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Background Population-based levels of the chronic low-grade systemic inflammation biomarker, C-reactive protein (CRP), vary widely among traditional populations, despite their apparent absence of chronic conditions associated with chronic low-grade systemic inflammation, such as type 2 diabetes, metabolic syndrome and cardiovascular disease. We have previously reported an apparent absence of aforementioned conditions amongst the traditional Melanesian horticulturalists of Kitava, Trobriand Islands, Papua New Guinea. Our objective in this study was to clarify associations between chronic low-grade systemic inflammation and chronic cardiometabolic conditions by measuring CRP in a Kitava population sample. For comparison purposes, CRP was also measured in Swedish controls matched for age and gender. Methods Fasting levels of serum CRP were measured cross-sectionally in ≥ 40-year-old Kitavans (N = 79) and Swedish controls (N = 83). Results CRP was lower for Kitavans compared to Swedish controls (Mdn 0.5 mg/L range 0.1—48 mg/L and Mdn 1.1 mg/L range 0.1—33 mg/L, respectively, r = .18 p = .02). Among Kitavans, there were small negative associations between lnCRP for CRP values Conclusions Chronic low-grade systemic inflammation, measured as CRP, was lower among Kitavans compared to Swedish controls, indicating a lower and average cardiovascular risk, respectively, for these populations.

Background A majority of recurrent pregnancy loss cases (RPL) remains unexplained. We hypothesized that complications in vascular and metabolic status may guide towards underlying problems that also predispose to RPL and that the number of pregnancy losses is related. Methods A retrospective study in 123 women with either a history of low-order RPL (2–3 pregnancy losses) or high-order RPL (≥ 4 pregnancy losses) and 20 women with a history of uncomplicated pregnancy (controls) was performed. Vascular status was assessed by measuring hemodynamic parameters, determining abnormal parameters and analyzing their contribution to the circulatory risk profile (CRP). In a similar way, metabolic status was assessed. Metabolic parameters were measured, used to determine abnormal parameters and analyzed for their contribution to the metabolic syndrome (MetS). Results No major differences were observed in vascular or metabolic parameters between women with RPL and controls. There was no relation with the number of pregnancy losses. However, when analyzing the presence of abnormal constituents, more than 80% of women with RPL had at least one abnormal constituent of the CRP. While only 27% had one or more abnormal constituent of the MetS. Conclusions The presence of abnormal circulatory factors prior to pregnancy, and to lesser extent constituents of the metabolic syndrome, may predispose to RPL and offer new insights to its pathophysiology.

Introduction Preeclampsia is associated with adverse maternal and neonatal outcomes. It is unclear whether multivitamin use reduces the risk of preeclampsia. This systematic review and meta-analysis aimed to evaluate the association between multivitamin use and the risk of preeclampsia. Material and methods We searched PubMed, Embase and the Cochrane Library from database inception to July 2021. Randomized controlled trials (RCTs), case-control and cohort studies assessing the association between multivitamin use and risk of preeclampsia were eligible. Studies of treatment with a single micronutrient were excluded. Relative risks and 95% confidence intervals (95% CI) were calculated using random-effects models. RoB2, the Newcastle Ottawa Scale and GRADE were used to assess risk of bias and quality of evidence. The protocol was registered in PROSPERO (no. CRD42021214153). Results Six studies were included (33 356 women). Only two RCTs were found, both showing a significantly decreased risk of preeclampsia in multivitamin users. These studies were not compatible for meta-analysis due to clinical heterogeneity. A meta-analysis of observational studies using a random-effects model showed an unchanged risk of preeclampsia following multivitamin use (relative risk 0.85, 95% CI 0.69-1.03). The quality of evidence according to GRADE was very low. Conclusions Very weak evidence suggests that multivitamin use might reduce the risk of preeclampsia; however, more research is needed. Large RCTs should be prioritized. The results of this review do not allow any final conclusions to be drawn regarding a preventive effect of multivitamin use in relation to preeclampsia.

Objective To investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D). Methods 156 OT1D born between 7/1995 and 12/2000 at Helsinki University Hospital, Finland, were invited for follow-up between 3/2019 and 11/2019. A control group of 442 adults born from non-diabetic pregnancies, matched for date and place of birth, was obtained from the Finnish Medical Birth Register. In total, 58 OT1D and 86 controls agreed to participate. All OT1D had amniotic fluid (AF) sampled for erythropoietin (EPO) measurement within two days before delivery in order to diagnose fetal hypoxia. In total, 29 OTID had an AF EPO concentration

Purpose: The main purpose of this study was to test the hypothesis that incidental cardiac irradiation is associated with changes in cardiac function in breast cancer (BC) survivors treated with radiation therapy (RT).Methods and Materials: We conducted a cross-sectional study consisting of 109 BC survivors treated with RT between 2005 and 2011. The endpoint was cardiac function, assessed by echocardiography. Systolic function was assessed with the left ventricular ejection fraction (LVEF) (n = 107) and the global longitudinal strain (GLS) of the left ventricle (LV) (n = 52). LV diastolic dysfunction (n = 109) was defined by e' at the lateral and septal region, which represents the relaxation velocity of the myocardium. The individual calculated RT dose parameters of the LV and coronary arteries were collected from 3-dimensional computed tomographyebased planning data. Univariable and multivariable analysis using forward selection was performed to identify the best predictors of cardiac function. Robustness of selection was assessed using bootstrapping. The resulting multivariable linear regression model was presented for the endpoints of systolic and diastolic function.Results: The median time between BC diagnosis and echocardiography was 7 years. No relation between RT dose parameters and LVEF was found. In the multivariable analysis for the endpoint GLS of the LV, the maximum dose to the left main coronary artery was most often selected across bootstrap samples. For decreased diastolic function, the most often selected model across bootstrap samples included age at time of BC diagnosis and hypertension at baseline. Cardiac dose-volume histogram parameters were less frequently selected for this endpoint.Conclusions: This study shows an association between individual cardiac dose distributions and GLS of the LV after RT for BC. No relation between RT dose parameters and LVEF was found. Diastolic function was most associated with age and hypertension at time of BC diagnosis. Further research is needed to make definitive conclusions. (C) 2019 Elsevier Inc. All rights reserved.

Contains fulltext : 232373.pdf (Publisher’s version ) (Closed access) AIMS: Adherence to statins ranges from 32% to 79%. Patients' beliefs about medication are associated with adherence. There is lack of insight into the possible association between beliefs of healthcare practitioners (HCPs) about statins and patients' beliefs and adherence. This study aims to examine whether HCPs' beliefs about statins are associated with patients' beliefs and adherence about/to statins. METHODS: Cross-sectional study in 48 pharmacies and affiliated physicians' practices between 3 September 2014 and 20 March 2015. HCPs' (prescribers and pharmacy staff) and patients' beliefs about statins were assessed with the Beliefs about Medicine Questionnaire (BMQ) specific. Adherence to statins was assessed with the MARS-5 questionnaire. Multilevel regression analysis was performed to assess the association between HCPs' beliefs and patients' beliefs and adherence. RESULTS: 1504 patients (mean age 66.8 [s.d. ± 9.9] years, 46.5% female) and 734 HCPs (209 physicians, 118 pharmacists and 366 pharmacy technicians) participated in this study. Patients have higher BMQ necessity (16.9 [s.d. ± 4.3]) and BMQ concern (12.3 [s.d. ± 3.9]) scores than HCPs (15.0 [s.d. ± 3.0] and 11.5 [s.d. ± 2.9], P < 0.001). No associations were found between any of the HCPs' BMQ and patients' BMQ scores and adherence to statins. Patients' BMQ necessity, concern and necessity-concerns (NC)-differential scores were associated with patients' adherence (MARS-5) scores. B (95% CI) coefficients were 0.057 (0.035-0.079), -0.040 (-0.064 to -0.016) and.061 (0.043-0.079). CONCLUSIONS: Patients have stronger beliefs about medication compared to HCPs. No associations were found between HCPs' BMQ scores on the one hand and patients' BMQ scores and adherence to statins on the other hand.

Purpose: Radiation-induced acute coronary events (ACEs) may occur as a treatment-related late adverse effect of breast cancer (BC) radiation. However, the underlying mechanisms behind this radiation-induced cardiac disease remain to be determined. The objective of this study was to test the hypothesis that radiation dose to calcified atherosclerotic plaques in the left anterior descending coronary artery (LAD) is a better predictor for ACEs than radiation dose to the whole heart or left ventricle in patients with BC treated with radiation therapy. Methods and Materials: The study cohort consisted of 910 patients with BC treated with postoperative radiation therapy after breast-conserving surgery. In total, 163 patients had an atherosclerotic plaque in the LAD. The endpoint was the occurrence of an ACE after treatment. For each individual patient, the mean heart dose, volume of the left ventricle receiving >= 5 Gy (LV-V5), mean LAD dose, and mean dose to calcified atherosclerotic plaques in the LAD, if present, were acquired based on planning computed tomography scans. Cox regression analysis was used to analyze the effects on the cumulative incidence of ACEs. Results: The median follow-up time was 9.2 years (range, 0.1-14.3 years). In total, 38 patients (4.2%) developed an ACE during follow-up. For patients with an atherosclerotic plaque (n = 163), the mean dose to the atherosclerotic plaque was the strongest predictor for ACEs, even after correction for cardiovascular risk factors (hazard ratio [HR], 1.269; 95% CI, 1.090-1.477; P =.002). The LV-V5 was associated with ACEs in patients without atherosclerotic plaques in the LAD (n = 680) (HR, 1.021; 95% CI, 1.003-1.039; P =.023). Conclusions: The results of this study suggest that radiation dose to pre-existing calcified atherosclerotic plaques in the LAD is strongly associated with the development of ACEs in patients with BC. (C) 2021 The Authors. Published by Elsevier Inc.

Background: Identifying unrecognizedmyocardial infarction (MI) is important for secondary prevention. The aim of this study is to determine the prevalence and correlates of unrecognizedMI and the associationwithmortality in the general population.Methods: All participants >= 18 years participating in the Lifelines population, a three- generation Cohort Study and Biobank, were included (n= 152,180). Participants with unrecognized MI were matched with controls without MI (1: 2) based on age and gender. Unrecognized MI was defined when no history of MI was reported in combinationwith electrocardiographic (ECG) signs corresponding to MI. A history ofMIwas defined as a reported history of MI in combination with ECG signs and/ or the use of antithrombotic medication.Results: MI was present in 1881(1.2%) of participants and was unrecognized in 431 (22.9%) participants. Under the age of 50 years, percentages of unrecognized MI relative to the total amount of MI were 34% and 55% in men and women respectively. Compared to recognized MI, classical cardiovascular risk factors were less prevalent in participants with unrecognized MI. During a median follow- up time of 5, 4 and 4 years, 4.4%, 6.4% and 2.2% of participants with unrecognizedMI, recognized MI and without MI died, respectively. In a multivariable logistic regression unrecognized MI was an independent predictor of death.Conclusions: The prevalence of unrecognized MI is substantial and classical cardiovascular risk factors are less prevalent in participants with unrecognized MI. Nevertheless, unrecognized MI is associated with mortality. Risk stratification and early diagnosis is necessary to reduce the morbidity and mortality after MI. (C) 2017 Elsevier B. V. All rights reserved.

Background and aims High-density lipoprotein cholesterol (HDL-C), an established risk marker for atherosclerotic cardiovascular disease (CVD), has been shown to be inversely and independently associated with incident hypertension. Paraoxonase-1 (PON-1) is an HDL-bound esterase enzyme associated with CVD, but its relationship with incident hypertension has not been previously investigated. We aimed at evaluating the prospective association between PON-1 and hypertension risk. Methods PON-1 arylesterase activity was measured in serum at baseline in 3988 participants without pre-existing hypertension in the Prevention of Renal and Vascular End-stage Disease (PREVEND) prospective population-based study. During a median follow-up of 10.7 years, 1206 participants developed hypertension. Results In age- and sex-adjusted analysis, the hazard ratio (95% CI) for incident hypertension per 1 standard deviation increase in PON-1 was 1.01 (0.96–1.07; p = 0.656), which remained non-significant after adjustment for several established hypertension risk factors and other potential confounders (0.99, 0.93 to 1.05; p = 0.764). The association was also non-existent on further adjustment for HDL-C (1.00 (0.94–1.06; p = 0.936)) and did not importantly vary across several clinical subgroups. In analyses in the same set of participants, HDL-C was continuously inversely and independently associated with hypertension risk; the association persisted after further adjustment for PON-1 activity and was not modified by PON-1 activity. Conclusions In this Caucasian cohort of men and women, HDL-C, but not its anti-oxidant constituent - PON-1, is inversely, continuously and independently associated with future risk of hypertension. The association is independent of and not modified by PON-1.

We examined the validity of the social inhibition component of Type D, its distinctiveness from negative affectivity, and value regarding emotional distress as measured with the DS14 in 173 coronary artery disease patients. In dimensional analysis, social inhibition and negative affectivity emerged as distinct traits. Analysis of continuous negative affectivity and social inhibition measures showed main effects for several emotional and inhibition markers and an interaction effect for social anxiety. Categorical analysis indicated that Type D patients reported more depression, negative mood, social anxiety, and less positive mood. Social inhibition is not a redundant trait, but has additional conceptual value.

BACKGROUND: Epidemiological research on effects of transportation noise on incident hypertension is inconsistent. OBJECTIVES: We aimed to investigate whether residential road traffic noise increases the risk for hypertension. METHODS: In a population-based cohort of 57,053 individuals 50-64 years of age at enrollment, we identified 21,241 individuals who fulfilled our case definition of filling formula presented prescriptions and formula presented defined daily doses of antihypertensive drugs (AHTs) within a year, during a mean follow-up time of 14.0 y. Residential addresses from 1987 to 2016 were obtained from national registers, and road traffic noise at the most exposed façade as well as the least exposed façade was modeled for all addresses. Analyses were conducted using Cox proportional hazards models. RESULTS: We found no associations between the 10-y mean exposure to road traffic noise and filled prescriptions for AHTs, with incidence rate ratios (IRRs) of 0.999 [95% confidence intervals (CI): 0.980, 1.019)] per 10-dB increase in road traffic noise at the most exposed façade and of 1.001 (95% CI: 0.977, 1.026) at the least exposed façade. Interaction analyses suggested an association with road traffic noise at the least exposed façade among subpopulations of current smokers and obese individuals. CONCLUSION: The present study does not support an association between road traffic noise and filled prescriptions for AHTs. https://doi.org/10.1289/EHP6273.

Purpose We developed a job exposure matrix (JEM) to study the association between long-term exposure to heavy physical effort or heavy lifting and carrying at work with disability pension due to musculoskeletal disorders and premature all-cause mortality. Methods Exposure to heavy physical effort at work during 1996–2005 was estimated with JEM developed for this study population, where the exposure was based on occupational titles of the participants. We included all employees of the City of Helsinki, Finland, who had annual data of exposure for 8–10 years (1996–2005, n = 18387). The outcome variables were register-based, and the follow-up was from 2006 until 2015. The risk estimates were evaluated using competing risk survival analysis. Results There were 530 (3%) disability pension events due to musculoskeletal disorders during the 10-year follow-up. After adjustment for sex, age, education and chronic diseases, employees in the second (SHR = 1.46, 95% CI 1.05–2.05), third (SHR = 2.73, 95% CI 2.00–2.29), and the highest exposure quartile (SHR = 2.56, 95% CI 1.88–3.50) had a higher risk of musculoskeletal disability pension than employees in the lowest quartile. A total of 110 (4%) men and 266 (2%) women died during the follow-up. Men in the third quartile (SHR = 2.29, 95% CI 1.23–4.24), and women in the highest exposure quartile (SHR = 1.54, 95% CI 0.99–2.41) had a higher risk of premature mortality than those in the lowest quartile. Conclusions Eight to ten years of exposure to heavy physical effort at work is strongly associated with disability pension due to musculoskeletal disorders. This exposure also increases the risk of premature mortality, particularly among men. Electronic supplementary material The online version of this article (10.1007/s00420-018-1393-5) contains supplementary material, which is available to authorized users.

Background and aims: Non-LDL dyslipidemia (NLD) confers cardiovascular risk, and prevalence rates appear to be high in elderly populations. Small cohorts have identified several lifestyle, anthropometric, and medical factors associated with NLD. We aimed to assess sex-and age-specific prevalence of NLD in a contemporary population cohort (n = 167 729), and to identify independent determinants of NLD, focusing on lifestyle, anthropometric, and medical factors.Methods: The prevalence of NLD was assessed per 10-year age intervals in adults without cardiovascular disease not using lipid-modifying drugs from the Dutch LifeLines cohort. NLD was defined as low HDL-cholesterol or high triglycerides or high remnant cholesterol as per guideline cut-off values. Multivariable regression was used to identify factors independently associated with NLD. Determinants included age, smoking, alcohol use, physical activity, diet, BMI, diabetes mellitus (DM), chronic kidney disease, and in women, menopausal state and oral contraceptive use.Results: NLD occurred in 15-19% of women and 13-30% of men in this cohort, with the highest prevalence of 30% in 35-55 year old men. In most age groups, the prevalence in women was lower than in men. Obesity (both sexes: Odds ratio (OR) 5.3, 95% confidence interval (95% CI) 5.0-5.7), current smoking (men: OR 1.8, 95% CI 1.7-1.9; women OR 2.2, 95% CI 2.1-2.3), and DM (men: OR 2.2, 95% CI 1.8-2.6; women: OR 2.7, 95% CI 2.3-3.1) were strongly associated with NLD.Conclusions: NLD already occurs frequently at an early age. Modifiable lifestyle choices, obesity, and DM were strong determinants of NLD. Public health efforts could substantially contribute to decrease NLD. (C) 2018 Elsevier B.V. All rights reserved.

The purpose of this review was to assess the relationship between premature ovarian insufficiency (POI), defined as natural menopause40 years, and risk of ischaemic heart disease (IHD), stroke and overall cardiovascular disease (CVD).We performed a systematic search in PubMed (1966-2012), EMBASE (1980-2012). Studies were included if they were prospective, follow-up3 years, assessment of age menopause40 years, and incident cases of fatal or nonfatal IHD, stroke, or overall CVD. Relative risks (RRs) and 95% confidence interval (CI) were pooled using a random-effect model. Overall, 10 observational studies were identified, comprising 190,588 women (follow-up 4-37 years) with 9440 events (2026 events for IHD (seven studies) and 6438 events for stroke (seven studies) and 976 for total CVD (two studies). POI was assessed by questionnaire and incident cases through certification and event registers. POI was related to an increased risk of developing or dying from IHD (hazard ratio (HR) 1.69, 95% CI 1.29-2.21, p = 0.0001) and total CVD (HR 1.61, 95% CI 1.22-2.12, p = 0.0007). No relation was found for stroke (HR 1.03, 0.88-1.19, p = 0.74). We found no evidence for heterogeneity.POI is an independent though modest risk factor of IHD and overall CVD but not of stroke. Because of the limited impact of POI on CVD risk compared to classical cardiovascular risk factors, it is unlikely that POI will be implemented as modifier of cardiovascular risk classification.

Background Increasing evidence suggests a relation between having had spontaneous preterm delivery and cardiovascular disease in the future. We performed a systematic review and meta-analysis to assess the relation between a history of spontaneous preterm delivery and risk of ischaemic heart disease (IHD), stroke or overall cardiovascular disease (CVD). Methods We carried out a systematic search in Medline (from 1966 to 17 July 2014) and Embase (from 1980 to 17 July 2014). We included studies with a cohort design assessing the relation between spontaneous preterm delivery and fatal or nonfatal IHD, stroke, or overall CVD. IHD, stroke and CVD were assessed through linkage with national registries. Hazard ratios (HRs) were pooled using a random-effects model. Results Of the 10 cohort studies included; sample sizes ranged from 3706 to 923,686 women and follow-up ranged from 12-35 years. Spontaneous preterm delivery was related to an increased risk of developing or dying from IHD (HR 1.38, 95% confidence interval (CI) 1.22-1.57), stroke (HR 1.71, 95% CI 1.53-1.91) and overall CVD (relative risk (HR) 2.01, 95% CI 1.52-2.65). All studies found a positive effect, although substantial between-study heterogeneity was found for IHD and CVD. Conclusion Spontaneous preterm delivery is an independent risk factor for the development of IHD, stroke and overall CVD.

BACKGROUND: Cardiac morbidity is an important late effect in long-term childhood cancer survivors (CCS) treated with cardiotoxic agents or radiotherapy (RT) on the chest. However, there is limited data on the long-term cardiac sequelae in CCS who only received cranial RT. We hypothesized that cranial RT might negatively influence cardiac structure and function.METHODS AND RESULTS: We studied 13 CCS [mean age 30.8 (18.1-39.3) years, 7 males] who received RT only on the head for a cranial tumor and 36 age- and sex-matched healthy sibling controls. Echocardiographic follow-up was performed at median 21.7 (12.6-30.8) years after diagnosis. CCS had lower indexed diastolic LV volumes [56.0 (31.4-68.3) vs. 60.5 (41.9-94.3) mL/m(2), p = 0.024]. CCS also had reduced LV systolic and diastolic function, reflected by lower systolic LV myocardial velocities (5.3 ± 0.9 vs. 7.1 ± 1.7 cm/s, p = 0.001) and longitudinal deformation (- 17.3 ± 3.1 vs. - 20.7 ± 2.0%, p < 0.001), as well as lower diastolic LV myocardial velocities (- 10.7 ± 1.7 vs. - 12.2 ± 1.5 cm/s, p = 0.006) and deformation speed (1.1 ± 0.3 vs. 1.5 ± 0.2 1/s, p = 0.005). Additionally, in CCS insulin-like growth factor levels [15.4 (9.2-34.6) vs. 24.4 (14.8-55.5) nmol/L, p = 0.007] were lower.CONCLUSION: Cranial RT in CCS is associated with smaller cardiac volumes and reduced systolic and diastolic LV function. This off target effect of RT might be related to lower insulin-like growth factor levels.

Objective— To assess the association of circulating total bilirubin and cardiovascular disease (CVD) risk in a new prospective study and to determine whether adding information on total bilirubin values to established cardiovascular risk factors is associated with improvement in prediction of CVD risk. Approach and Results— Circulating total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-stage Disease) prospective study of 7222 participants and 773 incident CVD events. Total bilirubin was log-linearly associated with CVD risk. Age- and sex-adjusted hazard ratio (95% confidence interval) for CVD per 1-SD increase in log e total bilirubin was 0.82 (0.76 to 0.88; P P =0.003) after further adjustment for established risk factors. In a meta-analysis of 12 population-based prospective studies involving 9378 incident CVD cases, the pooled multivariate-adjusted relative risk (95% confidence interval) for CVD was 0.93 (0.90 to 0.97; P P =0.018) and 0.93 (0.88 to 0.98; P =0.006), respectively. Addition of information on total bilirubin to a CVD risk prediction model containing established risk factors was associated with a C-index change of 0.0013 (−0.0004 to 0.0029; P =0.13). Conclusions— There is a log-linear inverse association between circulating total bilirubin level and CVD risk, which is independent of established risk factors. Nonetheless, inclusion of total bilirubin in the standard established risk factors panel provides no significant improvement in CVD risk prediction.

Purpose: The aim of this study was to verify if radiotherapy (RT) safely can be omitted in older women treated for estrogen-receptor positive early breast cancer with breast-conserving surgery (BCS) and endocrine therapy (ET). Patients and Methods: Eligibility criteria were: consecutive patients with age >= 65 years, BCS + sentinel node biopsy, clear margins, unifocal T1N0M0 breast cancer tumor, Elston-Ellis histological grade 1 or 2 and estrogen receptor-positive tumor. After informed consent, adjuvant ET for 5 years was prescribed. Primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were contralateral breast cancer and overall survival. Results: Between 2006 and 2012, 603 women were included from 14 Swedish centers. Median age was 71.1 years (range 65-90). After a median follow-up of 68 months 16 IBTR (cumulative incidence at five-year follow-up; 1.2%, 95% CI, 0.6% to 2.5%), 6 regional recurrences (one combined with IBTR), 2 distant recurrences (both without IBTR or regional recurrence) and 13 contralateral breast cancers were observed. There were 48 deaths. One death (2.1%) was due to breast cancer and 13 (27.1%) were due to other cancers (2 endometrial cancers). Five-year overall survival was 93.0% (95% CI, 90.5% to 94.9%). Conclusion: BCS and ET without RT seem to be a safe treatment option in women >= 65 years with early breast cancer and favorable histopathology. The risk of IBTR is comparable to the risk of contralateral breast cancer. Moreover, concurrent morbidity dominates over breast cancer as leading cause of death in this cohort with low-risk breast tumors. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Background-Transplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model. Methods and Results-We performed a blind, randomized, placebo-controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following invitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone. Conclusions-Immunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements. Madeddu is the recipient of grants from the British Heart Foundation and the Medical Research Council in support of research on human and swine APCs. Angelini is the recipient of a grant from the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust, which partially supported the present study. Fernandez-Jimenez was the recipient of nonoverlapping grants from the Ministry of Economy, Industry, and Competitiveness through the Instituto de Salud Carlos III (Rio Hortega fellowship); and the Fundacion Jesus Serra, the Fundacion Interhospitalaria de Investigacion Cardiovascular (FIC), and the CNIC (FICNIC fellowship). The use of QMass software was partly supported by a scientific collaboration between the CNIC and Medis Medical Imaging Systems BV. This study forms part of a Master Research Agreement (MRA) between the CNIC and Philips Healthcare. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Sí

Objective The objective of this study was to determine outcomes in pregnant women with pre-existing coronary artery disease (CAD) or following an acute coronary syndrome (ACS) including myocardial infarction (MI).Background The physiological changes of pregnancy can contribute to myocardial ischaemia. The pregnancy risk for women with pre-established CAD or a history of ACS/MI is not well studied.Methods This was a retrospective multicentre study. Adverse maternal cardiac, obstetric and fetal/neonatal events were examined. The primary outcome was a composite endpoint of cardiac arrest, ACS/MI, ventricular arrhythmia or congestive heart failure. The prevalence of new or progressive angina during pregnancy was also examined.Results Fifty pregnancies in 43 women (mean age 35 +/- 5 years) were included. Coronary atherosclerosis (40%) and coronary thrombus (36%) were the most common underlying diagnoses. The primary outcome occurred in 10% (5/50) of pregnancies and included one maternal death secondary to cardiac arrest. Other events included ACS/MI (3/50) and heart failure (1/50). New or progressive angina occurred in 18% of pregnancies. Ischaemic complications of any type (new or progressive angina, ACS/MI, ventricular arrhythmia, cardiac arrest) occurred more commonly in women with coronary atherosclerosis compared with those without (50% vs 10%, p=0.003). A high rate of adverse obstetric (16%) and fetal/neonatal (30%) events was observed.Conclusions Pregnant women with pre-existing CAD or ACS/MI before pregnancy are at increased risk of adverse events during pregnancy. Those with coronary atherosclerosis are at highest risk of adverse maternal cardiac events due to myocardial ischaemia during pregnancy.

Objective: The objective was to determine the risk of stroke associated with subclinical hypothyroidism. Data Sources and Study Selection: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T-4 levels. Data Extraction and Synthesis: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 personyears). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or >= 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. Conclusions: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

Background— Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance–based metabolomics platform. Methods and Results— We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low-density lipoprotein cholesterol (change in SD units [95% confidence interval]: −1.01 [−1.14, −0.88]), remnant cholesterol (change in SD units [95% confidence interval]: −1.03 [−1.17, −0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: −0.98 [−1.11, −0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios. Conclusions— These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT03073018.

Background: ST segment depression (STD) and T wave inversion (TWI) are typical electrocardiographic (ECG) findings in non-ST elevation myocardial infarction (NSTEMI). In ST elevation myocardial infarction, ST changes represent transmural ischemia. The pathophysiological mechanisms of the ECG changes in NSTEMI are unclear. Purpose: We studied the associations between ECG and the echocardiographic findings in NSTEMI patients. Methods: Twenty patients with acute NSTEMI were recruited during their hospital stay. A comprehensive echocardiography study was performed. The findings were compared with blinded ECG analyses. Results: Nine (45%) patients had STD, and 16 (85%) patients had TWI. In multivariable analysis, STD was independently associated with a lower global early diastolic strain rate (beta=-5.061, p=0.033). TWI was independently associated with lower circumferential strain (beta=0.132, p =0.032). Conclusions: The typical ECG changes in NSTEMI patients were associated with subtle echocardiographic changes. STD was related to changes in diastolic function, and TWI was associated with systolic deterioration. (C) 2017 Elsevier Inc. All rights reserved.

Background and aims Overt atherosclerotic cardiovascular disease (ASCVD) warrants aggressive lipid lowering. Imaging for ambiguous symptoms suggesting ischemia or for clarification of CV risk in asymptomatic individuals often uncovers previously unknown ASCVD. Guidelines do not provide clear recommendations for aggressive lipid lowering in such cases. We explored physicians' perception, as influenced by tests that detect ASCVD, regarding appropriateness of getting to lipid goals and for theoretically accessing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). Methods A questionnaire was developed including cases of low to high CV risk, chronic kidney disease (CKD) or type 2 diabetes mellitus (T2DM). Each case was considered with or without angina symptoms and, in turn, whether testing identified previously unknown advanced, early/subclinical or no ASCVD. Synthesis of responses was facilitated by using a scale for perceived appropriateness from 1 (lowest) to 9 (highest). Results Getting to goal and, if not achieved by statins and/or ezetimibe, accessing PCSK9i was considered appropriate in patients with T2DM with preclinical or advanced ASCVD, patients with moderate or high CV risk and advanced ASCVD, patients with CKD or low CV risk with angina symptoms and advanced ASCVD. For most of the remaining cases adding PCSK9i was considered only possibly appropriate. Conclusions Physicians' perception of appropriateness for achieving lipid goals, including access to PCSK9i, is markedly influenced by detection of previously unknown ASCVD. Since these commonly encountered scenarios do not clearly meet current indications for PCSK9i, our data identify pressing areas requiring further research.

Background: High von Willebrand factor (VWF) levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that von Willebrand disease (VWD) patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies. Objectives: To investigate the prevalence of arterial thrombosis in VWD patients relative to the general population. Patients/Methods: We included 635 adult patients with VWF levels ≤ 30 U dL-1, aged 16-85 years, from the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN) study and compared the prevalence of arterial thrombosis with two reference populations from the general Dutch population adjusted for age and sex as standardized morbidity ratios (SMRs). Results: Twenty-nine arterial thrombotic events occurred in 21 patients (3.3%). Five patients suffered an acute myocardial infarction and three an ischemic stroke. Unstable angina pectoris was recorded 12 times, transient ischemic attack nine. The prevalence of all arterial thrombotic events combined (acute myocardial infarction, ischemic stroke and coronary heart disease) was 39% and 63% lower than in the two reference populations. The prevalence of cardiovascular disease in VWD was lower than in the general population, SMR 0.60 (95% CI, 0.32-0.98) for coronary heart disease and SMR 0.40 (95% CI, 0.13-0.83) for acute myocardial infarction. For ischemic stroke the prevalence was 35-67% lower compared with two reference populations, SMR 0.65 (95% CI, 0.12-1.59) and 0.33 (95% CI, 0.06-0.80), respectively. Conclusions: This is the first study showing that VWD patients have a reduced prevalence of arterial thrombosis and provides important insights into the role of VWF in the pathogenesis of arterial thrombosis. © 2013 International Society on Thrombosis and Haemostasis.

Author(s): Korshoj, Mette; Krause, Niklas; Clays, Els; Sogaard, Karen; Krustrup, Peter; Holtermann, Andreas | Abstract: ObjectiveHigh occupational physical activity (OPA) increases cardiovascular risk and aerobic exercise has been recommended for reducing this risk. This paper investigates the effects of an aerobic exercise intervention on 24-hour ambulatory blood pressure (ABP) among cleaners with high OPA.MethodsHundred and sixteen cleaners between 18 and 65 years were randomized. During the 4-month intervention period, the aerobic exercise group (AE) (n = 57) performed worksite aerobic exercise (2 × 30 minutes/week), while the reference group (REF) (n = 59) attended lectures. Between-group differences in 4-month ABP changes were evaluated by intention-to-treat analysis using a repeated-measure 2 × 2 multiadjusted mixed-models design.ResultsRelative to REF, 24-hour ABP significantly increased in AE: systolic 3.6 mm Hg (95% confidence interval (CI) 1.6-5.7) and diastolic 2.3 mm Hg (95% CI 0.9-3.8). Cleaners with high aerobic workload exhibited particularly high 24-hour ABP increases: systolic 6.0 mm Hg (95% CI 2.4-9.6), and diastolic 3.8 mm Hg (95% CI 1.3-6.4).ConclusionAerobic exercise increased 24-hour ABP among cleaners. This adverse effect raises questions about the safety and intended benefits of aerobic exercise, especially among workers with high OPA and a demanding aerobic workload. http://www.controlled-trials.com/ISRCTN86682076. Unique identifier ISRCTN86682076.Clinical trial registrationTrial Number ISRCTN86682076.

Background Acute myocardial infarction (MI) causes significant changes in cardiac morphology and function. Galectin-3 is a novel and potentially therapeutically important mediator of cardiac remodelling. Myocardial and serum galectin-3 expression dynamics in response to the early cardiovascular outcomes after acute MI are not fully elucidated.Methods We first performed a comprehensive longitudinal microarray analyses in mice after acute MI. We then measured the serum levels of galectin-3 in a translational porcine model of coronary microembolism-induced post-ischaemic cardiac remodelling. We validated our pre-clinical studies in humans by measuring serum galectin-3 levels of 52 patients with acute ST-elevation MI (STEMI) and 11 healthy controls. We analysed galectin-3 data in relation to the development of major adverse cardiovascular outcomes (MACO).Results Of the 9,753 genes profiled at infarcted and remote myocardium at eight different time points, dynamic myocardial overexpression of galectin-3 mRNA was detected. In a pig model of diffuse myocardial damage and cardiac remodelling, galectin-3 localised to the areas of tissue damage and myocardial fibrosis, with proportionate increase of their serum galectin-3 expression levels. In humans, increased serum galectin-3 level was associated with in-hospital MACO.Conclusions In this translational study, we demonstrated that galectin-3 is dynamically overexpressed in response to acute MI-induced cardiac remodelling. Elevated galectin-3 levels are associated with the development of in-hospital MACO.

Although there is great interest in the notion that dysfunctional transformation of high-density lipoprotein (HDL) facilitates development of atherosclerosis and cardiovascular disease (CVD), few studies in human populations directly address this issue. As apolipoprotein E (apoE) is a constituent of HDL thought to be important for HDL antiatherogenic function, we sought to assess the role of apoE in CVD risk in subjects likely to display dysfunctional transformation of HDL. Association of apoE levels with incident CVD risk was investigated using Cox multivariable proportional hazards modeling. Analyses were performed in subgroups of women and men likely to display dysfunctional transformation of HDL deriving from previous subgroup identification based upon defining characteristics of concurrently high levels of HDL cholesterol and systemic inflammation as reflected by high C-reactive protein levels. Results revealed apoE levels (dichotomized as highest quartile vs combined 3 lowest quartiles) as predicting subgroup risk in women (hazard ratio, 4.52; 95% confidence interval, 1.07-19.12; P = .040) but not in men. Further sex differences were manifested in terms of the relationship of apoE levels with age. Analysis revealed positive correlation of apoE levels with age in women (r = 0.47, P

Few prospective studies have examined the effects of different types of dairy food on the risks of type 2 diabetes, CHD and mortality. We examined whether intakes of total dairy, high-fat dairy, low-fat dairy, milk and fermented dairy products were related to these outcomes in the Whitehall II prospective cohort study. At baseline, dairy consumption was assessed by FFQ among 4526 subjects (72 % men) with a mean age 56 (sd 6) years. Death certificates and medical records were used to ascertain CHD mortality and non-fatal myocardial infarction. Incident diabetes was detected by the oral glucose tolerance test or self-report. Incidence data were analysed using Cox proportional hazards models, adjusted for lifestyle and dietary factors. During approximately 10 years of follow-up, 273 diabetes, 323 CHD and 237 all-cause mortality cases occurred. In multivariable models, intakes of total dairy and types of dairy products were not significantly associated with incident diabetes or CHD (all P values for trend >0·1). Fermented dairy products was inversely associated with overall mortality (hazard ratios approximately 0·7 in the middle and highest tertiles; P for trend P>0·3). In conclusion, intakes of total dairy and types of dairy products showed no consistent relationship with incident diabetes, CHD or all-cause mortality.

Background. As many subjects with a cardiovascular (CV) risk factor are undiagnosed, guidelines to prevent cardiovascular disease argue for case finding on those risk factors. Such an approach is, however, labour and cost intensive. An elevated urinary albumin loss is an early marker of vascular damage and is associated with an increased CV risk. As albuminuria is easy to measure, we tested whether a screening approach in which detailed risk factor measurement is done only after selection of subjects with an elevated albuminuria results in a higher yield of subjects at risk.Methods. A random sample of the general population as investigated in the Prevention of Renal and Vascular End-Stage Disease study was used. Plasma glucose, blood pressure, serum cholesterol and renal function were measured in an overall random sample of the population, in subgroups according to their urinary albumin concentration (UAC) of one first morning urine void and in subgroups in whom the elevated albuminuria level was confirmed with two 24 h urine collections for measurement of urinary albumin excretion (UAE).Results. In the overall population, the number of subjects with any newly found CV risk factor was higher than the number of subjects already known with any CV risk factor (n = 1331 versus 370; 39.2 versus 10.9%). The prevalence of subjects with any newly diagnosed CV risk factor was higher in the group of 267 subjects with a first morning UAC of >= 20 mg/L (61.0%; P = 20 mg/L to detect a subject with at least one CV risk factor was relatively low (12%), the specificity was very high (96%). The positive predictive value was 70%. When the elevated UAC could be confirmed in two subsequent 24-h urine collections, the diagnostic yield still further improved.Conclusion. The prevalence of undiagnosed CV risk factors in the general population is much higher than the prevalence of known risk factors. After a selection of subjects with an elevated albuminuria, the relative prevalence of subjects with newly diagnosed CV risk factors increases while the number of subjects to test for presence of CV risk factors is smaller. Such an approach facilitates a more effective and simple strategy for risk factor screening.

Background: Lower birthweight is associated with increased susceptibility to cardiome-tabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults. Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birthweight were assessed by linear regression mod-els adjusted for sex, gestational age and age at blood sampling. The metabolic associ-ations with birthweight were compared with the corresponding associations with adult body mass index (BMI). Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 ¼ 0.77) as-sessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood. Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood. This study was supported by the Strategic Research Funding from the University of Oulu, Finland, the Sigrid Juselius Foundation, the Novo Nordisk Foundation, the Yrjo¨ Jahnsson Foundation, the Finnish Diabetes Research Foundation, the Finnish Medical Foundation, the Paulo Foundation, Biocenter Oulu, Finland, and the UK Medical Research Council via the University of Bristol Integrative Epidemiology Unit (IEU; MC_UU_12013/1 and MC_UU_12013/5). The Cardiovascular Risk in Young Finns Study is supported by the Academy of Finland (grants 286284, 134309, 126925, 121584, 124282, 129378, 117787 and 41071), Finnish Foundation for Cardiovascular Research, Oulu, Helsinki, Kuopio, Tampere, and Turku University Central Hospital Medical Funds, the Paavo Nurmi Foundation, the Juho Vainio Foundation, the Finnish Cultural Foundation and the Finnish Funding Agency for Technology and Innovation. The Northern Finland Birth Cohorts of 1966 and 1986 have received financial support from Academy of Finland, University Hospital Oulu, Biocenter Oulu, University of Oulu, the European Commission (EURO-BLCS, Framework 5 Award QLG1-CT-2000-01643, ENGAGE project and grant agree-ment HEALTH-F4-2007-201413, EurHEALTHAgeing (277849), European Regional Developmental Fund), EU H2020-PHC-2014 (grant no. 633595), DynaHEALTH, NHLBI grant 5R01HL087679-02 through the STAMPEED programme (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), Stanley Foundation, the UK Medical Research Council and Wellcome Trust. The UK Medical Research Council and Wellcome Trust (grant: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. The con-tribution of D.A.L to this study is supported by grants from the US National Institute of Health (R01 DK10324), European Research Council (ObesityDevelop: grant no. 669545) and UK National Institute for Health Research (NF-SI-0166-10196). F.D., D.A.L., G.D.S. and M.A.K. work in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1 and MC_UU_12013/5). The FinnTwin-12 and FinnTwin-16 studies have received support from the National Institute on Alcohol Abuse and Alcoholism (R37-AA12502, R01-AA09203 and K05-AA00145). The views expressed in this paper are those of the authors and not necessarily any funding body. Conflict of interest: P.W., A.J.K., P.S. and M.A.K. are shareholders of Brainshake Ltd, a company offering NMR-based metabolic profiling (www.brainshake.fi). P.W., T.T., M.T., P.S. and A.J.K. re-port employment relation with Brainshake Ltd. D.A.L. has received funding for biomarker research, unrelated to this paper, from Roche Diagnostics and Ferring Pharmaceuticals. K.A. is currently em-ployed by GSK. No other authors reported disclosures.

The endogenous fibrinolytic system describes a complex process resulting in the hydrolytic cleavage of fibrin by plasmin to promote clot dissolution and generate fibrin degradation products. This system helps protect the circulation from intravascular fibrin formation and thrombosis that would otherwise lead to vessel occlusion and tissue ischemia[1;2]. The efficacy of plasminogen activation and fibrin degradation is largely determined by the balance between local concentrations of tissue-type plasminogen activator (t-PA) and it’s cognate inhibitor, plasminogen activator inhibitor type 1 (PAI-1). There is substantial evidence indicating that plasma t-PA and PAI-1 are regulated in part by the renin-angiotensin system (RAS)[3]. Angiotensin II promotes the synthesis of PAI-1 in vitro[4;5]. Furthermore, ACE inhibitors have been shown to reduce plasma PAI-1 levels in patients post-myocardial infarction[6], in hypertensive subjects[7], and in postmenopausal females[8]. Conversely, bradykinin is a potent stimulator for t-PA in humans[9], and ACE-inhibition augments bradykinin induced t-PA release from the arterial vasculature[10;11]. Interactions between the RAS, bradykinin and fibrinolytic systems on t-PA and PAI-1 levels may explain at least part of the relationship between those systems and cardiovascular disease and the beneficial effects of ACE-inhibition on thrombotic events. Indeed, prior studies demonstrated interactions between genes from the fibrinolytic system and RAS on levels of t-PA and PAI-1[12–14]. However, these studies were either performed in selected high-risk populations or had small sample sizes. In addition, no study has yet investigated the interplay between genes from the RAS, bradykinin, and fibrinolytic systems on plasma levels of t-PA and PAI-1 in a single study. Therefore, the aim of the present study was to investigate the effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma levels of t-PA and PAI-1 in a large population-based sample, explicitly examining two-way epistatic interactions.

Epidemiological data indicate that women with preeclampsia are more likely to develop cardiovascular disease (CVD) later in life. Population-based studies relate preeclampsia to an increased risk of later chronic hypertension (RR, 2.00 to 8.00) and cardiovascular morbidity/mortality (RR, 1.3 to 3.07), compared with normotensive pregnancy. Women who develop preeclampsia before 36 weeks of gestation or have multiple hypertensive pregnancies are at highest risk (RR, 3.4 to 8.12). The underlying mechanism for the remote effects of preeclampsia is complex and probably multifactorial. Many risk factors are shared by CVD and preeclampsia, including endothelial dysfunction, obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia. Therefore, it has been proposed that the metabolic syndrome may be a possible underlying mechanism common to CVD and preeclampsia. Follow-up and counseling of women with a history of preeclampsia may offer a window of opportunity for prevention of future disease.

Objective: To analyse preventive interventions of women with cardiovascular risk factors postpartum. Methods: 3.5 years postpartum, women with history of hypertension in pregnancy were invited for a questionnaire, 1 year after a cardiovascular risk assessment. Results: Two hundred and fifty-seven women completed the questionnaire. At risk factor analyses, 35% had hypertension, 37% abnormal lipid-or glucose levels, 63% BMI >= 25 and 19% smoked. One year later, 36% of women with hypertension used anti-hypertensives, 0% of women with abnormal laboratory findings used anticholesterol and 1% anti-diabetes medication, 31% of the obese women achieved BMI reduction (>= 5%), 42% of the women who smoked, quit. Conclusion: A minority improved their risk profile.

Objectives: To assess, in a population-based study, whether secular trends in cardiovascular disease mortality in seven European countries were correlated with past trends in infant mortality rate (IMR) in these countries.Study Design and Setting: Data on ischemic heart disease (IHD) and stroke mortality in 1950-1999 in the Netherlands, England & Wales, France, and four Nordic countries were analyzed. We used Poisson regression to describe trends in mortality according to birth cohort, for the cohorts born between 1860 and 1939. Pearson correlation coefficients were calculated to determine associations between IMR and IHD, or stroke mortality.Results: IHD mortality increased for successive cohorts up to 1900, and then started to decline. Stroke mortality levels were virtually stable among birth cohorts up to 1880, but declined rapidly among later cohorts. A strong positive association was found between cohort-specific IMR levels and stroke mortality rates. There were no strong cohort-wise associations between IMR and IHD mortality.Conclusion: These results support other studies in suggesting that living conditions in early childhood may influence population levels of stroke mortality. Future studies should determine the contribution of specific early life factors to the mortality decline in IHD and especially stroke. (C) 2006 Elsevier Inc. All rights reserved.

Objective: To assess the association of depression following myocardial infarction (MI) and cardiovascular prognosis. Methods: The authors performed a meta-analysis of references derived from MEDLINE, EMBASE, and PSYCINFO (1975-2003) combined with crossreferencing without language restrictions. The authors selected prospective studies that determined the association of depression with the cardiovascular outcome of MI patients, defined as mortality and cardiovascular events within 2 years from index MI. Depression had to be assessed within 3 months after MI using established psychiatric instruments. A quality assessment was performed. Results: Twenty-two papers met the selection criteria. These studies described follow up (on average, 13.7 months) of 6367 MI patients (16 cohorts). Post-MI depression was significantly associated with all-cause mortality (odds ratio [OR], fixed 2.38; 95% confidence interval [CI], 1.76-3.22; p

Objective: Different from the general observed decline in old-age mortality, for The Netherlands and Norway there have been reports of stagnation in the decline since the 1980s. We detect periods of stagnation in recent old-age mortality trends, and explore for which causes of death the recent stagnation is most apparent.Study Design and Setting: We applied Poisson regression analysis to total and cause-specific mortality data by age (80+), period (1950-1999), and sex for seven European low-mortality countries.Results: We found large heterogeneity in the pace of decline in the countries under investigation, with periods of stagnation being widespread. In the 1980s and 1990s, stagnation was observed in Denmark, The Netherlands, and Norway (males). Continued mortality decline was observed especially in France. Although smoking has had a marked influence on the trends in old-age mortality, the role of smoking in the recent stagnation seems only modest and restricted to Norway. Mortality from cardiovascular diseases showed important crossnational variations in the pace of decline. Mortality from diseases specifically related to old age increased recently in all countries, except France.Conclusion: Old-age mortality seems highly plastic and susceptible to many factors, with both favorable and unfavorable effects on trends over time. (C) 2004 Elsevier Inc. All rights reserved.

BACKGROUND: The main goal of this randomized controlled single-blinded pilot study was to study whether, independent of weight loss, a Palaeolithic-type diet alters characteristics of the metabolic syndrome. Next we searched for outcome variables that might become favourably influenced by a Paleolithic-type diet and may provide new insights in the pathophysiological mechanisms underlying the metabolic syndrome. In addition, more information on feasibility and designing an innovative dietary research program on the basis of a Palaeolithic-type diet was obtained. METHODS: Thirty-four subjects, with at least two characteristics of the metabolic syndrome, were randomized to a two weeks Palaeolithic-type diet (n = 18) or an isoenergetic healthy reference diet, based on the guidelines of the Dutch Health Council (n = 14). Thirty-two subjects completed the study. Measures were taken to keep bodyweight stable. As primary outcomes oral glucose tolerance and characteristics of the metabolic syndrome (abdominal circumference, blood pressure, glucose, lipids) were measured. Secondary outcomes were intestinal permeability, inflammation and salivary cortisol. Data were collected at baseline and after the intervention. RESULTS: Subjects were 53.5 (SD9.7) year old men (n = 9) and women (n = 25) with mean BMI of 31.8 (SD5.7) kg/m2. The Palaeolithic-type diet resulted in lower systolic blood pressure (-9.1 mmHg; P = 0.015), diastolic blood pressure (-5.2 mmHg; P = 0.038), total cholesterol (-0.52 mmol/l; P = 0.037), triglycerides (-0.89 mmol/l; P = 0.001) and higher HDL-cholesterol (+0.15 mmol/l; P = 0.013), compared to reference. The number of characteristics of the metabolic syndrome decreased with 1.07 (P = 0.010) upon the Palaeolithic-type diet, compared to reference. Despite efforts to keep bodyweight stable, it decreased in the Palaeolithic group compared to reference (-1.32 kg; P = 0.012). However, favourable effects remained after post-hoc adjustments for this unintended weight loss. No changes were observed for intestinal permeability, inflammation and salivary cortisol. CONCLUSIONS: We conclude that consuming a Palaeolithic-type diet for two weeks improved several cardiovascular risk factors compared to a healthy reference diet in subjects with the metabolic syndrome. TRIAL REGISTRATION: Nederlands Trial Register NTR3002.

Introduction: Although both coagulation and fibrinolysis are associated with cardiovascular disease (CVD) the underlying nature and pathways of many of these associations are still unclear. Our aim was to determine which of the current or 5-year prior levels of total fibrinogen, fibrinogen gamma', plasminogen activator inhibitor-1 (PAI-1(act)) and global fibrinolytic potential were the stronger determinant of arterial structure and function. Materials and methods: This prospective study consisted of 2010 Africans over the age of 35 years with 5-year follow-up data available for 1288 participants. Cardiovascular measurements included arterial stiffness, blood pressure and carotid intima media thickness. Results: Fibrinogen gamma' showed stronger associations with blood pressure than total fibrinogen also in the presence of other CVD risk factors. PAI-1(act) was positively associated with blood pressure both cross-sectionally and prospectively, with the longitudinal association being the stronger determinant, also after adjustment for known CVD risk factors. Clot lysis time (CLT) was positively associated, both prospectively and crosssectionally, with intima media thickness and negatively with markers of arterial stiffness but not after adjustment for known CVD risk factors. Conclusions: Fibrinogen gamma' was more strongly associated with CVD function than total fibrinogen. PAI-1(act) was significantly associated with blood pressure with changes in PAI-1 levels preceding changes in blood pressure. Different mechanisms may be at play determining arterial wall stiffness/thickening and blood pressure as observed from the opposing associations with PAI-1act and CLT. CLT was not independently related to cardiovascular measures as its associations were weakened in the presence of other known CVD risk factors. (C) 2014 Elsevier Ltd. All rights reserved.

Introduction People born preterm at very low birth weight (VLBW, ≤1500g) have higher rates of risk factors for adult-onset diseases, including cardiovascular diseases and type 2 diabetes. These risks may be mediated through epigenetic modification of genes that are critical to normal growth and development. Methods We measured the methylation level of an imprinted insulin-like-growth-factor 2 (IGF2) locus (IGF2/H19) in young adults born preterm at VLBW and in their peers born at term. We studied 158 VLBW and 161 control subjects aged 18 to 27 years from the Helsinki Study of Very Low Birth Weight Adults. Methylation fraction at two IGF2 differentially methylated regions (DMRs) – IGF2 antisense transcript (IGF2AS, also known as IGF2 DMR0) and last exon of IGF2 (IGF2_05, also known as IGF2 DMR2) – were measured with Sequenom Epityper. We used linear regression and adjustment for covariates to compare methylation fractions at these DMRs between VLBW and control subjects. Results At one IGF2AS CpG site, methylation was significantly lower in VLBW than in control subjects, mean difference −0.017 (95% CI; −0.028, −0.005), P = 0.004. Methylation at IGF2_05 was not different between the groups. Conclusions Methylation of IGF2AS is altered 20 years after preterm birth at VLBW. Altered methylation may be a mechanism of later increased disease risk but more data are needed to indicate causality.

Background: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups.Methodology/Principal: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I: A-II levels interacted with high apoE levels in establishing subgroup risk.Conclusions/Significance: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP.

Not all patients treated on the basis of PET-proven viability benefit from revascularization. Myocardial perfusion reserve (MPR) predicts survival in patients not undergoing revascularization. In the present study, we investigated whether MPR is related to survival in ischemic heart disease (IHD) patients after a PET-driven intervention. Methods: Between 1995 and 2003, 119 consecutive patients with chronic IHD underwent a PET-driven revascularization procedure based on ischemia-viability assessment with PET. Patients were followed for all-cause mortality and major cardiovascular events. Results: One hundred nineteen patients underwent a PET-driven revascularization procedure (67 percutaneous coronary interventions, 52 coronary artery bypass grafts) because of angina complaints. The mean age was 67 +/- 11 y (96 men, 23 women); global left ventricle MPR was 1.54 +/- 0.43. MPR intertertile boundaries were 1.34 and 1.67. Significantly more cardiac deaths were observed in the lowest and middle MPR tertiles than in the highest tertile. The age-and sex-corrected hazard ratio for the middle tertile was 8.3 (95% confidence interval, 1.02-68.3) and for the lowest tertile 23.6 (95% confidence interval, 3.1-179) (P = 0.002). After left ventricular ejection fraction (LVEF) and viability were added to the model, MPR remained significant, with hazard ratios of 6.5 (0.8-54.4) and 18.5 (2.3-145.5) (P = 0.004), whereas neither LVEF nor viability reached significance in this model. Comparable results were found for major adverse cardiac events, with hazard ratios of 3.15 (0.82-12.0) and 8.24 (2.36-28.8) (P = 0.002). Conclusion: Patients with IHD revascularized on the basis of PET viability assessment who have a low MPR are at risk for cardiac death and subsequent cardiac events. MPR is a more sensitive predictor for cardiac death than LVEF and extent of viability.

Background Low birth weight and slow growth during infancy are associated with increased rates of chronic diseases in adulthood. Associations with risk factors such as fasting glucose and lipids concentrations are weaker than expected based on associations with disease. This could be explained by differences in postprandial responses, which, however, have been little studied. Our aim was to examine the impact of growth during infancy on postprandial responses to a fast-food meal (FF-meal) and a meal, which followed the macro-nutrient composition of the dietary guidelines (REC-meal). Methodology/Principal Findings We recruited 24 overweight 65–75 year-old subjects, 12 with slow growth during infancy (SGI-group) and 12 with normal early growth. All the subjects were born at term. The study meals were isocaloric and both meals were consumed once. Plasma glucose, insulin, triglycerides (TG) and free fatty acids (FFA) were measured in fasting state and over a 4-h period after both meals. Subjects who grew slowly during infancy were also smaller at birth. Fasting glucose, insulin or lipid concentrations did not differ significantly between the groups. The TG responses were higher for the SGI-group both during the FF-meal (P = 0.047) and the REC-meal (P = 0.058). The insulin responses were significantly higher for the SGI-group after the FF-meal (P = 0.036). Glucose and FFA responses did not differ significantly between the groups. Conclusions Small birth size and slow early growth predict postprandial TG and insulin responses. Elevated responses might be one explanation why subjects who were small at birth and experiencing slow growth in infancy are at an increased risk of developing cardiovascular diseases in later life.

Background Adults born preterm with very low birth weight (VLBW

Objective. We evaluated the thyroid function in women with a history of preeclampsia and/or HELLP syndrome at least 2 years after delivery. Design. Observational retrospective study. Setting. University Medical Center Groningen, The Netherlands. Population. Women with a history of preeclampsia and/or HELLP syndrome (n = 310) or uncomplicated pregnancies (n = 363), between January 1990 and February 2003. Methods. Measurement of serum thyroid stimulating hormone (TSH) levels and antibodies to thyroid peroxidase and the use of a questionnaire about relevant history and family history of auto-immune diseases related to thyroid disease. Main outcome measures. Prevalence of primary thyroid dysfunction and antibodies to thyroid peroxidase. Results. Mean serum TSH values were not significantly different between the preeclampsia and control group (1.62 vs. 1.80 mU/l). The percentage of women who have (have had) hypothyroidism and hyperthyroidism, respectively, did not differ significantly between the preeclampsia and the control group (3.3 vs. 6.1% and 10.0 vs. 7.7%). Furthermore the prevalence of antibodies to thyroid peroxidase was not significantly different (6.1 vs. 7.7%). Conclusion. Preeclampsia and/or HELLP syndrome are not associated with an increased risk of thyroid dysfunction in later life.

Background Cardiovascular disease is the cause of death in 32% of women in the Netherlands. Prediction of an individual's risk for cardiovascular disease is difficult, in particular in younger women due to low sensitive and specific tests for these women. 10% to 15% of all pregnancies are complicated by hypertensive disorders, the vast majority of which develop only after 36 weeks of gestation. Preeclampsia and cardiovascular disease in later life show both features of "the metabolic syndrome" and atherosclerosis. Hypertensive disorders in pregnancy and cardiovascular disease may develop by common pathophysiologic pathways initiated by similar vascular risk factors. Vascular damage occurring during preeclampsia or gestational hypertension may contribute to the development of future cardiovascular disease, or is already present before pregnancy. At present clinicians do not systematically aim at the possible cardiovascular consequences in later life after a hypertensive pregnancy disorder at term. However, screening for risk factors after preeclampsia or gestational hypertension at term may give insight into an individual's cardiovascular risk profile. Methods/Design Women with a history of preeclampsia or gestational hypertension will be invited to participate in a cohort study 2 1/2 years after delivery. Participants will be screened for established modifiable cardiovascular risk indicators. The primary outcome is the 10-year cardiovascular event risk. Secondary outcomes include differences in cardiovascular parameters, SNP's in glucose metabolism, and neonatal outcome. Discussion This study will provide evidence on the potential health gains of a modifiable cardiovascular risk factor screening program for women whose pregnancy was complicated by hypertension or preeclampsia. The calculation of individual 10-year cardiovascular event risks will allow identification of those women who will benefit from primary prevention by tailored interventions, at a relatively young age. Trial registration The HYPITAT trial is registered in the clinical trial register as ISRCTN08132825.

Background: During the past two decades, the hypothesis of fetal origins of adult disease has received considerable attention. However, critique has also been raised regarding the failure to take the explanatory role of accumulation of other exposures into consideration, despite the wealth of evidence that social circumstances during the life course impact on health in adulthood. The aim of the present prospective cohort study was to examine the contributions of birth weight and life course exposures (cumulative socioeconomic disadvantage and adversity) to dyslipidemia and serum lipids in mid-adulthood. Methods: A cohort (effective n = 824, 77%) was prospectively examined with respect to self-reported socioeconomic status as well as stressors (e.g., financial strain, low decision latitude, separation, death or illness of a close one, unemployment) at the ages of 16, 21, 30 and 43 years; summarized in cumulative socioeconomic disadvantage and cumulative adversity. Information on birth weight was collected from birth records. Participants were assessed for serum lipids (total cholesterol, low- and high-density lipoprotein cholesterol and triglycerides), apolipoproteins (A1 and B) and height and weight (for the calculation of body mass index, BMI) at age 43. Current health behavior (alcohol consumption, smoking and snuff use) was reported at age 43. Results: Cumulative life course exposures were related to several outcomes; mainly explained by cumulative socioeconomic disadvantage in the total sample (independently of current health behaviors but attenuated by current BMI) and also by cumulative adversity in women (partly explained by current health behavior but not by BMI). Birth weight was related only to triglycerides in women, independently of life course exposures, health behaviors and BMI. No significant association of either exposure was observed in men. Conclusions: Social circumstances during the life course seem to be of greater importance than birth weight for dyslipidemia and serum lipid levels in adulthood. Background Since the early 1990 s, the research field of life course epidemiology has studied the health effects of biological and social exposures during different periods of life and the corresponding long-term processes spanning over the life course [1]. One line of research focuses on fetal origins of disease, with one hypothesis stating that suboptimal metabolic conditions during fetal life, e.g. indicated by lower birth weight, increase the risk for cardiovascular disease in adulthood [2]. Low birth weight has been shown to be associated with cardiovascular mortality [3,4] and to predict a number of related disorders, such as hypertension, obesity and insulin resistance [5-7]. The fetal origins hypothesis has, however, been criticized for overestimation of effects [8] and failure to consider the wealth of other exposures between birth and adulthood. One of the challenges of studying the fetal origins hypothesis is how to incorporate confounding and explanatory effects of accumulated stress over the life span into the analyses [9], which is a manifest limitation of past and present research on the field. The present study will address this issue by examining the importance of birth weight as well as social

Prenatal life exposures, potentially manifested as altered birth size, may influence the later risk of major chronic diseases through direct biologic effects on disease processes, but also by modifying adult behaviors such as physical activity that may influence later disease risk. Methods/Principal Findings We investigated the association between birth weight and leisure time physical activity (LTPA) in 43,482 adolescents and adults from 13 Nordic cohorts. Random effects meta-analyses were performed on categorical estimates from cohort-, age-, sex- and birth weight specific analyses. Birth weight showed a reverse U-shaped association with later LTPA; within the range of normal weight the association was negligible but weights below and above this range were associated with a lower probability of undertaking LTPA. Compared with the reference category (3.26–3.75 kg), the birth weight categories of 1.26–1.75, 1.76–2.25, 2.26–2.75, and 4.76–5.25 kg, had odds ratios of 0.67 (95% confidence interval: 0.47, 0.94), 0.72 (0.59, 0.88), 0.89 (0.79, 0.99), and 0.65 (0.50, 0.86), respectively. The shape and strength of the birth weight-LTPA association was virtually independent of sex, age, gestational age, educational level, concurrent body mass index, and smoking. Conclusions/Significance The association between birth weight and undertaking LTPA is very weak within the normal birth weight range, but both low and high birth weights are associated with a lower probability of undertaking LTPA, which hence may be a mediator between prenatal influences and later disease risk. © 2009 Andersen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Objective: To investigate the association between dietary intakes of folate, betaine and choline and the risk of cardiovascular disease (CVD). Design: Prospective cohort study. Subjects: A total of 16 165 women aged 49¿70 years without prior CVD. Subjects were breast cancer screening participants in the PROSPECT¿EPIC cohort, which is 1 of the 2 Dutch contributions to the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Each participant completed a validated food frequency questionnaire. Folate intake was calculated with the Dutch National Food Database. Betaine and choline intakes were calculated with the USDA database containing choline and betaine contents of common US foods. Data on coronary heart disease (CHD) events and cerebrovascular accident (CVA) events morbidity data were obtained from the Dutch Centre for Health Care Information. Results: During a median follow-up period of 97 months, 717 women were diagnosed with CVD. After adjustment, neither folate, nor betaine, nor choline intakes were associated with CVD (hazard ratios for highest versus lowest quartile were 1.23 (95% confidence interval 0.75; 2.01), 0.90 (0.69; 1.17), 1.04 (0.71; 1.53), respectively). In a subsample of the population, high folate and choline intakes were statistically significantly associated with lower homocysteine levels. High betaine intake was associated with slightly lower high-density lipoprotein (HDL)-cholesterol concentrations. Conclusion: Regular dietary intakes of folate, betaine and choline were not associated with CVD risk in post-menopausal Dutch women. However, the effect of doses of betaine and choline beyond regular dietary intake ¿ for example, via supplementation or fortification ¿ remains unknown.

OBJECTIVE: The purpose of this study was to assess the relationship between road traffic noise exposure at home and the prevalence of hypertension. METHODS: We conducted cross-sectional analyses in a large random sample (N = 40,856) of inhabitants of Groningen City, and in a subsample (the Prevention of Renal and Vascular End-Stage Disease [PREVEND]) study cohort; N = 8592). RESULTS: Before adjustment for confounders, road traffic noise exposure was associated with self-reported use of antihypertensive medication in the city of Groningen sample (odds ratio [OR] = 1.31 per 10-dB increase in Lden). Adjusted odds ratios were significant for the subjects between 45 and 55 years old in the full model when adjusted for PM10 (OR = 1.19) and at higher exposure (Lden >55 dB) only (OR = 1.21; with adjustment for PM10, OR = 1.31). In the PREVEND cohort, the unadjusted odds ratio was 1.35 for hypertension (systolic and diastolic blood pressure >140 and >90 mm Hg, respectively, or use of antihypertensive medication). Again, the adjusted odds ratio was significant for subjects between 45 and 55 years old (OR = 1.27; with adjustment for PM10, OR = 1.39). CONCLUSIONS: Exposure to road traffic noise may be associated with hypertension in subjects who are between 45 and 55 years old. Associations seemed to be stronger at higher noise levels. ©2007The American College of Occupational and Environmental Medicine.