The possible role of the vasopressin system in hematopoiesis.

Vasopressin is a pleiotropic hormone that controls body fluid homeostasis. Vasopressin has also been proposed to be involved in erythropoiesis, thrombocyte activity and inflammation. However, whether increasing vasopressin is associated with changes in hematopoietic markers is not known. To evaluate this gap of knowledge we measured the vasopressin marker copeptin and markers of erythropoiesis (erythrocyte count, hemoglobin (Hb), red blood cell distribution width (RDW), mean corpuscular volume (MCV), erythrocyte volume fraction (EVF)), leukocyte count (total count, lymphocytes, neutrophils) and thrombocyte count in 5312 participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS). The associations between increasing copeptin tertile and the hematopoietic markers were analyzed in multivariate linear regression analyses. We found that increasing copeptin tertile was significantly (p < 0.001) associated with increasing erythrocytes, RDW, EVF, Hb, leukocytes and neutrophils after adjustment for age, sex, current smoking, prevalent diabetes, hypertension, creatinine, body mass index and physical activity. Increasing copeptin tertile was, however, not associated with change in MCV, lymphocyte or thrombocyte count. In conclusion, we found that increasing copeptin levels are positively associated with markers of erythropoiesis and leukocyte count in the general population. These results warrant further research on possible mechanistic effects of vasopressin on hematopoiesis.

Incident Cardiovascular Disease in Women With Type 1 or Type 2 Diabetes Following a Hypertensive Disorder of Pregnancy.

BACKGROUND: The extent to which a history of hypertensive disorders of pregnancy is associated with incident cardiovascular disease also among women with diabetes is unknown. METHODS: In this nationwide register-based cohort study, parous women aged 18 to 69 years with a first delivery in the Swedish Medical Birth Register, regardless of diabetic status at that time, and a subsequent clinical visit in the Swedish National Diabetes Register were included. Time to first cardiovascular disease event (myocardial infarction, stroke, or heart failure) before age 70 years by hypertensive disorders of pregnancy history was separately analyzed by diabetes type using Cox regression models that included conventional risk factors. RESULTS: In total, 1748 (18.9%) of 9230 women with type 1 and 5904 (10.6%) of 55 773 women with type 2 diabetes had their first delivery complicated by a hypertensive disorder of pregnancy. Median time (25-75th percentile) between first delivery and start of follow-up was 3.3 (1.4-13.0) years for women with type 1 and 29.8 (22.4-35.6) years for women with type 2 diabetes. In modeling, the risk for any cardiovascular disease event among women with a history of hypertensive disorders of pregnancy was generally 10% to 20% higher, with main models estimating hazard ratios to 1.20 (95% CI, 0.99-1.47) for women with type 1 and 1.15 (95% CI, 1.02-1.29) for women with type 2 diabetes. CONCLUSIONS: In women with diabetes, a history of hypertensive disorders of pregnancy was associated with an increased risk of incident cardiovascular disease and should be considered as a risk enhancer.

Short-term association between outdoor temperature and the hydration-marker copeptin: a pooled analysis in five cohorts.

BACKGROUND: Whereas outdoor temperature is linked to both mortality and hydration status, the hormone vasopressin, measured through the surrogate copeptin, is a marker of cardiometabolic risk and hydration. We recently showed that copeptin has a seasonal pattern with higher plasma concentration in winter. Here, we aimed to investigate the association between outdoor temperature and copeptin. METHODS: Copeptin was analysed in fasting plasma from five cohorts in Malmö, Sweden (n = 26,753, 49.7% men, age 18-86 years). We utilized a multivariable adjusted non-linear spline model with four knots to investigate the association between short-term temperature (24 h mean apparent) and log copeptin z-score. FINDINGS: We found a distinct non-linear association between temperature and log copeptin z-score, with both moderately low and high temperatures linked to higher copeptin concentration (p < 0.0001). Between 0 °C and nadir at the 75th temperature percentile (corresponding to 14.3 °C), log copeptin decreased 0.13 z-scores (95% CI 0.096; 0.16), which also inversely corresponded to the increase in z-score log copeptin between the nadir and 21.3 °C. INTERPRETATION: The J-shaped association between short-term temperature and copeptin resembles the J-shaped association between temperature and mortality. Whereas the untangling of temperature from other seasonal effects on hydration warrants further study, moderately increased water intake constitutes a feasible intervention to lower vasopressin and might mitigate adverse health effects of both moderately cold and hot outdoor temperatures. FUNDING: Swedish Research Council, Å Wiberg, M Stephen, A Påhlsson, Crafoord and Swedish Heart-Lung Foundations, Swedish Society for Medical Research and Swedish Society of Medicine.

Coronary artery restenosis and target lesion revascularisation in women by pregnancy history.

BACKGROUND: Women's pregnancy history is associated with incident risk of coronary artery disease with some evidence also suggesting a relevance for prognosis following treatment. OBJECTIVES: To study the associations between maternal history of preterm delivery, a history of small for gestational age infant, parity and age at first delivery with clinical restenosis after percutaneous coronary intervention (PCI). METHODS: In this prospective cohort study, we included 6027 women <65 years undergoing their first PCI 2006-2017, merging clinical register data on PCI procedures in Sweden with comprehensive registry data on deliveries since 1973. We used proportional hazards regression to study the association between aspects of pregnancy history and clinical restenosis in per-segment analyses, and with target lesion revascularisation (TLR) in per-patient analyses. We adjusted models for procedural-related and patient-related predictors of restenosis. RESULTS: During 15 981 segment-years of follow-up, 343 (3.7%) events of clinical restenosis occurred. We found no strong evidence of associations between the studied aspects of pregnancy history and clinical restenosis following PCI. For example, the restenosis HR for a history of preterm delivery in the fully adjusted model was 1.09 (95% CI 0.77 to 1.55) and the TLR HR was 1.18 (95% CI 0.91 to 1.52). CONCLUSION: Risk of restenosis following treatment with PCI did not differ by the studied aspects of pregnancy history, including preterm delivery, in young and middle-aged women. Larger studies are needed to obtain more precise estimates.

Association Between History of Adverse Pregnancy Outcomes and Coronary Artery Disease Assessed by Coronary Computed Tomography Angiography.

Importance: Adverse pregnancy outcomes are recognized risk enhancers for cardiovascular disease, but the prevalence of subclinical coronary atherosclerosis after these conditions is unknown. Objective: To assess associations between history of adverse pregnancy outcomes and coronary artery disease assessed by coronary computed tomography angiography screening. Design, Setting, and Participants: Cross-sectional study of a population-based cohort of women in Sweden (n = 10 528) with 1 or more deliveries in 1973 or later, ascertained via the Swedish National Medical Birth Register, who subsequently participated in the Swedish Cardiopulmonary Bioimage Study at age 50 to 65 (median, 57.3) years in 2013-2018. Delivery data were prospectively collected. Exposures: Adverse pregnancy outcomes, including preeclampsia, gestational hypertension, preterm delivery, small-for-gestational-age infant, and gestational diabetes. The reference category included women with no history of these exposures. Main Outcomes and Measures: Coronary computed tomography angiography indexes, including any coronary atherosclerosis, significant stenosis, noncalcified plaque, segment involvement score of 4 or greater, and coronary artery calcium score greater than 100. Results: A median 29.6 (IQR, 25.0-34.9) years after first registered delivery, 18.9% of women had a history of adverse pregnancy outcomes, with specific pregnancy histories ranging from 1.4% (gestational diabetes) to 9.5% (preterm delivery). The prevalence of any coronary atherosclerosis in women with a history of any adverse pregnancy outcome was 32.1% (95% CI, 30.0%-34.2%), which was significantly higher (prevalence difference, 3.8% [95% CI, 1.6%-6.1%]; prevalence ratio, 1.14 [95% CI, 1.06-1.22]) compared with reference women. History of gestational hypertension and preeclampsia were both significantly associated with higher and similar prevalence of all outcome indexes. For preeclampsia, the highest prevalence difference was observed for any coronary atherosclerosis (prevalence difference, 8.0% [95% CI, 3.7%-12.3%]; prevalence ratio, 1.28 [95% CI, 1.14-1.45]), and the highest prevalence ratio was observed for significant stenosis (prevalence difference, 3.1% [95% CI, 1.1%-5.1%]; prevalence ratio, 2.46 [95% CI, 1.65-3.67]). In adjusted models, odds ratios for preeclampsia ranged from 1.31 (95% CI, 1.07-1.61) for any coronary atherosclerosis to 2.21 (95% CI, 1.42-3.44) for significant stenosis. Similar associations were observed for history of preeclampsia or gestational hypertension among women with low predicted cardiovascular risk. Conclusions and Relevance: Among Swedish women undergoing coronary computed tomography angiography screening, there was a statistically significant association between history of adverse pregnancy outcomes and image-identified coronary artery disease, including among women estimated to be at low cardiovascular disease risk. Further research is needed to understand the clinical importance of these associations.

Coronary Artery Restenosis in Women by History of Preeclampsia.

Background A history of preeclampsia is associated with increased risk of coronary artery disease and experimental evidence suggests that a history of preeclampsia also increases the risk of restenosis. However, the extent to which a history of preeclampsia is associated with risk of restenosis after percutaneous coronary intervention in women is unknown. Methods and Results We included 6065 parous women aged ≤65 years with first percutaneous coronary intervention on 9452 segments 2006 to 2017, linking nationwide data on percutaneous coronary intervention and delivery history in Sweden. Main outcomes were clinical restenosis and target lesion revascularization within 2 years. We accounted for segment-, procedure-, and patient-related potential predictors of restenosis in proportional hazards regression models. Restenosis occurred in 345 segments (3.7%) and target lesion revascularization was performed on 383 patients (6.3%). A history of preeclampsia was neither significantly associated with risk of restenosis (predictor-accounted hazard ratio [HR], 0.71 [95% CI, 0.41-1.23]) nor target lesion revascularization (0.74 [95% CI, 0.51-1.07]) compared with a normotensive pregnancy history. When term and preterm preeclampsia were investigated separately, segments in women with a history of term preeclampsia had a lower risk of restenosis (predictor-accounted HR, 0.45 [95% CI, 0.21-0.94]). A history of preeclampsia was not significantly associated with death by any cause within 2 years of the index procedure (predictor-accounted HR 1.06, [95% CI, 0.62-1.80]). Conclusions A history of preeclampsia was not associated with increased risk of restenosis but instead some evidence pointed to a decreased risk. To facilitate future studies and allow for replication, concomitant collection of data on pregnancy complication history and percutaneous coronary intervention outcomes in women is warranted.

Seasonal variation of vasopressin and its relevance for the winter peak of cardiometabolic disease: A pooled analysis of five cohorts.

BACKGROUND: Vasopressin concentration is typically higher at night, during stress, and in males, but readily lowered by water intake. Vasopressin is also a causal candidate for cardiometabolic disease, which shows seasonal variation. OBJECTIVE: To study whether vasopressin concentration varies by season in a temperate climate. METHODS: The vasopressin surrogate marker copeptin was analyzed in fasting plasma samples from five population-based cohorts in Malmö, Sweden (n = 25,907, 50.4% women, age 18-86 years). We investigated seasonal variation of copeptin concentration and adjusted for confounders in sinusoidal models. RESULTS: The predicted median copeptin level was 5.81 pmol/L (7.18 pmol/L for men and 4.44 pmol/L for women). Copeptin exhibited a distinct seasonal pattern with a peak in winter (mid-February to mid-March) and nadir in late summer (mid-August to mid-September). The adjusted absolute seasonal variation in median copeptin was 0.62 pmol/L (95% confidence interval [CI] 0.50; 0.74, 0.98 pmol/L [95% CI 0.73; 1.23] for men and 0.46 pmol/L [95% CI 0.33; 0.59] for women). The adjusted relative seasonal variation in mean log copeptin z-score was 0.20 (95% CI 0.17; 0.24, 0.18 [95% CI 0.14; 0.23] in men and 0.24 [95% CI 0.19; 0.29] in women). The observed seasonal variation of copeptin corresponded to a risk increase of 4% for incident diabetes mellitus and 2% for incident coronary artery disease. CONCLUSION: The seasonal variation of the vasopressin marker copeptin corresponds to increased disease risk and mirrors the known variation in cardiometabolic status across the year. Moderately increased water intake might mitigate the winter peak of cardiometabolic disease.

A prospective study of the relationships between movement and glycemic control during day and night in pregnancy.

Both disturbed sleep and lack of exercise can disrupt metabolism in pregnancy. Accelerometery was used to objectively assess movement during waking (physical activity) and movement during sleeping (sleep disturbance) periods and evaluated relationships with continuous blood glucose variation during pregnancy. Data was analysed prospectively. 15-women without pre-existing diabetes mellitus wore continuous glucose monitors and triaxial accelerometers from February through June 2018 in Sweden. The relationships between physical activity and sleep disturbance with blood glucose rate of change were assessed. An interaction term was fitted to determine difference in the relationship between movement and glucose variation, conditional on waking/sleeping. Total movement was inversely related to glucose rate of change (p < 0.001, 95% CI (- 0.037, - 0.026)). Stratified analyses showed total physical activity was inversely related to glucose rate of change (p < 0.001, 95% CI (- 0.040, - 0.028)), whereas sleep disturbance was not related to glucose rate of change (p = 0.07, 95% CI (< - 0.001, 0.013)). The interaction term was positively related to glucose rate of change (p < 0.001, 95% CI (0.029, 0.047)). This study provides temporal evidence of a relationship between total movement and glycemic control in pregnancy, which is conditional on time of day. Movement is beneficially related with glycemic control while awake, but not during sleep.

Preeclampsia and high blood pressure in early pregnancy as risk factors of severe maternal cardiovascular disease during 50-years of follow-up.

OBJECTIVES: Studies suggest preeclampsia as a risk factor for long term cardiovascular diseases (CVD), while evidence is limited regarding the risk of high blood pressures (BP) in early pregnancy. STUDY DESIGN: A register-based follow-up of 2434 mothers in the Helsingborg Birth Cohort. Associations of high BP in early pregnancy (>95th percentile systolic [SBP], diastolic [BDP], or mean arterial BP [MAP]) during the first antenatal visit and/or preeclampsia with an incident CVD event (ischemic heart disease or stroke) were assessed. To model risks and adjust for co-variables, Cox proportional hazard regression was used. RESULTS: Of the included women, 120 (4.9%) had high SBP, 49 (2%) high DBP, 104 (4.3%) high MAP in early pregnancy; and 115 (4.7%) developed preeclampsia. During 52 years of follow-up, totalling 121,457 person-years, 534 (21.9%) women experienced a CVD event. Women with preeclampsia had a higher risk of developing CVD compared to women without preeclampsia (HR 1.5, 95%CI: 1.1-2.2), while risks among women with high BPs were slightly higher. In adjusted analysis, risk estimates were approximately 50% higher than that of the reference groups for all four studied exposures. Of women with later CVD, 35 (6.6%) had preeclampsia, and another 31 (5,8%) women high SBP or high MAP. Without later preeclampsia, high SBP constituted a significant risk factor (HR 1.6, 95%CI: 1.1-2.4) for CVD. CONCLUSIONS: Women with SBP > 95th percentile in early pregnancy, but without later preeclampsia, have a higher risk of developing CVD that is comparable to women with history of preeclampsia.

Copeptin as a predictive marker of incident heart failure.

AIMS: Heart failure (HF) is a common disease with increasing prevalence and poor prognosis. The vasopressin (VP) marker copeptin predicts development of diabetes mellitus, diabetic heart disease, coronary artery disease, and premature mortality. Copeptin is elevated in HF patients and predicts a worse outcome. This study aims to investigate whether copeptin can predict HF development. METHODS: Copeptin was analysed in 5297 individuals (69.6% men) without prevalent HF from the Malmö Preventive Project, a population-based prospective cohort. Cox proportional hazards models were used to analyse risk of incident HF by copeptin levels after adjusting for conventional cardiovascular risk factors. RESULTS: During a median follow-up time of 11.1 years, 350 subjects (6.6%) were diagnosed with HF. Of these events, 99 were classified as myocardial infarction (MI) related HF and 251 as non-MI-related HF. Individuals in the top quartile of copeptin had, after multivariate adjustment for conventional risk factors (age, sex, systolic blood pressure, diabetes mellitus, body mass index, antihypertensive therapy, smoking, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), a significantly increased risk of developing HF by 1.63 [confidence interval (CI) 1.20-2.21] for HF compared with the reference quartile 1. After adjustment for conventional risk factors, the hazard ratio (HR) per standard deviation increase of log-transformed copeptin for any HF was 1.30 (95% CI 1.17-1.46), whereas it was 1.39 (CI 1.13-1.71) for MI-related HF and 1.26 (CI 1.11-1.44) for non-MI-related HF. The associations remained after additional adjustment for estimated glomerular filtration rate [HR 1.24 (95% CI: 1.10-1.40)] and for pro atrial natriuretic peptide on top of conventional risk factors [HR 1.14 (95% CI: 1.02-1.28)]. CONCLUSIONS: Elevated copeptin predicts development of HF in older adults. Copeptin is a risk marker of VP-driven HF susceptibility and a candidate to guide prevention efforts of HF targeting the VP system.

Smoking and Alcohol Intake but Not Muscle Strength in Young Men Increase Fracture Risk at Middle Age: A Cohort Study Linked to the Swedish National Patient Registry.

We aimed to determine the relationship between handgrip strength, smoking, and alcohol consumption in young men and fracture risk at middle age. Thus, we carried out a cohort study including young men undergoing conscription examination in Sweden from September 1969 to May 1970 at a typical age of 18 years. Data on muscle strength, height, weight, and lifestyle factors were linked to the National Patient Register 1987-2010. Handgrip strength was considered the main exposure and smoking and alcohol consumption as secondary exposures. Outcomes were all fractures (except face, skull, digits), major osteoporotic fractures (thoracic/lumbar spine, proximal humerus, distal forearm or hip), and major traumatic fractures (shaft of humerus, forearm, femur, or lower leg) based on ICD-9 and -10 codes. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) according to handgrip strength as a continuous variable (per 1 SD), after adjustment for weight, height, parental education, smoking, and alcohol consumption. A total of 40,112 men were included, contributing 892,572 person-years. Overall, 3974 men fractured in middle age with the incidence rate (95% CI) of 44.5 (43.2-45.9) per 1000 person-years. The corresponding rates were12.2 and 5.6 per 1000 person-years for major osteoporotic and traumatic fractures, respectively. Handgrip strength-adjusted HR (95% CI) was 1.01 (0.98-1.05), 0.94 (0.88-1.00), and 0.98 (0.88-1.08) per SD for all, major osteoporotic, and major traumatic fractures, respectively. Adjusted HR (95% CI) for smokers (>21 cigarettes/d) was 1.44 (1.21, 1.71) for all fractures, while the association between alcohol consumption and hazards of fracture was J-shaped. Therefore, young adult handgrip strength was not associated with fracture risk in middle-age men, although smoking and high alcohol consumption did confer an increased risk. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Does pregnancy complication history improve cardiovascular disease risk prediction? Findings from the HUNT study in Norway.

AIM: To evaluate whether history of pregnancy complications [pre-eclampsia, gestational hypertension, preterm delivery, or small for gestational age (SGA)] improves risk prediction for cardiovascular disease (CVD). METHODS AND RESULTS: This population-based, prospective cohort study linked data from the HUNT Study, Medical Birth Registry of Norway, validated hospital records, and Norwegian Cause of Death Registry. Using an established CVD risk prediction model (NORRISK 2), we predicted 10-year risk of CVD (non-fatal myocardial infarction, fatal coronary heart disease, and non-fatal or fatal stroke) based on established risk factors (age, systolic blood pressure, total and HDL-cholesterol, smoking, anti-hypertensives, and family history of myocardial infarction). We evaluated whether adding pregnancy complication history improved model fit, calibration, discrimination, and reclassification. Among 18 231 women who were parous, ≥40 years of age, and CVD-free at start of follow-up, 39% had any pregnancy complication history and 5% experienced a CVD event during a median follow-up of 8.2 years. While pre-eclampsia and SGA were associated with CVD in unadjusted models (HR 1.96, 95% CI 1.44-2.65 for pre-eclampsia and HR 1.46, 95% CI 1.18-1.81 for SGA), only pre-eclampsia remained associated with CVD after adjusting for established risk factors (HR 1.60, 95% CI 1.16-2.17). Adding pregnancy complication history to the established prediction model led to small improvements in discrimination (C-index difference 0.004, 95% CI 0.002-0.006) and reclassification (net reclassification improvement 0.02, 95% CI 0.002-0.05). CONCLUSION: Pre-eclampsia independently predicted CVD after controlling for established risk factors; however, adding pre-eclampsia, gestational hypertension, preterm delivery, and SGA made only small improvements to CVD prediction among this representative sample of parous Norwegian women.

A Prediction Model for the 40-Year Risk of Knee Osteoarthritis in Adolescent Men.

OBJECTIVE: To simplify the previously published Nottingham 12-year risk prediction model for knee osteoarthritis (OA) and examine whether it can be used to predict the 40-year risk of knee OA in young men. METHODS: Our cohort included 40,118 men who were 18 years of age and had undergone military conscription in Sweden from 1969 to 1970. Diagnostic OA codes were obtained from the Swedish National Patient Register for persons registered from 1987 to 2010. The original Nottingham model included as predictors age, sex, body mass index (BMI), knee injury, occupational risk, and family history of OA, with a receiver operating characteristic area under the curve (AUC) of 0.70 (95% confidence interval [95% CI] 0.61-0.79) in the model development sample, and AUC 0.60 (95% CI 0.58-0.63) in an external validation sample. In our sample, we used predictors that were available only in adolescence (age, BMI, and knee injury) and evaluated the discrimination of the simplified model using AUC. RESULTS: The AUC statistic of the modified knee OA model to predict 40-year risk was 0.60 (95% CI 0.59-0.61). Hence, using the reduced model, an 18-year-old man with a BMI of 30 and a knee injury would have 3 times the risk of developing knee OA within 40 years when compared to a man of similar age having a BMI of 25 and no knee injury (predicted risks 22% and 7%, respectively). CONCLUSION: The 40-year risk of knee OA on individual and population levels can be predicted in 18-year-olds from a few easily measured covariates with moderate discrimination. The discrimination of this simplified model based on data available in adolescents was comparable to that of the full Nottingham model in middle-aged individuals.

Postpregnancy BMI in the Progression From Hypertensive Disorders of Pregnancy to Type 2 Diabetes.

OBJECTIVE: To study the extent to which BMI after pregnancy adds to the elevated risk of postpregnancy type 2 diabetes in women with a history of hypertensive disorders of pregnancy (HDP) (preeclampsia or gestational hypertension). RESEARCH DESIGN AND METHODS: We used data from the Nurses' Health Study II, a prospective cohort study. In women aged 45-54 years without prior gestational diabetes mellitus, we investigated the interaction between BMI and HDP history on the risk of type 2 diabetes. For clinical and public health relevance, we focused on additive interaction. The main outcome measure was the relative excess risk due to interaction calculated from multivariable Cox proportional hazards models using normal weight as the reference group. RESULTS: In total, 6,563 (11.7%) of 56,159 participants had a history of HDP and 1,341 women developed type 2 diabetes during 436,333 person-years. BMI was a strong risk factor for type 2 diabetes regardless of HDP history. However, there was evidence of an additive interaction between BMI and HDP for the risk of type 2 diabetes (P = 0.004). The attributable proportion of risk due to the interaction ranged from 0.12 (95% CI -0.22, 0.46) in women who were overweight to 0.36 (95% CI 0.13, 0.59) in women with obesity class I. CONCLUSIONS: Maintaining a healthy weight may be of even greater importance in women with a history of HDP, compared with other women with a history of only normotensive pregnancies, to reduce midlife risk of type 2 diabetes.

Maternal Hypertensive Disorders of Pregnancy and Offspring Risk of Hypertension: A Population-Based Cohort and Sibling Study.

BACKGROUND: Women with a history of hypertensive disorders of pregnancy (HDP) are at increased risk of hypertension, cardiovascular disease, and type 2 diabetes. Offspring from pregnancies complicated by HDP also have worse cardiometabolic status in childhood and young adulthood, but the offspring risk of clinical hypertension in adulthood is largely unknown. METHODS: We studied 13,893 first-born adult offspring (49.4% female) who attended a structured population-based primary care visit (The Västerbotten Health Survey) at age 40 years in Sweden between 1994 and 2013. Data on maternal HDP were collected from a population-based birth register. We investigated the association between maternal HDP and the risk of adult offspring hypertension and worse cardiometabolic risk factor status utilizing multivariable poisson and linear regression models. We also conducted a sibling comparison, which inherently accounted for familial factors shared by siblings (N = 135). RESULTS: Offspring participants of women with HDP (N = 383, 2.8%) had increased relative risk of hypertension (1.67, 95% confidence interval: 1.38, 2.01) and also higher mean body mass index, systolic blood pressure, diastolic blood pressure, and worse 2-hour 75 g oral glucose tolerance test result at age 40 years. No difference was observed for serum cholesterol. Point estimates for the cardiometabolic risk factors were attenuated in the sibling analyses. CONCLUSION: Offspring born to mothers with a history of HDP are on an adverse cardiometabolic trajectory and should be considered as concomitant targets for primordial prevention of hypertension in the maternal post-pregnancy period.

Midlife development of type 2 diabetes and hypertension in women by history of hypertensive disorders of pregnancy.

BACKGROUND: Women with history of hypertensive disorders of pregnancy (HDP) are at increased risk of early onset cardiovascular disease and type 2 diabetes (T2D). We aimed to investigate the extent to which HDP is also associated with midlife development of T2D and hypertension above and beyond established risk factors. METHODS: We included parous women who attended population-based structured clinical visits at age 50 and 60 years in Sweden 1991-2013 (N = 6587). Women with prior diabetes mellitus, stroke, or ischemic heart disease at age 50 years were excluded. Data on reproductive history were collected from registries. To study the association between history of HDP and the between-visits development of T2D, hypertension, and clinical risk factors of cardiometabolic disease (body mass index (BMI), blood pressure, and total cholesterol), we utilized multivariable adjusted regression models (logistic, log binomial, and linear regression, respectively). Models included data on outcome risk factors at age 50 years, e.g. BMI, 75 g 2 h oral glucose tolerance test result, and mean arterial pressure, respectively. RESULTS: Between ages 50 and 60 years, 5.8% of initially disease-free women developed T2D and 31.6% developed hypertension. History of HDP was associated with increased risk of developing T2D between age 50 and 60 years even when adjusting for risk factors, including BMI, at age 50 years (odds ratio (OR) 1.96, 95% confidence interval (CI) 1.29-2.98). By contrast, the higher risk of developing hypertension observed in women with history of HDP (relative risk (RR) 1.47, 95% CI 1.22-1.78) was attenuated when adjusted for risk factors (RR 1.09, 95% CI 0.94-1.25). Participants with a history of HDP had higher mean BMI and blood pressure at age 50 years, with levels roughly corresponding to those observed at age 60 years in unaffected women. CONCLUSIONS: Women with history of HDP are not only at higher risk of cardiometabolic disease during their reproductive years, but HDP is also associated with midlife T2D development above and beyond established risk factors.

The value of pregnancy complication history for 10-year cardiovascular disease risk prediction in middle-aged women.

Women with a history of hypertensive disorders of pregnancy (HDP; preeclampsia and gestational hypertension) or delivering low birth weight offspring (LBW; < 2500 g) have twice the risk of cardiovascular disease (CVD). We aimed to study the extent to which history of these pregnancy complications improves CVD risk prediction above and beyond conventional predictors. Parous women attended standardized clinical visits in Sweden. Data were linked to registries of deliveries and CVD. Participants were followed for a first CVD event within 10 years from age 50 (n = 7552) and/or 60 years (n = 5360) and the predictive value of each pregnancy complication above and beyond conventional predictors was investigated. History of LBW offspring was associated with increased risk of CVD when added to conventional predictors in women 50 years of age [Hazard ratio 1.68, 95% Confidence interval (CI) 1.19, 2.37] but not at age 60 (age interaction p = 0.04). However, at age 50 years CVD prediction was not further improved by information on LBW offspring, except that a greater proportion of the women who developed CVD were assigned to a higher risk category (categorical net reclassification improvement for events 0.038, 95% CI 0.003, 0.074). History of HDP was not associated with CVD when adjusted for reference model predictors. In conclusion, a history of pregnancy complications can identify women with increased risk of CVD midlife. However, considered with conventional risk factors, history of HDP or having delivered LBW offspring did not meaningfully improve 10-year CVD risk prediction in women age 50 years or older.

Lifestyle in progression from hypertensive disorders of pregnancy to chronic hypertension in Nurses' Health Study II: observational cohort study.

Objectives To study the association between lifestyle risk factors and chronic hypertension by history of hypertensive disorders of pregnancy (HDP: gestational hypertension and pre-eclampsia) and investigate the extent to which these risk factors modify the association between HDP and chronic hypertension.Design Prospective cohort study.Setting Nurses' Health Study II (1991-2013).Participants 54 588 parous women aged 32 to 59 years with data on reproductive history and without previous chronic hypertension, stroke, or myocardial infarction.Main outcome measure Chronic hypertension diagnosed by a physician and indicated through nurse participant self report. Multivariable Cox proportional hazards models were used to investigate the development of chronic hypertension contingent on history of HDP and four lifestyle risk factors: post-pregnancy body mass index, physical activity, adherence to the Dietary Approaches to Stop Hypertension (DASH) diet, and dietary sodium/potassium intake. Potential effect modification (interaction) between each lifestyle factor and previous HDP was evaluated with the relative excess risk due to interaction.Results 10% (n=5520) of women had a history of HDP at baseline. 13 971 cases of chronic hypertension occurred during 689 988 person years of follow-up. Being overweight or obese was the only lifestyle factor consistently associated with higher risk of chronic hypertension. Higher body mass index, in particular, also increased the risk of chronic hypertension associated with history of HDP (relative excess risk due to interaction P<0.01 for all age strata). For example, in women aged 40-49 years with previous HDP and obesity class I (body mass index 30.0-34.9), 25% (95% confidence interval 12% to 37%) of the risk of chronic hypertension was attributable to a potential effect of obesity that was specific to women with previous HDP. There was no clear evidence of effect modification by physical activity, DASH diet, or sodium/potassium intake on the association between HDP and chronic hypertension.Conclusion This study suggests that the risk of chronic hypertension after HDP might be markedly reduced by adherence to a beneficial lifestyle. Compared with women without a history of HDP, keeping a healthy weight seems to be especially important with such a history.

Knee extensor strength and body weight in adolescent men and the risk of knee osteoarthritis by middle age.

OBJECTIVES: To assess the extent to which knee extensor strength and weight in adolescence are associated with knee osteoarthritis (OA) by middle age. METHODS: We studied a cohort of 40 121 men who at age 18 years in 1969/1970 underwent mandatory conscription in Sweden. We retrieved data on isometric knee extensor strength, weight, height, smoking, alcohol consumption, parental education and adult occupation from Swedish registries. We identified participants diagnosed with knee OA or knee injury from 1987 to 2010 through the National Patient Register. We estimated the HR of knee OA using multivariable-adjusted Cox proportional regression model. To assess the influence of adult knee injury and occupation, we performed a formal mediation analysis. RESULTS: The mean (SD) knee extensor strength was 234 (47) Nm, the mean (SD) weight was 66 (9.3) kg. During 24 years (median) of follow-up starting at the age of 35 years, 2049 persons were diagnosed with knee OA. The adjusted HR (95% CI) of incident knee OA was 1.12 (1.06 to 1.18) for each SD of knee extensor strength and 1.18 (1.15 to 1.21) per 5 kg of body weight. Fifteen per cent of the increase in OA risk due to higher knee extensor strength could be attributed to knee injury and adult occupation. CONCLUSION: Higher knee extensor strength in adolescent men was associated with increased risk of knee OA by middle age, challenging the current tenet of low muscle strength being a risk factor for OA. We confirmed higher weight to be a strong risk factor for knee OA.

Hypertensive Disorders of Pregnancy and Offspring Cardiac Structure and Function in Adolescence.

BACKGROUND: Fetal exposure to preeclampsia is associated with higher blood pressure and later risk of stroke. We aimed to investigate the associations of maternal preeclampsia, gestational hypertension, and maternal blood pressure change in pregnancy with offspring cardiac structure and function in adolescence. METHODS AND RESULTS: Using data from a prospective birth cohort study, we included offspring who underwent echocardiography (mean age, 17.7 years; SD, 0.3; N=1592). We examined whether hypertensive disorders of pregnancy were associated with offspring cardiac structure and systolic/diastolic function using linear regression. Using multilevel linear spline models (measurement occasions within women), we also investigated whether rate of maternal systolic/diastolic blood pressure change during pregnancy (weeks 8-18, 18-30, 30-36, and 36 or more) were associated with offspring outcomes. Main models were typically adjusted for maternal age, offspring age and sex, prepregnancy body mass index, parity, glycosuria/diabetes mellitus, education, and maternal smoking. Exposure to maternal preeclampsia (0.025; 95% CI, 0.008-0.043) and gestational hypertension (0.010; 0.002-0.017) were associated with greater relative wall thickness. Furthermore, preeclampsia was also associated with a smaller left ventricular end-diastolic volume (-9.0 mL; -15 to -3.1). No associations were found between hypertensive disorders of pregnancy and offspring cardiac function. Positive rate of maternal systolic blood pressure change during weeks 8 to 18 was associated with greater offspring left ventricular end-diastolic volume, left ventricular mass indexed to height2.7, and E/A. CONCLUSIONS: Adolescent offspring exposed to maternal preeclampsia had greater relative wall thickness and reduced left ventricular end-diastolic volume, which could be early signs of concentric remodeling and affect future cardiac function as well as risk of cardiovascular disease.