Adiposity associates with lower plasma resolvin E1 (Rve1): a population study.

BACKGROUND: Inadequate inflammation resolution may contribute to persistent low-grade inflammation that accompanies many chronic conditions. Resolution of inflammation is an active process driven by Specialized Pro-resolving Mediators (SPM) that derive from long chain n-3 and n-6 fatty acids. This study examined plasma SPM in relation to sex differences, lifestyle and a broad range cardiovascular disease (CVD) risk factors in 978, 27-year olds from the Australian Raine Study. METHODS: Plasma SPM pathway intermediates (18-HEPE, 17-HDHA and 14-HDHA), and SPM (E- and D-series resolvins, PD1, MaR1) and LTB4 were measured by liquid chromatography-tandem mass spectrometry (LCMSMS). Pearson correlations and multiple regression analyses assessed relationships between SPM and CVD risk factors. Unpaired t-tests or ANOVA assessed the effect of sex, smoking, unhealthy alcohol consumption and obesity on SPM. RESULTS: Women had higher 17-HDHA (p = 0.01) and lower RvE1 (p < 0.0001) and RvD1 (p = 0.05) levels compared with men. In univariate analysis, obesity associated with lower RvE1 (p = 0.002), whereas smoking (p < 0.001) and higher alcohol consumption (p < 0.001) associated with increased RvE1. In multiple regression analysis, plasma RvE1 was negatively associated with a range of measures of adiposity including BMI, waist circumference, waist-to-height ratio, abdominal subcutaneous fat volume, and skinfold thicknesses in both men and women. CONCLUSION: This population study suggests that a deficiency in plasma RvE1 may occur in response to increasing adiposity. This observation could be relevant to ongoing inflammation that associates with CVD and other chronic diseases.

Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

Relationship between TV Watching during Childhood and Adolescence, and Artery Function in Adulthood.

PURPOSE: Artery dysfunction is an early, integral stage in atherogenesis that predicts future cardiovascular events. Sedentary behavior, such as TV watching, is highly prevalent and associated with increased risk of developing cardiovascular diseases. This study investigated whether patterns of TV watching throughout childhood and adolescence were associated with artery function in adulthood. METHODS: TV watching data were collected when participants of the Raine Study were aged 5, 8, 10, 14, 17, and 20 yr. Previous latent class analysis indicated three trajectory groups of TV watching: low TV (<14 h·wk -1 ), high TV (>14 h·wk -1 ), and increasing TV (change from low TV to high TV). At age 28 yr, participants were invited to undergo tests of brachial and femoral artery function by flow-mediated dilation (FMD). General linear models examined differences in artery function between TV trajectory groups for men and women. RESULTS: Five hundred sixty participants (n = 261 women, n = 299 men) were included in the study. In women, the low TV group had significantly greater femoral artery FMD (10.8 ± 1.6%) than both High TV (9.0 ± 1.3%, P = 0.005) and Increasing TV groups (8.5 ± 1.3%, P < 0.001); these results were maintained following mediation analysis, including contemporaneous risk factors. There were no significant differences in femoral artery FMD between TV trajectory groups in men ( P = 0.955). CONCLUSIONS: This study suggests that TV watching behaviors during childhood and adolescence may have legacy impacts on artery function at age 28 yr, particularly in women. This may increase the risk of atherosclerotic vascular pathologies in later life.

Effects of an Unripe Avocado Extract on Glycaemic Control in Individuals with Obesity: A Double-Blinded, Parallel, Randomised Clinical Trial.

BACKGROUND: Unripe avocados (Persea americana) are naturally enriched in mannoheptulose (MH), which is a candidate caloric restriction mimetic. OBJECTIVES: To evaluate the effects of a diet supplement made from unripe avocado on glucose tolerance, and cardiometabolic risk factors in free-living nondiabetic adults with obesity. METHODS: In a double-blinded, randomised controlled trial, 60 adults (female n = 47, age 48 ± 13 years, BMI 34.0 ± 2.6 kg/m2) were stratified by sex and randomised to avocado extract (AvX, 10 g finely ground, freeze-dried unripe avocado) or placebo (10 g finely ground cornmeal plus 5% spinach powder) daily, for 12 weeks. The primary outcome was a change in glucose area under the curve (AUC) in response to a 75 g oral glucose tolerance test. A post-hoc analysis was subsequently performed in a subgroup with insulin AUC above the median of baseline values after removal of participants >2 SD from the mean. RESULTS: There were no between-group differences in glucose AUC (p = 0.678), insulin AUC (p = 0.091), or cardiovascular outcomes. In the subgroup analysis, insulin AUC was lower in AxV versus placebo (p = 0.024). CONCLUSIONS: Daily consumption of unripe avocado extract enriched in MH did not alter glucose tolerance or insulin sensitivity in nondiabetic adults with obesity, but the data provided preliminary evidence for a benefit in insulin AUC in a subgroup of participants with elevated baseline postprandial insulin levels.

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

Improved arterial inflammation with high dose omega-3 fatty acids in patients with elevated lipoprotein(a): Selective effect of eicosapentaenoic acid?

Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease. However, there are no approved and effective treatments for lowering Lp(a) and the associated cardiovascular risks. Omega-3 fatty acids (ω-3FAs), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have both triglyceride-lowering and anti-inflammatory properties. This pilot study investigated the effect of high dose ω-3FAs (3.6 g/day) on arterial inflammation in 12 patients with elevated Lp(a) (> 0.5 g/L) and stable coronary artery disease (CAD) receiving cholesterol-lowering treatment. Arterial inflammation was determined using 18F-fluorodexoyglucose positron emission tomography/computed tomography before and after 12-weeks intervention. ω-3FAs significantly lowered plasma concentrations of triglycerides (-17%, p < 0.01), Lp(a) (-5%, p < 0.01) as well as aortic maximum standardized uptake value (SUVmax) (-4%, p < 0.05). The reduction in SUVmax was significantly inversely associated with average on-treatment EPA (r = -0.750, p < 0.01), but not DHA and triglyceride, concentrations. In conclusion, high dose ω-3FAs decrease arterial inflammation in patients with elevated Lp(a) and stable CAD, which may involve a direct arterial effect of EPA.

Fetal Growth Trajectories and Measures of Insulin Resistance in Young Adults.

CONTEXT: Events during gestation greatly influence the risk of cardiometabolic diseases including diabetes in offspring during later life. OBJECTIVE: This study aimed to investigate relationships between serial ultrasound-derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort. METHODS: Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385), and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, adult lifestyle factors, and maternal factors during pregnancy. RESULTS: The study identified 7 AC, 5 FL, and 5 HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%; P = .005) and 2 low HC growth trajectories (20%; P = .006% and 8%; P = .021) were associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC were associated with 12% (P = .002) and 9% (P = .021) lower adult HOMA-IR, respectively, compared to the reference group. CONCLUSION: Restricted fetal HC and AC from early pregnancy are associated with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders.

Normative cut-offs for polycystic ovary syndrome diagnostic features in adolescents using cluster analysis.

OBJECTIVE: The diagnosis of polycystic ovary syndrome (PCOS) remains challenging with international guidelines prioritising accurate cut-offs for individual diagnostic features. These diagnostic cut-offs are currently based on arbitrary percentiles, often from poorly characterised cohorts, and are dependent on variable laboratory ranges defined by assay manufacturers, limiting diagnostic accuracy. Cluster analysis is the recommended approach for defining normative cut-offs within populations for clinical syndromes. Few PCOS adult studies have applied cluster analysis, with no studies in adolescents. We aimed to define normative cut-offs for individual PCOS diagnostic features in a community-based population of adolescents using cluster analysis. DESIGN: This analysis utilised data from the Menstruation in Teenagers Study, a subgroup of the Raine Study, which is a population based prospective cohort of 244 adolescents whose mean age at PCOS assessment was 15.2 years. METHODS: K-means cluster analysis and receiver operating characteristics curves were used to define normative cut-offs for modified Ferriman-Gallwey (mFG) score, free testosterone (free T), free androgen index (FAI), and menstrual cycle length. RESULTS: Normative cut-offs for mFG, free T, FAI, and menstrual cycle lengths were 1.0, 23.4 pmol/L, 3.6, and 29 days, respectively. These corresponded to the 65th, 71st, 70th, and 59th population percentiles, respectively. CONCLUSION: In this novel study, we define the normative diagnostic criteria cut-offs in this unselected adolescent population and show that these cut-offs correspond to lower percentiles than conventional cut-offs. These findings highlight the pertinent need to re-define PCOS diagnostic cut-offs in adolescents. Validation is required in larger, multi-ethnic, and well-characterised adolescent cohorts.

Dairy Foods: Beneficial Effects of Fermented Products on Cardiometabolic Health.

PURPOSE OF REVIEW: This review of recent observational studies and understanding of the complex nature of dairy foods is intended to reappraise the effects of different types of dairy foods on cardiovascular disease (CVD). RECENT FINDINGS: Recent guidelines from major cardiovascular societies suggest that apart from the adverse effect of butter, consumption of more complex dairy products notably fermented varieties and yogurt in particular, appear to be inversely associated with outcomes of CVD and type 2 diabetes (T2D). Reduced fat in dairy food remains preferred for people at increased CVD risk. Changed evidence has led to new advice regarding consumption of some dairy foods. The apparent beneficial effects of fermented milk products, particularly yogurt, allow for increased consumption of nutritious staple foods. Recent national guidelines reflect this view.

A Review of Low-Density Lipoprotein-Lowering Diets in the Age of Anti-Sense Technology.

This narrative review discusses an important issue, the primary role of diet in reducing low-density lipoprotein cholesterol (LDLc) concentrations in polygenic hypercholesterolemia. Two effective drugs, statins, and ezetimibe, that lower LDLc > 20% are relatively inexpensive and potential competitors to strict dieting. Biochemical and genomic studies have shown that proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) and lipid metabolism. Clinical trials have demonstrated that inhibitory monoclonal antibodies of PCSK9 dose-dependently lower LDLc up to 60%, with evidence of both regression and stabilization of coronary atherosclerosis and a reduction in cardiovascular risk. Recent approaches using RNA interference to achieve PCSK9 inhibition are currently undergoing clinical evaluation. The latter presents an attractive option of twice-yearly injections. They are, however, currently expensive and unsuitable for moderate hypercholesterolemia, which is largely due to inappropriate patterns of eating. The best dietary approach, the substitution of saturated fatty acids by polyunsaturated fatty acids at 5% energy, yields > 10% lowering of LDLc. Foods such as nuts and brans, especially within a prudent, plant-based diet low in saturates complemented by supplements such as phytosterols, have the potential to reduce LDLc further. A combination of such foods has been shown to lower LDLc by 20%. A nutritional approach requires backing from industry to develop and market LDLc-lowering products before pharmacology replaces the diet option. Energetic support from health professionals is vital.

Long-term dietary nitrate supplementation slows the progression of established atherosclerosis in ApoE-/- mice fed a high fat diet.

BACKGROUND AND AIMS: Atherosclerosis is associated with a reduction in the bioavailability and/or bioactivity of endogenous nitric oxide (NO). Dietary nitrate has been proposed as an alternate source when endogenous NO production is reduced. Our previous study demonstrated a protective effect of dietary nitrate on the development of atherosclerosis in the apoE-/- mouse model. However most patients do not present clinically until well after the disease is established. The aims of this study were to determine whether chronic dietary nitrate supplementation can prevent or reverse the progression of atherosclerosis after disease is already established, as well as to explore the underlying mechanism of these cardiovascular protective effects. METHODS: 60 apoE-/- mice were given a high fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis. The mice were then randomized to (i) control group (HFD + 1 mmol/kg/day NaCl), (ii) moderate-dose group (HFD +1 mmol/kg/day NaNO3), or (iii) high-dose group (HFD + 10 mmol/kg/day NaNO3) (20/group) for a further 12 weeks. A group of apoE-/- mice (n = 20) consumed a normal laboratory chow diet for 24 weeks and were included as a reference group. RESULTS: Long-term supplementation with high dose nitrate resulted in ~ 50% reduction in plaque lesion area. Collagen expression and smooth muscle accumulation were increased, and lipid deposition and macrophage accumulation were reduced within atherosclerotic plaques of mice supplemented with high dose nitrate. These changes were associated with an increase in nitrite reductase as well as activation of the endogenous eNOS-NO pathway. CONCLUSION: Long-term high dose nitrate significantly attenuated the progression of established atherosclerosis in the apoE-/- mice fed a HFD. This appears to be mediated in part through a XOR-dependent reduction of nitrate to NO, as well as enhanced eNOS activation via increased Akt and eNOS phosphorylation.

Effect of Oral Contraception on Screening Tests for Primary Aldosteronism: A 10-Year Longitudinal Study.

CONTEXT: Primary aldosteronism (PA) and oral contraception (OC) can both cause hypertension in young women. However, the effect of OC on the screening test for PA, the aldosterone to renin ratio (ARR), is not clear. OBJECTIVE: We evaluated the impact of OC on the screening test for PA. METHODS: In this retrospective cohort study, we analyzed data from the female offspring (Gen2) of women enrolled in the Raine Study, a population-based birth cohort, who had blood pressure (BP) measurements, blood samples, and information about OC use at age 17 years (N = 484) and/or age 27 years (N = 486). RESULTS: Aldosterone concentration was significantly higher in OC users than nonusers at 17 years (median 486 pmol/L vs 347 pmol/L, P < 0.001). Renin concentration was significantly lower in OC users at both 17 years (13.4 mU/L vs 20.6 mU/L) and 27 years (9.2 mU/L vs 11.8 mU/L), hence the ARR was significantly higher in OC users compared to nonusers at both 17 years (31.5 vs 18.3) and 27 years (27.3 vs 21.1). The proportion of participants with ARR > 70 pmol/mU (current threshold for PA detection) was significantly higher in OC users at both 17 years (12.6% vs 2.1%) and 27 years (6.4% vs 0.4%); however, they had comparable BP to those with ARR < 70. OC use at any age abolished the relationship between ARR and BP that is observed in nonusers. CONCLUSION: OC can increase the ARR and cause a false positive PA screening result. Until more reliable criteria for PA screening in OC users are established, alternative contraception should be considered during screening.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.

Relationship between TV watching during childhood and adolescence and fitness in adulthood in the Raine Study cohort.

To investigate: (1) whether TV watching habits throughout childhood and adolescence, a proxy of sedentary behaviour, impacted cardiorespiratory fitness (CRF) in adulthood, and (2) whether any potential impact of TV watching in childhood and adolescence on CRF in adulthood was changed by adult physical activity (PA) levels. A longitudinal study with questionnaire data available regarding TV watching collected at ages 5, 8, 10, 14, 17 and 20 yrs, allowed trajectories of TV watching to be developed. At age 28 yrs, participants completed a V̇O2peak test and the International Physical Activity Questionnaire. General linear models tested for differences in CRF (time to exhaustion TTE and V̇O2peak mL·kg-1·min-1) between TV watching trajectories. The secondary analysis tested the potential effect current PA levels has on the relationship between TV trajectory and fitness. In total, 449 participants [male n = 255 (56.8%), 28.3 ± 0.5 yrs; female n = 194 (43.2%), 28.2 ± 0.4 yrs] were included in the study. Three distinct trajectories of TV watching were identified: High TV, Increasing TV and Low TV. CRF was lowest in the High TV watching trajectory and increased progressively from High to Increasing TV and Increasing to Low TV (all P < .05). Within each of the TV trajectories, those engaging in high levels of current PA had greater CRF than those engaging in low and moderate PA. TV watching in childhood and adolescence negatively impacts upon adult fitness at the age of 28 years. However, this negative impact of historical TV watching on CRF can largely be attenuated by engaging in higher levels of PA in adulthood.

Relationship between dietary intake and erythrocyte PUFA in adolescents from a Western Australian cohort.

BACKGROUND: Population-based studies show that the intake of omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA) are associated with a range of health conditions. Therefore, the reliability of food frequency questionnaires (FFQ) as rapid and easily accessible screening tools for PUFA intake deserve investigation. OBJECTIVE: We aimed to assess the relationship between erythrocyte fatty acids and fatty acid intake collected using the Commonwealth Scientific and Industrial Research Organisation (CSIRO) food frequency questionnaire in an adolescent cohort. DESIGN: A cross-sectional study using data from 1155 young adolescents participating in the 14-year follow-up of the Raine Study. Bland-Altman plots were used to determine the agreement between dietary intake and erythrocyte levels of each fatty acid. RESULTS: The main dietary source of n-3 long-chain (LC) PUFA was 'fresh fish' (53% of total n-3 LC-PUFA). Docosahexaenoic acid (DHA) showed the strongest correlation between erythrocyte and diet assessment (r = 0.274; p < 0.001), whilst linoleic acid (LA) (r = 0.103; p < 0.001) and arachidonic acid (AA) (r = -0.06; p = 0.042) showed weaker correlations, with limits of agreement relatively narrow. Bland-Altman plots showed a dose-dependent bias between the FFQ fatty acid data and corresponding erythrocyte data. CONCLUSIONS: For the major n-3 and n-6 PUFA, dietary intakes derived from the FFQ showed weaker correlations and poorer agreement with erythrocyte levels, and the deviation between the two increased with higher intake levels.

Willingness to be tested for a secondary cause of hypertension: a survey of the Australian general community.

BACKGROUND: Primary aldosteronism (PA) represents the most common and potentially curable cause of secondary hypertension. However, PA is not commonly screened for, and up to 34% of patients who screen positive do not complete the full diagnostic process. This suggests that the diagnostic process may pose a barrier to patients and may contribute to the under-diagnosis of PA. AIMS: To evaluate the willingness of the Australian general public to undergo testing for secondary causes of hypertension and identify enablers or barriers to testing from the patients' perspective. METHODS: An online survey containing questions on knowledge and attitudes towards hypertension, willingness to be tested and enablers/barriers towards testing was distributed to the Australian community. RESULTS: Of 520 adult respondents (mean age 50.4 years, SD 27.3 years; 28.8% hypertensive; 56.0% female), the majority of non-hypertensive and hypertensive respondents (82.7% vs 70.0%; P = 0.03) were willing to undergo testing for a secondary cause of hypertension that involved blood and urine tests. Greater knowledge of hypertensive risk modification strategies and complications was predictive of willingness to be tested, whereas age, sex, education level, geographic location, socio-economic status and cardiovascular comorbidities were not. The top three barriers to testing included fear of a serious underlying condition, lack of belief in further testing and increased stress associated with further testing. CONCLUSION: A high proportion of patients are willing to engage in testing for a secondary cause of hypertension. Education about the risks associated with hypertension and the testing process may overcome several barriers to testing.

Associations between Prenatal Exposure to Phthalates and Features of the Metabolic Syndrome in Males from Childhood into Adulthood.

Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored samples taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the consistent themes were limited to a few metabolites and the outcomes of systolic blood pressure, fasting insulin and glucose.

Relationships between intrauterine fetal growth trajectories and markers of adiposity and inflammation in young adults.

BACKGROUND: There is now good evidence that events during gestation significantly influence the developmental well-being of an individual in later life. This study aimed to investigate the relationships between intrauterine growth trajectories determined by serial ultrasound and subsequent markers of adiposity and inflammation in the 27-year-old adult offspring from the Raine Study, an Australian longitudinal pregnancy cohort. METHODS: Ultrasound fetal biometric measurements including abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs (Gen1-Gen2) in the Raine Study were used to develop fetal growth trajectories using group-based trajectory modeling. Linear mixed modeling investigated the relationship between adult body mass index (BMI), waist circumference (WC), and high-sensitivity C-reactive protein (hs-CRP) of Gen2 at 20 (n = 485), 22 (n = 421) and 27 (n = 437) years and the fetal growth trajectory groups, adjusting for age, sex, adult lifestyle factors, and maternal factors during pregnancy. RESULTS: Seven AC, five FL and five HC growth trajectory groups were identified. Compared to the average-stable (reference) group, a lower adult BMI was observed in two falling AC trajectories: (ß = -1.45 kg/m2, 95% CI: -2.43 to -0.46, P = 0.004) and (ß = -1.01 kg/m2, 95% CI: -1.96 to -0.05, P = 0.038). Conversely, higher adult BMI (2.58 kg/m2, 95% CI: 0.98 to 4.18, P = 0.002) and hs-CRP (37%, 95% CI: 9-73%, P = 0.008) were observed in a rising FL trajectory compared to the reference group. A high-stable HC trajectory associated with 20% lower adult hs-CRP (95% CI: 5-33%, P = 0.011). CONCLUSION: This study highlights the importance of understanding causes of the unique patterns of intrauterine growth. Different fetal growth trajectories from early pregnancy associate with subsequent adult adiposity and inflammation, which predispose to the risk of diabetes and cardiometabolic disease.

Mediators of inflammation resolution and vasoactive eicosanoids in gestational diabetes and preeclampsia.

OBJECTIVE: Women with gestational diabetes (GDM) have an increased risk of preeclampsia and postpartum diabetes. Inflammation associates with both GDM and preeclampsia. This study examined specialized proresolving mediators (SPM) that direct inflammation resolution and eicosanoids that are involved in inflammation, in relation to the development of preeclampsia and ongoing postpartum glucose intolerance in GDM. METHODS: Participants were selected from a prospective study examining the development of preeclampsia in women with GDM. Four groups of age-matched women were studied: GDM ( n  = 20), GDM who developed preeclampsia (GDM+PE, n  = 21), GDM who remained glucose-intolerant postpartum (GDM+PPIGT, n  = 20), or pregnancies with glucose tolerance within the normal range (NGT, n  = 21). Measurement of SPM (E-series resolvins and D-series resolvins), SPM pathway intermediates (14-HDHA, 18-HEPE and 17-HDHA), 20-hydroxyeicosatetraenoic acid (20-HETE), and the urinary metabolite of the vasodilator prostacyclin 2,3-dinor-6-Keto-PGF 1α , were made at 28, 32 and 36 weeks gestation and at 6 months postpartum. RESULTS: Compared with GDM, GDM+PE had elevated levels of 20-HETE and the SPM pathway intermediates 14-HDHA, 18-HEPE, 17-HDHA, at 32 weeks, and the SPM RvE1 at 32 and 36 weeks gestation. Compared with NGT and regardless of whether they developed preeclampsia or PPIGT, GDM had lower levels of 2,3-dinor-6-Keto-PGF 1α during pregnancy. CONCLUSION: Reduced levels of the prostacyclin metabolite 2,3-dinor-6-Keto-PGF 1α may contribute to the increased risk of preeclampsia in women with GDM. The increase in 20-HETE, a vasoconstrictor and mediator of inflammation, and SPM that contribute to inflammation resolution, prior to the onset of preeclampsia require further investigation to clarify their clinical significance.

Prospective dietary polyunsaturated fatty acid intake is associated with trajectories of fatty liver disease: an 8 year follow-up study from adolescence to young adulthood.

BACKGROUND AND AIM: Dietary fat intake has long been associated with fatty liver. Our study aimed to determine the effect of dietary fats on longitudinal fatty liver index (FLI) trajectories from adolescence to young adulthood. METHODS: Nine hundred eighty-five participants in the Raine Study, Perth, Western Australia, Australia, had cross-sectional assessments at ages 14, 17, 20 and 22 years, during which anthropometric measurements and blood tests were obtained. FLI trajectories were derived from the longitudinal FLI results. Dietary fat intake was measured with a semi-quantitative food frequency questionnaire at 14 years and log multinominal regression analyses were used to estimate relative risks. RESULTS: Three FLI trajectories were identified and labelled as stable-low (79.1%, N = 782), low-to-high (13.9%, N = 132), and stable-high (7%, N = 71). The low-to-high group associated with an increased intake of the long-chain polyunsaturated fatty acids EPA, DPA and DHA (RR 1.27, 95% CI 1.10-1.48) relative to the stable-low group. Compared to the stable-low group, omega-6 and the ratio of omega-6 to omega-3 in the stable-high group were associated with an increased relative risk of 1.34 (95% CI 1.02-1.76) and 1.10 (95% CI 1.03-1.16), respectively. CONCLUSION: For those at high risk of fatty liver in early adolescence, high omega-6 fatty acid intake and a high ratio of omega-6 to omega-3 fatty acids are associated with increased risk of fatty liver. There should be caution in assuming these associations are causal due to possible undetected and underestimated confounding factors.