red O staining was used to measure lipid droplet accumulation and qPCR was used to measure adipogenic markers. Flow cytometry was utilized to quantify adipogenic progenitors in SVF. Adipokine secretion was measured with ELISA. Several indices of adipose tissue function were measured in adult offspring, including adipose tissue insulin resistance (Adipo‐IR).ResultsNMR whole‐body fat mass was 1.3 fold higher (p < 0.01) and plasma resistin levels were 1.7 fold higher (p < 0.01) in Wt neonates born to Hetdb pregnancies. The iSAT of Wt neonates and adults born to Hetdb vs. Wt dams exhibited a shift in the cell size distribution from smaller adipocytes to larger adipocytes (p < 0.05), indicating that adipogenesis was accelerated in the iSAT of Hetdb neonates. The percentage of CD31‐CD45‐CD29+CD34+ viable SVF cells was higher in neonates from the Hetdb vs. Wt pregnancy. Preadipocytes isolated from Hetdb offspring exhibited a pro‐adipogenic phenotype in early life that persisted into adulthood. After HF/HS feeding, preadipocytes isolated from Wt female (p < 0.05) and male (p < 0.05) adult offspring born to Hetdb pregnancies accumulated more lipid during differentiation. Heightened adipogenesis in adult offspring was also accompanied by impaired insulin‐stimulated inhibition of lipolysis.ConclusionsAdipose tissue dysfunction in offspring born to metabolically adverse pregnancies stems from in utero programming of a pro‐adipogenic phenotype in preadipocytes.Support or Funding InformationCanadian Institutes of Health Research, Alberta Children’s Hospital Research Institute, Heart & Stroke Foundation of Canada and Libin Cardiovascular Institute of Alberta

Mechanisms linking exposure to preeclampsia in utero and the risk for cardiovascular disease.

Preeclampsia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE inutero may also be at increased risk of cardiovascular disease (CVD) in later life. Individuals exposed to PE inutero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE inutero. The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preeclamptic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE inutero may benefit from targeted primary CVD preventive strategies.

Early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn

IntroductionPreeclampsia (PE) carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. We hypothesize that PE is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes might elucidate the increased cardiovascular- and metabolic disease susceptibility in PE offspring. MethodsA nested case-control study was conducted in The Rotterdam Periconceptional Cohort comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, newborn umbilical cord white blood cells (UC-WBC) and umbilical vein endothelial cells were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. ResultsEpigenome-wide tissue-specific analysis between EOPE and PTB controls revealed 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular-metabolic developmental pathways. DiscussionThis study shows differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring.

OP 54 Early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn

Introduction Preeclampsia (PE) carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. We hypothesize that PE is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes link both PE phenotypes with features of cardiovascular- and metabolic diseases in offspring. Objectives In this study we examined tissue-specific genome-wide DNA methylation of umbilical cord blood leucocytes (UC-WBC), placental tissue and human umbilical cord endothelial cells (HUVEC) in relation to EOPE and LOPE. Patients and methods A nested case-control study was conducted in The Rotterdam Periconceptional Cohort (Predict study) comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, UC-WBC and HUVEC were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. Results Epigenome-wide analysis revealed significant differences only between tissues from EOPE and PTB controls, with 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular system developmental pathways. (Fig. 1. Density plot of β -values per tissue and per group). (Fig. 2. Heatmap based on clustering of methylation ( β -value) of all differentially methylated CpGs). Conclusion This study shows differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring. Download : Download high-res image (160KB) Download : Download full-size image Download : Download high-res image (215KB) Download : Download full-size image

Family history of cardiovascular disease and parental lifestyle behaviors are associated with offspring cardiovascular disease risk markers in childhood.

Cardiovascular disease risk markers have become more prevalent in childhood. To provide increased understanding of the etiology of this public health issue, we investigated associations between family characteristics with cardiovascular disease risk markers in adolescents from a developing nation. In this cross-sectional study data for fasting glucose, lipoproteins (LDL-C and HDL-C), triglycerides, and total cholesterol were collected from 991 adolescents aged 10-17 who were recruited from public schools in Londrina city, Southern Brazil. Family history of cardiovascular disease and parental engagement in risk behavior (alcohol consumption and tobacco smoking) were collected using a self-reported parental questionnaire. Socioeconomic status, adolescent physical activity (estimated by Baecke questionnaire), self-reported tobacco and alcohol intake, and somatic maturation (age at peak height velocity) were used as covariates. Logistic regression was used for the main analyses. Independent of adolescent lifestyle behaviors, associations (ORadj [95% CI]) were found between: (1) paternal family history of cardiovascular disease with increased likelihood of high adolescent offspring BMI (1.53 [1.01 to 2.32]) and high triglycerides (2.93 [1.04 to 8.27]); (2) maternal family history of cardiovascular disease with heightened odds of high adolescent offspring triglycerides (2.84 [1.02 to 7.91]); (3) maternal cardiovascular disease with higher odds of high fasting glucose (2.16 [1.13 to 4.14]), and (4) maternal smoking with increased odds of high LDL-C (1.78 [1.14 to 2.79]) and high total cholesterol (1.77 [1.01 to 3.10]) in adolescent offspring. Family history of cardiovascular disease and maternal tobacco smoking are related to increased cardiovascular risk in adolescents, potentially independent of their own lifestyle behaviors.

LDL cholesterol in early pregnancy and offspring cardiovascular disease risk factors

Vast amounts of data show associations between maternal obesity, dysglycemia, diabetes, and undernutrition during pregnancy and increased cardiovascular disease risk in offspring. However, elevated maternal LDL cholesterol (LDL-C) in pregnancy and offspring cardiovascular disease (CVD) risk has scarcely been studied. Our objective was to investigate the associations between elevated maternal LDL-C in pregnancy and CVD risk factors in 6-to-13-year-old offspring. We recruited 6-to-13-year-old children whose mothers attended a pregnancy cohort and who had high or low cholesterol in pregnancy, defined as LDL-C over the 90th percentile or below the 10th percentile within the pregnancy cohort, respectively. We measured CVD risk factors in the children in the 2 groups. Maternal plasma LDL-C at gestational week 14 to 16 was 4.0 and 1.4mmol/L in the hypercholesterolemic (n=27) and hypocholesterolemic (n=34) groups, respectively (P<.001). Interestingly, offspring plasma LDL-C was 0.4mmol/L higher in children whose mothers had hypercholesterolemia during pregnancy (P<.01). We found no difference in birthweight or any other clinical or biochemical CVD risk factors or dietary intake between the children at 6-13years. Women with elevated LDL-C during early pregnancy have offspring with higher LDL-C already at the age of 6-13years. Unless cholesterol-reducing measures are successfully implemented, the affected children may be at increased cardiovascular risk.

Does intrauterine exposure to hypercholesterolemia adversely affect familial hypercholesterolemia phenotype?

There is currently limited information as to whether maternally or paternally inherited familial hypercholesterolemia confers different phenotype risk to offspring. Knowledge about the differences in risk conferred by inheritance could be important with respect to follow-up and more individually targeted treatment of subjects with familial hypercholesterolemia. Few studies have, with inconsistent results so far, investigated the significance of familial hypercholesterolemia inheritance on cardiovascular risk markers in offspring. Maternal inheritance of familial hypercholesterolemia includes hypercholesterolemic in-utero conditions for the offspring. How this may influence later risk is briefly discussed in the article. Current data suggest that the dominating factor of the familial hypercholesterolemia (FH) phenotype is the mutation and not the inheritance, however, maternal inheritance of FH has been reported to adversely affect FH phenotype in terms of increased mortality. More knowledge about how intrauterine hypercholesterolemia during pregnancy influences epigenetic modifications and later cardiovascular disease risk in offspring is needed and this may open up new avenues of treatment of pregnant women with familial hypercholesterolemia.

Maternal Phytosterol Supplementation during Pregnancy and Lactation Modulates Lipid and Lipoprotein Response in Offspring of apoE-Deficient Mice1–3

Background: In utero exposure to excessive cholesterol has been shown to increase fetal plasma cholesterol concentration and predispose adult offspring to cardiovascular disease (CVD) risk. Because lipid-lowering drugs are contraindicated during pregnancy, natural cholesterol-lowering compounds may be a safe and effective alternative to reduce CVD risk in offspring born to hypercholesterolemic mothers.Objective: This study used the hypercholesterolemic apolipoprotein E–deficient (apoE−/−) mouse model to test the hypothesis that mothers supplemented with phytosterols during gestation and lactation would produce offspring with a more favorable lipid profile than offspring from unsupplemented mothers, despite having a genetic predisposition toward hypercholesterolemia.Methods: Sixteen female apoE−/− mice were randomly assigned to 2 diets fed throughout the gestation and lactation periods: a cholesterol-enriched diet (CH) (0.15%) or the cholesterol-enriched diet supplemented with phytosterols (CH/PS) (2%). Serum lipids and lipoproteins were measured by enzyme assay and nuclear magnetic resonance spectroscopy, respectively, and liver cholesterol was analyzed by GC.Results: Compared with the CH-fed dams at the end of lactation, phytosterol-supplemented dams displayed lower (P < 0.05) serum total cholesterol (−55%), non-HDL cholesterol (−56%), and LDL cholesterol (−47%), but no change (P > 0.05) in HDL cholesterol and triacylglycerol (TG) concentrations. Pups from phytosterol-fed dams demonstrated lower (P < 0.05) total cholesterol (−25%), non-HDL cholesterol (−25%), LDL cholesterol (−47%), and TGs (−41%), without any change (P > 0.05) in HDL cholesterol compared with pups from CH-fed dams. Furthermore, compared with pups from CH-fed dams, pups from phytosterol-supplemented dams displayed a lower (P < 0.05) number of total LDL particles (−34%), VLDL particles (−31%), and HDL particles (−30%).Conclusion: Our results in apoE−/− mice suggest that even under strong genetic predisposition to hypercholesterolemia, pups born to mothers supplemented with phytosterols during gestation and lactation exhibit favorable liver and serum lipid responses compared with pups from unsupplemented mothers.

Maternal salt and fat intake causes hypertension and sustained endothelial dysfunction in fetal, weanling and adult male resistance vessels.

Maternal salt and fat intake can independently programme adult cardiovascular status, increasing risk of cardiovascular disease in offspring. Despite its relevance to modern western-style dietary habits, the interaction between increased maternal salt and fat intake has not been examined. Female virgin Sprague-Dawley rats were fed, a standard control diet (CD) (10% kcal fat, 1% NaCl), High-fat diet (HF) (45% kcal fat, 1% NaCl), High-salt diet (SD) (10% kcal fat, 4% NaCl), High-fat high-salt diet (HFSD) (45% kcal fat, 4% NaCl) prior to pregnancy, during pregnancy and throughout lactation. Fetal, weanling and adult vessels were mounted on a pressure myograph at fetal day 18, weaning day 21 and day 135 of adulthood. Increased blood pressure in SD, HFD and HFSD male offspring at day 80 and 135 of age was consistent with perturbed vascular function in fetal, weanling and adult vessels. Maternal salt intake reduced EDHF and calcium-mediated vasodilation, maternal fat reduced NO pathways and maternal fat and salt intake, a combination of the two pathways. Adult offspring cardiovascular disease risk may, in part, relate to vascular adaptations caused by maternal salt and/or fat intake during pregnancy, leading to persistent vascular dysfunction and sustained higher resting blood pressure throughout life.

Parental weight status and offspring cardiovascular disease risks: a cross-sectional study of Chinese children.

IntroductionPrevalence of childhood obesity in China is increasing, and parental weight is a risk factor for the development of obesity in children. We examined the relationship of parental body weight status with risk of offspring cardiovascular disease (CVD) in Chinese children.MethodWe conducted a cross-sectional study in Wuhan, China, during May and June 2010. Parental body mass index (BMI) was calculated according to self-reported height and weight. Offspring CVD risk factors, including BMI, waist circumference, blood pressure, fasting glucose, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, cardiorespiratory fitness (CRF), and metabolic risk score (MRS), were assessed through anthropometric measures, blood samples, and a CRF test. Multiple linear regression and analysis of covariance were used to examine the effects of maternal and paternal weight status on offspring CVD risks.ResultsA total of 580 Chinese children (339 boys and 241 girls, mean [standard deviation] age, 9.6 [0.7] years) participated in the study. Maternal BMI was significantly associated with offspring elevated BMI (β = 0.134, P = .002), waist circumference (β = 0.253, P = .04), and decreased CRF (β = −0.134, P = .01). Paternal BMI was significantly associated with elevated offspring BMI (β = 0.161, P < .001), waist circumference (β = 0.404, P < .001), triglycerides (β = 0.017, P = .03), MRS (β = 0.084, P = .03), and decreased CRF (β = −0.174, P < .001). BMI (P < .001), waist circumference (P < .001), and MRS (P < .05) were positively associated with additional overweight/obese parents, whereas CRF was negatively associated (P < .001).ConclusionParental weight status was significantly associated with increased risk of CVD in their children, and the association was stronger for paternal weight status.

Paternal or maternal history of cardiovascular disease and the risk of cardiovascular disease in offspring. A systematic review and meta-analysis

BackgroundParental history of cardiovascular disease (CVD) is an established risk factor for the development of CVD in offspring. Several studies have suggested that a maternal transmission of CVD is more important for the development of CVD than paternal transmission. MethodsA systematic search and meta-analysis were conducted, using the Medline and Embase databases. Included were cohort, case–control and cross-sectional studies (n=26) focusing on the relation between paternal and maternal histories of cardiovascular disease and offspring CVD (myocardial infarction, stroke or cardiovascular mortality). The pooled estimates were calculated using a random-effects model. ResultsThe pooled OR of CVD in offspring having a positive paternal history of CVD compared to not having a positive parental history was 1.91 (95% CI 1.56–2.34; I253%), the RR1.54 (95% CI 1.33–1.77; I296%). The OR of a maternal history was 2.16 (95% CI 1.71–2.74; I250%), RR1.59 (95% CI 1.38–1.84; I290%). Regarding different age limits, a maternal history <50years (3.15, 95% CI 2.18–4.55) and paternal history <55years (2.82, 95% CI 2.25–3.54) were associated with the highest cardiovascular risk. Additional analyses for sons demonstrated an estimate for a positive paternal history of 1.55 (95% CI 1.39–1.71; I274%) and 1.56 (95% CI 1.46–1.67; I216%) for maternal history. For daughters, the estimate for paternal history was 1.48 (95% CI 1.26–1.74; I273%) and 1.79 (95% CI 1.50–2.13; I268%) for maternal history . ConclusionsThe conferred risk of CVD in offspring was not substantially different between positive paternal and maternal histories of CVD, the highest risk was observed for maternal history <50years. Since a positive parental history of CVD involves an increased cardiovascular risk, parental history inquiry is useful in clinical practice. No distinction has to be made whether the affected parent is the mother or the father.

Nutritional supplementation during pregnancy and offspring cardiovascular disease risk in The Gambia

Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring. The objective was to follow up the offspring in 2 randomized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease (CVD) risk in offspring. We recruited offspring born during 2 trials in The Gambia, West Africa. One trial provided protein-energy-dense food supplements (1015 kcal and 22 g protein/d) to pregnant (intervention, from 20 wk gestation until delivery) or lactating (control, for 20 wk from birth) women and was randomized at the village level. The second was a double-blind, individually randomized, placebo-controlled trial of calcium supplementation (1.5 g/d), which was also provided from 20 wk gestation until delivery. Sixty-two percent (n = 1267) of children (aged 11-17 y) born during the protein-energy trial were recruited and included in the analysis, and 64% (n = 350) of children (aged 5-10 y) born during the calcium trial were recruited and included in the analysis. Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group (adjusted mean difference: -0.05 mmol/L; 95% CI: -0.10, -0.001 mmol/L). There were no other differences in CVD risk factors, including blood pressure, body composition, and cholesterol, between children born to intervention and control women from the protein-energy trial. Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure. These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring, at least in this setting and at the ages studied here. This trial was registered at www.controlled-trials.com as ISRCTN96502494.