Device-measured physical activity and cardiometabolic health: the Prospective Physical Activity, Sitting, and Sleep (ProPASS) consortium.

BACKGROUND AND AIMS: Physical inactivity, sedentary behaviour (SB), and inadequate sleep are key behavioural risk factors of cardiometabolic diseases. Each behaviour is mainly considered in isolation, despite clear behavioural and biological interdependencies. The aim of this study was to investigate associations of five-part movement compositions with adiposity and cardiometabolic biomarkers. METHODS: Cross-sectional data from six studies (n = 15 253 participants; five countries) from the Prospective Physical Activity, Sitting and Sleep consortium were analysed. Device-measured time spent in sleep, SB, standing, light-intensity physical activity (LIPA), and moderate-vigorous physical activity (MVPA) made up the composition. Outcomes included body mass index (BMI), waist circumference, HDL cholesterol, total:HDL cholesterol ratio, triglycerides, and glycated haemoglobin (HbA1c). Compositional linear regression examined associations between compositions and outcomes, including modelling time reallocation between behaviours. RESULTS: The average daily composition of the sample (age: 53.7 ± 9.7 years; 54.7% female) was 7.7 h sleeping, 10.4 h sedentary, 3.1 h standing, 1.5 h LIPA, and 1.3 h MVPA. A greater MVPA proportion and smaller SB proportion were associated with better outcomes. Reallocating time from SB, standing, LIPA, or sleep into MVPA resulted in better scores across all outcomes. For example, replacing 30 min of SB, sleep, standing, or LIPA with MVPA was associated with -0.63 (95% confidence interval -0.48, -0.79), -0.43 (-0.25, -0.59), -0.40 (-0.25, -0.56), and -0.15 (0.05, -0.34) kg/m2 lower BMI, respectively. Greater relative standing time was beneficial, whereas sleep had a detrimental association when replacing LIPA/MVPA and positive association when replacing SB. The minimal displacement of any behaviour into MVPA for improved cardiometabolic health ranged from 3.8 (HbA1c) to 12.7 (triglycerides) min/day. CONCLUSIONS: Compositional data analyses revealed a distinct hierarchy of behaviours. Moderate-vigorous physical activity demonstrated the strongest, most time-efficient protective associations with cardiometabolic outcomes. Theoretical benefits from reallocating SB into sleep, standing, or LIPA required substantial changes in daily activity.

Relationship of device measured physical activity type and posture with cardiometabolic health markers: pooled dose-response associations from the Prospective Physical Activity, Sitting and Sleep Consortium.

AIMS/HYPOTHESIS: The aim of this study was to examine the dose-response associations of device-measured physical activity types and postures (sitting and standing time) with cardiometabolic health. METHODS: We conducted an individual participant harmonised meta-analysis of 12,095 adults (mean ± SD age 54.5±9.6 years; female participants 54.8%) from six cohorts with thigh-worn accelerometry data from the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. Associations of daily walking, stair climbing, running, standing and sitting time with a composite cardiometabolic health score (based on standardised z scores) and individual cardiometabolic markers (BMI, waist circumference, triglycerides, HDL-cholesterol, HbA1c and total cholesterol) were examined cross-sectionally using generalised linear modelling and cubic splines. RESULTS: We observed more favourable composite cardiometabolic health (i.e. z score <0) with approximately 64 min/day walking (z score [95% CI] -0.14 [-0.25, -0.02]) and 5 min/day stair climbing (-0.14 [-0.24, -0.03]). We observed an equivalent magnitude of association at 2.6 h/day standing. Any amount of running was associated with better composite cardiometabolic health. We did not observe an upper limit to the magnitude of the dose-response associations for any activity type or standing. There was an inverse dose-response association between sitting time and composite cardiometabolic health that became markedly less favourable when daily durations exceeded 12.1 h/day. Associations for sitting time were no longer significant after excluding participants with prevalent CVD or medication use. The dose-response pattern was generally consistent between activity and posture types and individual cardiometabolic health markers. CONCLUSIONS/INTERPRETATION: In this first activity type-specific analysis of device-based physical activity, ~64 min/day of walking and ~5.0 min/day of stair climbing were associated with a favourable cardiometabolic risk profile. The deleterious associations of sitting time were fully attenuated after exclusion of participants with prevalent CVD and medication use. Our findings on cardiometabolic health and durations of different activities of daily living and posture may guide future interventions involving lifestyle modification.

Association between device-measured stepping behaviors and cardiometabolic health markers in middle-aged women: The Australian Longitudinal Study on Women's Health.

The associations between different types and contexts of stepping behaviors and cardiometabolic (CM) health markers are unclear. This study aimed to examine the associations of daily total, walking, stair, incidental and purposeful steps with cardiometabolic risk. A total of 943 women (mean age ± SD = 44.1 ± 1.6 years) from the Australian Longitudinal Study on Women's Health (ALSWH) were included in this cross-sectional study. Daily total, walking, stair, incidental, and purposeful steps were measured using thigh-worn accelerometry. Outcomes comprised of CM markers of adiposity, blood pressure, resting heart rate, lipids, glycaemia, and the composite CM score. We used generalized linear modeling and multiple linear regression to assess the associations. We observed that all stepping behaviors were beneficial to CM health, for example, compared to the lowest quartile (Q1), the change of the composite CM score across low to high quartile of purposeful steps was -0.12 (Q2, 95% CI: -0.41, 0.17), -0.16 (Q3, -0.46, 0.14), and -0.36 (Q4, -0.66, -0.05). Stair steps showed linear associations with blood pressure and adiposity biomarkers, for example, the change of quartile of waist circumference was -1.45 cm (Q2, -4.35, 1.44), -3.56 cm (Q3, -6.52, -0.60), and -7.08 cm (Q4, -10.31, -3.86). Peak 30-min walking intensity showed independent association with adiposity biomarkers (p linear < 0.001 and p = 0.002 for waist circumference and BMI, respectively). Our study showed that all stepping forms were beneficial to CM health. Higher stair steps and peak 30-min walking cadence were associated with a steep decline of adiposity biomarkers. Purposeful steps showed more consistent associations with CM biomarkers than incidental steps.

Stimulation of the four isoforms of receptor tyrosine kinase ErbB4, but not ErbB1, confers cardiomyocyte hypertrophy.

Epidermal growth factor (EGF) receptors (ErbB1-ErbB4) promote cardiac development and growth, although the specific EGF ligands and receptor isoforms involved in growth/repair versus pathology remain undefined. We challenged ventricular cardiomyocytes with EGF-like ligands and observed that selective activation of ErbB4 (the receptor for neuregulin 1 [NRG1]), but not ErbB1 (the receptor for EGF, EGFR), stimulated hypertrophy. This lack of direct ErbB1-mediated hypertrophy occurred despite robust activation of extracellular-regulated kinase 1/2 (ERK) and protein kinase B. Hypertrophic responses to NRG1 were unaffected by the tyrosine kinase inhibitor (AG1478) at concentrations that are selective for ErbB1 over ErbB4. NRG1-induced cardiomyocyte enlargement was suppressed by small interfering RNA (siRNA) knockdown of ErbB4 and ErbB2, whereas ERK phosphorylation was only suppressed by ErbB4 siRNA. Four ErbB4 isoforms exist (JM-a/JM-b and CYT-1/CYT-2), generated by alternative splicing, and their expression declines postnatally and following cardiac hypertrophy. Silencing of all four isoforms in cardiomyocytes, using an ErbB4 siRNA, abrogated NRG1-induced hypertrophic promoter/reporter activity, which was rescued by coexpression of knockdown-resistant versions of the ErbB4 isoforms. Thus, ErbB4 confers cardiomyocyte hypertrophy to NRG1, and all four ErbB4 isoforms possess the capacity to mediate this effect.

Flexible age-period-cohort modelling illustrated using obesity prevalence data.

BACKGROUND: Use of generalized linear models with continuous, non-linear functions for age, period and cohort makes it possible to estimate these effects so they are interpretable, reliable and easily displayed graphically. To demonstrate the methods we use data on the prevalence of obesity among Australian women from two independent data sources obtained using different study designs. METHODS: We used data from two long-running nationally representative studies: seven cross-sectional Australian National Health Surveys conducted between 1995 and 2017-18, each involving 6000-8000 women; and the Australian Longitudinal Study on Women's Health which started in 1996 and involves more than 57,000 women in four age cohorts who are re-surveyed at three-yearly intervals or annually. Age-period-cohort analysis was conducted using generalized linear models with splines to describe non-linear continuous effects. RESULTS: When analysed in the same way both data sets showed similar patterns. Prevalence of obesity increased with age until late middle age and then declined; increased only slightly across surveys; but increased steadily with birth year until the 1960s and then accelerated. CONCLUSIONS: The methods illustrated here make the estimation and visualisation of age, period and cohort effects accessible and interpretable. Regardless of how the data are collected (from repeated cross-sectional surveys or longitudinal cohort studies), it is clear that younger generations of Australian women are becoming heavier at younger ages. Analyses of trends in obesity should include cohort, in addition to age and period, effects in order to focus preventive strategies appropriately.

The rat placental renin-angiotensin system - a gestational gene expression study.

BACKGROUND: The placenta is an essential organ that provides nutrients and oxygen to the developing fetus and removes toxic waste products from the fetal circulation. Maintaining placental blood osmotic pressure and blood flow is crucial for viable offspring. The renin-angiotensin system (RAS) in the placenta is a key player in the regulation of maternal-fetal blood flow during pregnancy. Therefore, the aim of this study was to determine if RAS genes are differentially expressed in mid to late gestation in rat placenta. METHODS: Whole placental tissue samples from pregnant Sprague Dawley rats at embryonic (E) days 14.25, 15.25, 17.25 and 20 (n = 6 for each gestational age) were used for genome-wide gene expression by microarray. RAS genes with expression differences of >2 fold were further analyzed. Quantitative Real-Time PCR (qPCR) was performed on independent samples to confirm and validate microarray data. Immunohistochemisty and Western blotting were performed on a differentially expressed novel RAS pathway gene (ANPEP). RESULTS: Six out of 17 genes of the RAS pathway were differentially expressed at different gestational ages. Gene expression of four genes (Angiotensin converting enzyme (Ace), angiotensin converting enzyme 2 (Ace2), membrane metalloendopeptidase (Mme) and angiotensin II receptor 1A (Agtr1a)) were significantly upregulated at E20 whereas two others (Thimet oligopeptidase 1 (Thop1) and Alanyl aminopeptidase (Anpep)) were downregulated at E20 prior to the onset of labour. These changes were confirmed by qPCR. Western blots revealed no overall differences in ANPEP protein expression in the placentae. Immunohistochemical studies, however, indicated that the localization of ANPEP differed at E17.25 and E20 as ANPEP localization in the giant trophoblast cell of the junctional zone was no longer detectable at E20. CONCLUSIONS: The current study investigated the expression of members of the RAS pathway in rat placentae and observed significantly altered expression of 6 RAS genes at 4 gestational ages. These findings present the need for further comprehensive investigation of RAS genes in normal and complicated pregnancies.

Gestation Related Gene Expression of the Endocannabinoid Pathway in Rat Placenta.

Mammalian placentation is a vital facet of the development of a healthy and viable offspring. Throughout gestation the placenta changes to accommodate, provide for, and meet the demands of a growing fetus. Gestational gene expression is a crucial part of placenta development. The endocannabinoid pathway is activated in the placenta and decidual tissues throughout pregnancy and aberrant endocannabinoid signaling during the period of placental development has been associated with pregnancy disorders. In this study, the gene expression of eight endocannabinoid system enzymes was investigated throughout gestation. Rat placentae were obtained at E14.25, E15.25, E17.25, and E20, RNA was extracted, and microarray was performed. Gene expression of enzymes Faah, Mgll, Plcd4, Pld1, Nat1, Daglα, and Ptgs2 was studied (cohort 1, microarray). Biological replication of the results was performed by qPCR (cohort 2). Four genes showed differential expression (Mgll, Plcd4, Ptgs2, and Pld1), from mid to late gestation. Genes positively associated with gestational age were Ptgs2, Mgll, and Pld1, while Plcd4 was downregulated. This is the first comprehensive study that has investigated endocannabinoid pathway gene expression during rat pregnancy. This study provides the framework for future studies that investigate the role of endocannabinoid system during pregnancy.

The role of endocannabinoids in pregnancy.

Endocannabinoids are a family of lipid signalling molecules. As with prostaglandins (PGs), endocannabinoids are derived from polyunsaturated fatty acids and affect cell function via receptor-mediated mechanisms. They also bind to PG receptors, although at a lower affinity. The endocannabinoid network is regulated in pregnancy from embryo development to labour onset. Even small changes in endocannabinoid exposure can retard embryo development and affect implantation success. There is now compelling evidence that aberrant expression of factors involved in the endocannabinoid pathway in the placenta and circulating lymphocytes results in spontaneous miscarriage and poor pregnancy outcomes. It is likely that competition between endocannabinoids, PGs and other similar lipids ultimately determines how phospholipid/fatty acid substrates are metabolised and, thus, the balance between the uterotonic and tocolytic activities. We, therefore, hypothesise that endocannabinoid profiles may be used as a biomarker to predict and/or identify spontaneous labour onset.

Physical Activity Accumulated Across Adulthood and Resting Heart Rate at Age 41-46 Years in Women: Findings From the Menarche to Premenopause Study.

OBJECTIVE: To investigate the association between physical activity accumulated from early (age 22-27 y) to mid (age 40-45 y) adulthood and resting heart rate at age 41-46 years in women. METHODS: Data were from 479 participants in the 1973-1978 cohort of the Australian Longitudinal Study on Women's Health. Participants reported physical activity every 3 years from age 22-27 years to 40-45 years. Linear regression models were used to investigate the associations of a cumulative physical activity score (average physical activity across 18 y; up to 7 surveys) and changes in physical activity from age 22-33 years to 34-45 years with resting heart rate at age 41-46 years. RESULTS: Average resting heart rate at age 41-46 years was 75 (SD: 11) beats per minute. An inverse nonlinear dose-response association between cumulative physical activity and resting heart rate was observed. Overall, accumulation of physical activity was associated with lower resting heart rate regardless of the age when physical activity was accumulated. Women in the highest tertile of physical activity at both age 22-33 years and 34-45 years had a resting heart rate, on average, 8 beats per minute lower (95% confidence interval, -11.42 to -4.69) than those consistently in the lowest tertile of physical activity. CONCLUSION: Accumulating physical activity, irrespective of timing, appears to provide cardiovascular health benefits for women before the transition to menopause.

Cohort profile: a prospective Australian cohort study of women's reproductive characteristics and risk of chronic disease from menarche to premenopause (M-PreM).

PURPOSE: Previous studies have identified associations between individual reproductive factors and chronic disease risk among postmenopausal women. However, few have investigated the association of different markers of reproductive function, their interactions and risk factors of chronic disease among women approaching menopause. The Menarche-to-PreMenopause (M-PreM) Study aims to examine the relationship between reproductive factors across the reproductive lifespan and risk indicators for chronic disease among women in their early-to-mid-40s. The purpose of this cohort profile paper is to describe the rationale, study design and participant characteristics of the M-PreM Study. PARTICIPANTS: Women born in 1973-1978 who participated in the Australian Longitudinal Study on Women's Health (ALSWH) were invited to undertake a clinical or self-administered assessment. A total of 1278 women were recruited from June 2019 to June 2021. FINDINGS TO DATE: The study measures included functional, cognitive and cardiometabolic tests, anthropometry, spirometry, respiratory health questionnaires, physical activity, sleep patterns, sex hormones, and cardiovascular and metabolic markers; whereas blood and saliva samples were used for the analysis of genetic variants of genes associated with reproductive characteristics and chronic disease. The mean age of the clinic and self-assessed participants was 44.6 and 45.3 years, respectively. The menopausal status of participants was similar between the two arms of the study: 38%-41% premenopausal, 20% perimenopausal, and 36% took oral contraception or hormone replacement therapy. Approximately 80% of women had at least one child and participants reported experiencing pregnancy complications: preterm birth (8%-13% of pregnancies), gestational diabetes (10%) and gestational hypertension (10%-15%). FUTURE PLANS: The biomedical data collected in the M-PreM Study will be linked to existing ALSWH survey data on sociodemographic factors, health behaviour, reproductive function, and early life factors collected over the past 20 years and health administrative data. The association between reproductive factors and risk indicators of chronic disease will be analysed.