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Background and Aims: Despite statin treatment, a high prevalence of severe vascular calcification is found in patients with familial hypercholesterolemia (FH). We assessed the relation between the circulating soluble form of low-density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11), a risk factor for cardiovascular disease, and vascular calcification in asymptomatic statin-treated heterozygous FH patients., Methods: In 123 asymptomatic heterozygous FH patients (age 40-69 years), aortic root (ARC), aortic valve (AVC) and coronary artery calcification (CAC) were determined with CT-based calcium scoring expressed in Agatston units. Plasma sLR11 levels were measured by sandwich ELISA., Results: Seventy-three patients displayed ARC, 48 had AVC and 96 CAC. Plasma sLR11 levels were positively correlated with the presence of ARC (r = 0.2, p = 0.03), but not with AVC or CAC. The correlation between sLR11 levels and ARC was restricted to male FH patients (r = 0.31, p = 0.006). Multivariate logistic analyses showed that the association of plasma sLR11 with the presence of ARC was independent of other determinants (Adjusted Odds Ratio, 2.01 (95% CI = 1.28-3.16) p = 0.002)., Conclusions: Plasma sLR11 is associated with ARC in male FH patients and may be mechanistically involved in the differential distribution of atherosclerotic lesions in the vasculature., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Changes in the microvasculature associated with pre-eclampsia and gestational hypertension have been proposed as a potential pathway in the development of cardiovascular disease. We examined whether gestational hypertensive disorders, such as pre-eclampsia and gestational hypertension, are related to the maternal retinal microvasculature status after pregnancy., Methods: This study is part of an ongoing population-based prospective cohort study. During pregnancy and 6.2 years after the index pregnancy (90% range 5.7-7.4 years), we examined 3391 women with available information on pre-eclampsia, gestational hypertension, and retinal vascular calibers. Retinal arteriolar and venular calibers were measured in the left eye from digitized retinal photographs., Results: Women with pre-eclampsia had smaller retinal arteriolar calibers 6 years after pregnancy than women with a normotensive pregnancy (adjusted difference: -0.40 standard deviation score [SDS]; 95% confidence interval [CI]: -0.62, -0.19). For women with previous gestational hypertension, similar trends were observed (-0.20 SDS; 95% CI: -0.34, -0.05). With respect to retinal venular calibers, we did not observe consistent trends for women with previous pre-eclampsia. However, in women with previous gestational hypertension, we observed larger venular calibers (0.22 SDS; 95% CI: 0.07-0.36) than in women with a previous normotensive pregnancy. The association of gestational hypertensive disorders with retinal vessel calibers was mediated through mean arterial pressure at the time of retinal imaging., Conclusions: Compared to women with a previous normotensive pregnancy, women with pre-eclampsia and gestational hypertension show an altered status of the microvasculature 6 years after the index pregnancy. This is reflected by smaller retinal arteriolar calibers and wider retinal venular calibers. These microvascular changes may possibly contribute to the development of cardiovascular disease in later life.

Background: Reproductive disorders, such as polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI) and hypertensive pregnancy disorders (HPD) like pre-eclampsia (PE), are associated with an increased risk of cardiovascular disease (CVD). Detection of early signs of cardiovascular disease (CVD), as well as identification of risk factors among women of reproductive age which improve cardiovascular risk prediction, is a challenge and current models might underestimate long-term health risks. The aim of this study is to assess cardiovascular disease in patients with a history of a reproductive disorder by low-dose computed tomography (CT)., Methods: Women of 45 - 55 years, who experienced a reproductive disorder (PCOS, POI, HPD), are invited to participate in this multicenter, prospective, cohort study. Women will be recruited after regular cardiovascular screening, including assessment of classical cardiovascular risk factors. CT of the coronary arteries (both coronary artery calcium scoring (CACS), and contrast-enhanced coronary CT angiography (CCTA)) and carotid siphon calcium scoring (CSC) is planned in 300 women with HPD and 300 women with PCOS or POI. In addition, arterial stiffness (non-invasive pulse wave velocity (PWV)) measurement and cell-based biomarkers (inflammatory circulating cells) will be obtained., Discussion: Initial inclusion is focused on women of 45 - 55 years. However, the age range (40 - 45 years and/or ≥ 55 years) and group composition may be adjusted based on the findings of the interim analysis. Participants can potentially benefit from information obtained in this study concerning their current cardiovascular health and expected future risk of cardiovascular events. The results of this study will provide insights in the development of CVD in women with a history of reproductive disorders. Ultimately, this study may lead to improved cardiovascular prediction models and will provide an opportunity for timely adjustment of preventive strategies. Limitations of this study include the possibility of overdiagnosis and the average radiation dose of 3.5 mSv during coronary and carotid siphon CT, although the increased lifetime malignancy risk is negligible., Trial Registration: Netherlands Trial Register, NTR5531 . Date registered: October 21st, 2015.

Background and Aims: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia., Methods: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands., Results: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004]., Conclusions: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims/hypothesis: Elevated levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease (CVD), particularly in individuals with type 2 diabetes. Although weight loss improves conventional risk factors for CVD in type 2 diabetes, the effects on Lp(a) are unknown and may influence the long-term outcome of CVD after diet-induced weight loss. The aim of this clinical study was to determine the effect of diet-induced weight loss on Lp(a) levels in obese individuals with type 2 diabetes., Methods: Plasma Lp(a) levels were determined by immunoturbidimetry in plasma obtained before and after 3-4 months of an energy-restricted diet in four independent study cohorts. The primary cohort consisted of 131 predominantly obese patients with type 2 diabetes (cohort 1), all participants of the Prevention Of Weight Regain in diabetes type 2 (POWER) trial. The secondary cohorts consisted of 30 obese patients with type 2 diabetes (cohort 2), 37 obese individuals without type 2 diabetes (cohort 3) and 26 obese individuals without type 2 diabetes who underwent bariatric surgery (cohort 4)., Results: In the primary cohort, the energy-restricted diet resulted in a weight loss of 9.9% (95% CI 8.9, 10.8) and improved conventional CVD risk factors such as LDL-cholesterol levels. Lp(a) levels increased by 14.8 nmol/l (95% CI 10.2, 20.6). In univariate analysis, the change in Lp(a) correlated with baseline Lp(a) levels (r = 0.38, p < 0.001) and change in LDL-cholesterol (r = 0.19, p = 0.033). In cohorts 2 and 3, the weight loss of 8.5% (95% CI 6.5, 10.6) and 6.5% (95% CI 5.7, 7.2) was accompanied by a median increase in Lp(a) of 13.5 nmol/l (95% CI 2.3, 30.0) and 11.9 nmol/l (95% CI 5.7, 19.0), respectively (all p < 0.05). When cohorts 1-3 were combined, the diet-induced increase in Lp(a) correlated with weight loss (r = 0.178, p = 0.012). In cohort 4, no significant change in Lp(a) was found (-7.0 nmol/l; 95% CI -18.8, 5.3) despite considerable weight loss (14.0%; 95% CI 12.2, 15.7)., Conclusions/interpretation: Diet-induced weight loss was accompanied by an increase in Lp(a) levels in obese individuals with and without type 2 diabetes while conventional CVD risk factors for CVD improved. This increase in Lp(a) levels may potentially antagonise the beneficial cardiometabolic effects of diet-induced weight reduction.

Background: Despite optimal lipid-lowering therapy, a minority of patients with familial hypercholesterolemia (FH) reach low-density lipoprotein cholesterol (LDL-c) target goals. In randomized trials, proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors led to impressive LDL-c reductions and a favorable safety profile. However, data about the efficacy and safety outside clinical trials are not available yet., Objective: The purpose of the study is to describe efficacy and side effects of PCSK9 inhibitors in FH patients in clinical practice., Methods: Registry of all consecutive FH patients who started with a PCSK9 inhibitor at a lipid clinic of a university hospital., Results: We analyzed 83 FH patients (79 heterozygous FH [heFH]-65 with a genetically confirmed heFH and 14 with clinical heFH-and 4 homozygous FH [hoFH]), with a mean age of 55.1 ± 11.6 years. Treatment with a PCSK9 inhibitor resulted in an additional reduction of 55% ± 21% in mean LDL-c levels. Patients with heFH had more LDL-c decrease than those with hoFH (56% vs 38%). Patients using ezetimibe monotherapy because of statin intolerance (n = 24, 29%) had less LDL-c decrease compared with patients who concurrently used statin therapy (47% and 58%, P = .03). Side effects of PCSK9 inhibitors were reported by 32 patients (39%). Flu-like symptoms (n = 12) and injection site reactions (n = 11) were most frequent. Seven patients (8%) discontinued treatment, 5 because of side effects and 2 because of nonresponse., Conclusion: Our initial experience of PCSK9 inhibition in FH patients in a clinical setting showed comparable reduction in LDL-c levels but more side effects compared with clinical trials., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Patients with autosomal dominant hypercholesterolemia (ADH), caused by mutations in either low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9) are characterized by high low-density lipoprotein cholesterol levels and in some studies also high lipoprotein(a) (Lp(a)) levels were observed. The question remains whether this effect on Lp(a) levels is gene-dose-dependent in individuals with either 0, 1, or 2 LDLR or APOB mutations., Objective: We set out to study whether Lp(a) levels differ among bi-allelic ADH mutation carriers, and their relatives, in the Netherlands., Methods: Bi-allelic ADH mutation carriers were identified in the database of the national referral laboratory for DNA diagnostics of inherited dyslipidemias. Family members were invited by the index cases to participate. Clinical parameters and Lp(a) levels were measured in bi-allelic ADH mutation carriers and their heterozygous and unaffected relatives., Results: We included a total of 119 individuals; 34 bi-allelic ADH mutation carriers (20 homozygous/compound heterozygous LDLR mutation carriers (HoFH), 2 homozygous APOB mutation carriers (HoFDB), and 12 double heterozygotes for an LDLR and APOB mutation), 63 mono-allelic ADH mutation carriers (50 heterozygous LDLR [HeFH], 13 heterozygous APOB [HeFDB] mutation carriers), and 22 unaffected family members. Median Lp(a) levels in unaffected relatives, HeFH, and HoFH patients were 19.9 (11.1-41.5), 24.4 (5.9-70.6), and 47.3 (14.9-111.7) mg/dL, respectively (P = .150 for gene-dose dependency). Median Lp(a) levels in HeFDB and HoFDB patients were 50.3 (18.7-120.9) and 205.5 (no interquartile range calculated), respectively (P = .012 for gene-dose-dependency). Double heterozygous carriers of LDLR and APOB mutations had median Lp(a) levels of 27.0 (23.5-45.0), which did not significantly differ from HoFH and HoFDB patients (P = .730 and .340, respectively)., Conclusion: A (trend toward) increased plasma Lp(a) levels in homozygous ADH patients compared with both heterozygous ADH and unaffected relatives was observed. Whether increased Lp(a) levels in homozygous ADH patients add to the increased cardiovascular disease risk and whether this risk can be reduced by therapies that lower both low-density lipoprotein cholesterol and Lp(a) levels remains to be elucidated., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

We present the case history of 2 patients with low-density lipoprotein receptor-negative compound heterozygous familial hypercholesterolemia who did not receive lipoprotein apheresis. We describe the subsequent effect of all lipid-lowering medications during their life course including resins, statins, ezetimibe, nicotinic acid/laropiprant, mipomersen, and lomitapide. These cases tell the story of siblings affected with this rare disease, who are free of symptoms but still are at a very high cardiovascular disease risk, and their treatment from childhood., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Statins reduce subclinical atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). However, some FH patients still develop ASCVD despite statin therapy. We compared subclinical atherosclerosis assessed by carotid plaque presence and intima media thickness (C-IMT), in long-term statin-treated FH patients and healthy controls. Furthermore, we analysed whether carotid ultrasonography findings associated with subclinical coronary atherosclerosis., Methods: We assessed the presence of carotid plaques and C-IMT in 221 asymptomatic heterozygous FH patients (48% men; 46 ± 15 years) on long-term (10.0 ± 7.8 years) statin treatment and 103 controls (32% men, 47 ± 16 years)., Results: The frequency of carotid plaques and C-IMT did not differ significantly between the FH patients and controls (69 (31%) versus 24 (23%), p = 0.1 and 0.58 ± 0.13 versus 0.58 ± 0.12 mm, p = 0.9, respectively). In a subgroup of 49 FH patients who underwent cardiac computed tomography, coronary artery calcification correlated with carotid plaque presence (R = 0.47; p = 0.001), but not with C-IMT (R = 0.20; p = 0.2)., Conclusions: Carotid plaques and C-IMT did not differ between long-term statin-treated heterozygous FH patients and healthy controls. This shows that long-term statin treatment in these FH patients reduces carotid atherosclerosis to a degree of a healthy population. These findings strongly suggests that sonography of the carotid arteries during follow-up of statin-treated FH patients has limited value., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Autosomal dominant hypercholesterolemia (ADH), characterized by high-plasma low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD) risk, is caused by mutations in LDLR, APOB, and/or PCSK9., Objective: To describe the clinical characteristics of "double-heterozygous carriers," with 2 mutations in 2 different ADH causing genes, that is, LDLR and APOB or LDLR and PCSK9., Methods: Double heterozygotes were identified in the database of the national referral laboratory for DNA diagnostics of inherited dyslipidemias. We collected the medical data (comprising lipids and CVD events) from double heterozygotes and compared these with data from their heterozygous and unaffected relatives and homozygote/compound heterozygous LDLR mutation carriers, identified in a previously described cohort (n = 45)., Results: A total of 28 double heterozygotes (23 LDLR/APOB and 5 LDLR/PCSK9 mutation carriers) were identified. Off treatment, LDL-C levels were significantly higher in double heterozygotes (mean ± SD, 8.4 ± 2.8 mmol/L) compared with 28 heterozygous (5.6 ± 2.2) and 18 unaffected relatives (2.5 ± 1.1; P ≤ .01 for all comparisons) and significantly lower compared with homozygous/compound heterozygous LDLR mutation carriers (13.0 ± 5.1; P < .001)., Conclusions: Double-heterozygous carriers of mutations in ADH genes express an intermediate phenotype compared with heterozygous and homozygous/compound heterozygous carriers and might well be misconceived to suffer from a severe form of heterozygous ADH. The molecular identification of double heterozygosity is of relevance from both a screening and an educational perspective., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: In the past decades evidence has accumulated that women with reproductive and pregnancy-related disorders are at increased risk of developing cardiovascular disease (CVD) in the future. Up to now there is no standardised follow-up of these women becausee guidelines on cardiovascular risk management for this group are lacking. However, early identification of high-risk populations followed by prevention and treatment of CVD risk factors has the potential to reduce CVD incidence. Therefore, the Dutch Society of Obstetrics and Gynaecology initiated a multidisciplinary working group to develop a guideline for cardiovascular risk management after reproductive and pregnancy-related disorders., Methods: The guideline addresses the cardiovascular risk consequences of gestational hypertension, preeclampsia, preterm delivery, small-for-gestational-age infant, recurrent miscarriage, polycystic ovary syndrome and premature ovarian insufficiency. The best available evidence on these topics was captured by systematic review. Recommendations for clinical practice were formulated based on the evidence and consensus of expert opinion. The Dutch societies of gynaecologists, cardiologists, vascular internists, radiologists and general practitioners reviewed the guideline to ensure support for implementation in clinical practice., Results: For all reproductive and pregnancy-related disorders a moderate increased relative risk was found for overall CVD, except for preeclampsia (relative risk 2.15, 95% confidence interval 1.76-2.61)., Conclusion: Based on the current available evidence, follow-up is only recommended for women with a history of preeclampsia. For all reproductive and pregnancy-related disorders optimisation of modifiable cardiovascular risk factors is recommended to reduce the risk of future CVD., (© The European Society of Cardiology 2016.)

Context: A young age at menopause has been associated with increased cardiovascular disease (CVD) risk., Objective: To compare the cardiovascular risk profile between women with premature ovarian insufficiency (POI) and premenopausal controls of comparable age., Design: Cross-sectional case control study., Setting: Two university medical centers., Participants: Women above 45 years of age who were previously diagnosed with POI (n = 83) and premenopausal population controls of comparable age (n = 266)., Main Outcome Measures: Blood pressure, body mass index, waist circumference, electrocardiogram, bilateral carotid intima media thickness, estradiol, T, androstenedione, dehydroepiandrosterone sulfate, SHBG, insulin, glucose, lipids, TSH, free T4, N-terminal pro-B-type natriuretic peptide, C-reactive protein, uric acid, creatinine, and homocysteine were measured. Potential associations between POI status and subclinical atherosclerosis were assessed., Results: Women with POI exhibited an increased waist circumference (β = 5.7; 95% confidence interval [CI], 1.6, 9.9), C-reactive protein (β = 0.75; 95% CI, 0.43, 1.08), free T4 levels (β = 1.5; 95% CI, 0.6, 2.4), and lower N-terminal pro-B-type natriuretic peptide (β = -0.35; 95% CI, -0.62, -0.08), estradiol (β = -1.98; 95% CI, -2.48, -1.48), T (β = -0.21; 95% CI, -0.37, -0.06), and androstenedione (β = -0.54; 95% CI, -0.71, -0.38) concentrations compared to controls, after adjusting for confounders. After adjustment, a trend toward increased hypertension (odds ratio = 2.1; 95% CI, 0.99; 4.56) and decreased kidney function was observed in women with POI (creatinine β = 3.5; 95% CI, -0.05, 7.1; glomerular filtration rate β = -3.5; 95% CI, -7.5, 0.46). Women with POI exhibited a lower mean carotid intima media thickness (β = -0.17; 95% CI, -0.21, -0.13) and decreased odds of plaque presence compared to controls (odds ratio = 0.08; 95% CI, 0.03; 0.26)., Conclusions: Women with POI exhibited an unfavorable cardiovascular risk profile, including higher abdominal fat, elevated chronic inflammatory factors, and a trend toward increased hypertension and impaired kidney function compared to controls. However, we observed no signs of increased subclinical atherosclerosis in women with POI. Additional studies are required to identify specific determinants of long-term CVD risk in women with POI.

Background: Lomitapide reduces low-density lipoprotein-cholesterol (LDL-C) but also high-density lipoprotein-cholesterol (HDL-C) levels. The latter may reduce the clinical efficacy of lomitapide. We investigated the effect of lomitapide on HDL-C levels and on cholesterol efflux capacity (CEC) of HDL in patients with homozygous familial hypercholesterolemia (HoFH)., Methods and Results: Four HoFH patients were treated with increasing dosages of lomitapide. Lomitapide decreased LDL-C (range -34 to -89%). Total HDL-C levels decreased (range -16 to -34%) with a shift to buoyant HDL. ABCA1-mediated CEC decreased in all patients (range -39 to -99%). The changes of total, ABCG1- and SR-BI-mediated CEC were less consistent., Conclusion: Lomitapide decreased LDL-C and HDL-C levels. Our report raises the hypothesis that the anti-atherogenic potential of HDL seems to be unaffected as total CEC did not seem to change consistently. Combined with the reduction of atherogenic lipoproteins, the net effect of lomitapide appears to be beneficial in HoFH patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Study Question: Is the maternal cardiovascular (CV) risk profile associated with human embryonic growth trajectories and does the mode of conception affect this association?, Summary Answer: This small study suggests that the maternal CV risk profile is inversely associated with first trimester embryonic growth trajectories in in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) pregnancies, but not in spontaneously conceived pregnancies., What Is Known Already: Maternal high-blood pressure and smoking affect placental function, accompanied by increased risk of fetal growth restriction and low-birthweight. Mothers who experience pregnancies complicated by fetal growth restriction are at increased risk of CV disease in later life., Study Design, Size, Duration: In a prospective periconception birth cohort conducted in a tertiary hospital, 111 singleton ongoing pregnancies with reliable pregnancy dating, no pre-existing maternal disease and no malformed live borns were investigated., Participants/materials, Settings, Methods: Spontaneously conceived pregnancies with a reliable first day of the last menstrual period and a regular menstrual cycle of 25-31 days only (n = 66) and IVF/ICSI pregnancies (n = 45) were included. Women underwent weekly three-dimensional ultrasound scans (3D US) from 6- to 13-week gestational age. To estimate embryonic growth, serial crown-rump length (CRL) measurements were performed using the V-Scope software in a BARCO I-Space. Maternal characteristics and CV risk factors were collected by self-administered questionnaires. The CV risk profile was created based on a score of risk factors, including maternal age, body-mass index, CV disease in the family, diet and smoking. Quartiles of the CV risk score were calculated. Associations between the CV risk score and embryonic growth were assessed using square root transformed CRL in multivariable linear mixed model analyses., Main Results and the Role of Chance: From the 111 included pregnancies, 696 3D US data sets were obtained of which 637 (91.5%) CRLs could be measured. In the total group, The CV risk score was inversely, but not significantly associated with embryonic growth (-0.03√mm; P = 0.291). Stratified by mode of conception, the CV risk score was inversely and significantly associated with embryonic growth (β = -0.04√mm; P = 0.025, adjusted for possible confounders) in the IVF/ICSI group. Compared with the first quartile, embryos in the upper quartile were 10.4% smaller at 6(+0) weeks (4.4 versus 4.9 mm) and 3.1% smaller at 12(+0) weeks (56.5 versus 58.4 mm) of gestation. Although the CV risk score was slightly, but significantly, higher in women conceiving spontaneously compared with those undergoing IVF/ICSI treatment [CV risk score = 2.06 (SD: 1.23) and 1.60 (SD: 1.15), respectively], no association was established with embryonic growth in that particular group., Limitations, Reasons for Caution: Participants included in the present cohort are women with a singleton ongoing pregnancy without any pre-existing disease and selected from a tertiary hospital. Hence, they represent a selected group of women. Larger and population-based periconception birth cohort studies are recommended to demonstrate external validity., Wider Implications of the Findings: Differences in embryonic growth between pregnancies conceived spontaneously and after IVF/ICSI treatment in relation with CV risk factors substantiate the importance of more investigation into differences in sensitivity of endometrial, endothelial, placental and embryonic tissues., Study Funding/competing Interests: Funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands. The authors declare no conflict of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The influence of ethnicity in women with gestational diabetes in relation to maternal, pregnancy and neonatal outcome is not well defined., Aim: To compare the perinatal outcome in women with gestational diabetes between different ethnic groups reflecting the multi-ethnic population in the Netherlands., Methods: Patients with gestational diabetes (n = 388) who visited the multidisciplinary outpatient clinic for Diabetes Care and Obstetrics of the Sint Franciscus Gasthuis in Rotterdam between 2010 and 2013 were included. Ethnicity was distinguished into six groups: Moroccan (n = 100); Turkish (n = 43); Caucasian (n = 146); Suriname-Creole (n = 23); Suriname-Hindu (n = 32); and Miscellaneous (n = 44)., Results: Caucasians were the largest group with gestational diabetes (37.7%), followed by Moroccans (25.8%). Body mass index before pregnancy was highest in Surinamese-Creole women, followed by Turks and Moroccans (p &lt; 0.001). Gravidity and parity were highest in Moroccans. Gravidity was lowest in Surinamese-Hindus and parity was lowest in Caucasians (p &lt; 0.001). There was also a remarkable, significant difference in the mode of delivery between the ethnicities with the lowest number of normal deliveries in Caucasians and the highest in Moroccans (p = 0.03). Assisted delivery occurred most frequently in Caucasian women, although there was no difference in the frequency of caesarean sections. Birth weight was the only neonatal parameter showing significant differences between the ethnicities, with the highest birth weight for Moroccan children and the lowest for Surinamese children (3542 g vs. 3200; p = 0.001)., Conclusion: This study did not show major differences in maternal or neonatal complications, however there are significant disparities in (percentile) birth weight and mode of delivery across the different ethnic groups.

- In various non-medical publications, red yeast rice (red fermented rice, RYR) is recommended as a cholesterol-lowering substance. This supplement contains a naturally occurring statin, namely monacolin K.- Patients who wish to use RYR should be advised to only take products from reputable pharmaceutical companies. Pharmacists can provide advice on this.- Users of RYR should be alerted to the potential drug interactions and serious risks associated with its use during pregnancy.- RYR appears to be better tolerated than statins. This difference in tolerance can be traced back to the applied dosages. On average, the daily RYR dosage contains less statin than the standard dosage for statins.- The Netherlands Food and Consumer Product Safety Authority should urgently test the RYR supplements available in the Netherlands to gain more insight into the quality of said products.- Mandatory registration of RYR as an herbal medicine appears necessary to guarantee the quality of, and monacolin levels in, the products and to reduce health risks.

Aims: The purpose of this review was to assess the relationship between premature ovarian insufficiency (POI), defined as natural menopause <40 years, and risk of ischaemic heart disease (IHD), stroke and overall cardiovascular disease (CVD)., Methods and Results: We performed a systematic search in PubMed (1966-2012), EMBASE (1980-2012). Studies were included if they were prospective, follow-up>3 years, assessment of age menopause <40 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., Conclusion: 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., (© The European Society of Cardiology 2014.)

Background: Familial hypercholesterolemia is typically caused by LDL receptor (LDLR) mutations that result in elevated levels of LDL cholesterol (LDL-C). In homozygous FH, the prevalence of aortic valve calcification (AoVC) reaches 100% and is often symptomatic., Objectives: The objective of this study was to investigate the prevalence, extent, and risk-modifiers of AoVC in heterozygous FH (he-FH) that are presently unknown., Methods: Asymptomatic patients with he-FH and 131 non-familial hypercholesterolemia controls underwent CT computed tomography calcium scoring. AoVC was defined as the presence of calcium at the aortic valve leaflets. The extent of AoVC was expressed in Agatston units, as the AoVC-score. We compared the prevalence and extent of AoVC between cases and controls. In addition, we investigated risk modifiers of AoVC, including the presence of LDLR mutations without residual function (LDLR-negative mutations), maximum untreated LDL-cholesterol (maxLDL), LDL-C, blood pressure, and coronary artery calcification (CAC)., Results: We included 145 asymptomatic patients with he-FH (93 men; mean age 52 ± 8 years) and 131 non-familial hypercholesterolemia controls. The prevalence (%) and AoVC-score (median, IQR) were higher in he-FH patients than in controls: 41%, 51 (9-117); and 21%, 21 (3-49) (p < 0.001 and p = 0.007). Age, untreated maxLDL, CAC, and diastolic blood pressure were independently associated with AoVC. LDLR-negative mutational he-FH was the strongest predictor of the AoVC-score (OR: 4.81; 95% CI: 2.22 to 10.40; p = <0.001)., Conclusions: Compared to controls, he-FH is associated with a high prevalence and a large extent of subclinical AoVC, especially in patients with LDLR-negative mutations, highlighting the critical role of LDL-C metabolism in AoVC etiology., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: This study assesses the success of the recently terminated Dutch nationwide cascade screening by examining whether children with familial hypercholesterolemia (FH) were identified through family screening or due to cardiovascular (CVD) events in the FH parent., Methods: We collected clinical information of all children (0-18 years) with FH with a pathogenic variant at our outpatient lipid clinic between 1992 and 2014 and their FH parents and FH grandparents., Results: We analysed 292 FH children from 205 parents with FH. A history of premature CVD was present in 20% of the parents (29% of the fathers, 9% of the mothers) and 49% of the FH grandparents., Conclusion: The fact that CVD is still a presenting event of FH in especially fathers shows that nationwide screening might have been terminated too early. Therefore we recommend to proceed the cascade screening., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Lipoprotein (a), also called Lp(a), is a cardiovascular disease (CVD) risk factor. Statins do not lower Lp(a), this may at least partly explain residual CVD risk in statin-treated patients with familial hypercholesterolemia (FH). We investigated the association of Lp(a) levels with atherosclerosis in these patients., Methods and Results: We performed ultrasonography in 191 statin-treated FH patients (50% men; 48 ± 15 years) to detect carotid plaques and determine carotid intima-media thickness (C-IMT). Patients with high versus low Lp(a) levels (≤0.3 g/L) had similar plaque prevalence (36 and 31%, p = 0.4) and C-IMT (0.59 ± 0.12 and 0.59 ± 0.13 mm, p = 0.8). Patients with and without plaques had similar Lp(a) levels (median 0.35 (IQR: 0.57) and 0.24 (0.64) g/L, respectively, p = 0.4)., Conclusions: The Lp(a) levels were not associated with atherosclerosis in the carotid arteries of statin-treated FH patients. This suggests that adequate statin treatment delays carotid atherosclerosis in FH independently of Lp(a) levels., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Lipoprotein(a) [Lp(a)] is an independent risk factor for aortic valve stenosis and aortic valve calcification (AVC) in the general population. In this study, we determined the association between AVC and both plasma Lp(a) levels and apolipoprotein(a) [apo(a)] kringle IV repeat polymorphisms in asymptomatic statin-treated patients with heterozygous familial hypercholesterolaemia (FH)., Methods: A total of 129 asymptomatic heterozygous FH patients (age 40-69 years) were included in this study. AVC was detected using computed tomography scanning. Lp(a) concentration and apo(a) kringle IV repeat number were measured using immunoturbidimetry and immunoblotting, respectively. Univariate and multivariate logistic regression were used to assess the association between Lp(a) concentration and the presence of AVC., Results: Aortic valve calcification was present in 38.2% of patients, including three with extensive AVC (>400 Agatston units). Lp(a) concentration was significantly correlated with gender, number of apo(a) kringle IV repeats and the presence and severity of AVC, but not with coronary artery calcification (CAC). AVC was significantly associated with plasma Lp(a) level, age, body mass index, blood pressure, duration of statin use, cholesterol-year score and CAC score. After adjustment for all significant covariables, plasma Lp(a) concentration remained a significant predictor of AVC, with an odds ratio per 10-mg dL(-1) increase in Lp(a) concentration of 1.11 (95% confidence interval 1.01-1.20, P = 0.03)., Conclusion: In asymptomatic statin-treated FH patients, plasma Lp(a) concentration is an independent risk indicator for AVC., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Objectives: Vascular calcification has been associated inconsistently to low bone mineral density and fractures. The aims of the present study were to investigate the associations between coronary artery calcification (CAC) and BMD change, BMD and fracture risk in elderly subjects of the population-based Rotterdam Study., Methods: BMD was assessed through dual-energy X-ray absorptiometry and CAC through Electron-Beam Computed Tomography in 582 men and 694 women. We investigated the associations between BMD change (6.4 years follow-up) and CAC at follow-up and between BMD and CAC (measured simultaneously). In sensitivity analyses we stratified analyses for estradiol levels in women. The association between CAC and fracture risk (9 years follow-up) was tested through competing-risks models. Models were sex-stratified and adjusted for age, body mass index, smoking, bisphosphonate use and age at menopause., Results: There was no association between BMD change and CAC in men. In women, each 1% increase in annual BMD loss was significantly associated with higher follow-up CAC [β = 0.22 (0.06-0.38), p=0.006; prevalence ratio: 4%]. Stratified analyses showed significant associations between BMD loss and follow-up CAC only in women with lower estradiol levels. We found no association between CAC and fracture risk and no association between BMD and CAC cross-sectionally., Conclusions: BMD loss was associated with higher follow-up CAC in women, which might be related to low estrogen levels. No association between CAC and BMD or fracture risk was found. Further studies are required to elucidate the mechanisms that might underlie the association between BMD change and coronary calcification in women., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Middle-aged and elderly women constitute a large and growing proportion of the population. The peri and postmenopausal period constitutes a challenging transition time for women's health, and menopausal health is a crucial aspect in healthy and successful aging. Currently, no framework for the concept of healthy menopause exists, despite its recognized importance. Therefore, we aimed to: (i) characterize healthy menopause; (ii) identify aspects that contribute to it; and (iii) explore potential approaches to measure it. We propose healthy menopause as a dynamic state, following the permanent loss of ovarian function, which is characterized by self-perceived satisfactory physical, psychological and social functioning, incorporating disease and disability, allowing the attainment of a woman's desired ability to adapt and capacity to self-manage. The concept of healthy menopause applies to all women from the moment they enter the menopausal transition, up until they reach early and late postmenopause and includes women with spontaneous, iatrogenic, and premature menopause. This conceptualization can be considered as a further step in the maintenance and improvement of health in menopausal women from different perspectives, foremost the woman's own perspective, followed by the clinical, public health, and societal perspectives, and can be seen as a further step in delineating lines for future research. Furthermore, it could facilitate the improvement of adequate preventive and treatment strategies, guide scientific efforts, and aid education and communication to health care practitioners and the general public, allowing women the achievement of their potential and the fulfillment of their fundamental role in society., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands., Methods and Results: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be ∼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event., Conclusion: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Familial hypercholesterolemia (FH) is a monogenic autosomal dominant disorder. FH is the most common hereditary cause of raised serum cholesterol levels and is associated with an increased risk of premature cardiovascular disease (CVD). This disorder is known to have a genetic cause, and effective drug therapies exist for patients with FH. Successful cascade screening, within the framework of a national screening programme, gave the Netherlands an international role as model and pioneer as far as FH detection is concerned. With the ending of this screening programme as of 1 January 2014 the care for FH patients, including screening and counselling has had to be incorporated within the basic Dutch healthcare insurance system. It is essential that detection of FH should continue in as efficient and cost-effective a manner as possible. Our proposal is that this detection should be performed and co-ordinated by those treating patients with FH so that FH screening, counselling and treatment are integrated.

The CHIPS (Control of Hypertension In Pregnancy Study) trial showed that tight blood pressure control in women with hypertension during pregnancy was safe with respect to neonatal outcome. However it was not linked to improvement of the predefined maternal composite outcome. The CHIPS trial is without doubt a landmark study in this field; however some questions are still unresolved. The study population consists of pregnant women with pre-existing hypertension and those with gestational hypertension. As these groups differ regarding pathophysiology and are however covered in separate guidelines in the Netherlands. Unfortunately no sub-analyses were performed for these groups. Moreover the primary neonatal endpoint is defined too broadly because of the inclusion of the rather vague component "higher than usual neonatal care". An endpoint combining major neonatal and maternal comorbidities would have been more clinically relevant. It is unlikely that the results of this trial will influence the Dutch guidelines.

Recently a Dutch research group published an analysis of the Dutch screening programme for familial hypercholesterolemia (FH) in JAMA. They showed that the prevalence of type 2 diabetes mellitus (DM2) was lower among persons with a mutation causing FH than in their unaffected relatives. FH patients who were carriers of mutations without residual LDL receptor function had DM2 less often than those with residual LDL receptor function. Although it is tempting to speculate about a causal relationship between cholesterol transport and DM2, another explanation could be the healthier lifestyle of patients with FH. This study should not change clinical practice and should certainly not lead to discontinuation of statin therapy.

Objective: Patients with heterozygous familial hypercholesterolemia (FH) are at severely increased risk of developing atherosclerosis at relatively young age. The aim of this study was to assess the prevalence of subclinical atherosclerosis and intraplaque neovascularization (IPN) in patients with FH, using contrast-enhanced ultrasound (CEUS) of the carotid arteries., Methods: The study population consisted of 69 consecutive asymptomatic patients with FH (48% women, mean age 55 ± 8 years). All patients underwent carotid ultrasound to evaluate the presence and severity of carotid atherosclerosis, and CEUS to assess IPN. IPN was assessed in near wall plaques using a semi-quantitative grading scale and semi-automated quantification software., Results: Carotid plaque was present in 62 patients (90%). A total of 49 patients had plaques that were eligible for the assessment of IPN: 7 patients (14%) had no IPN, 39 (80%) had mild to moderate IPN and 3 (6%) had severe IPN. Semi-automated quantification software showed no statistical significant difference in the amount of IPN between patients > 50 years and patients ≤ 50 years and between patients with a defective low-density lipoprotein receptor (LDLR) mutation and patients with a negative LDLR mutation. Plaques with irregular or ulcerated surface had significantly more IPN than plaques with a smooth surface (p < 0.05)., Conclusion: Carotid ultrasound demonstrated atherosclerotic plaque in 90% of asymptomatic patients with FH without known atherosclerosis. IPN assessed with CEUS, was present in 86% of these patients. Irregular and ulcerated plaques exhibited significantly more IPN than plaques with a smooth surface., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Familial hypercholesterolaemia is a relatively frequently occurring disease that is strongly associated with vascular disease. Current treatment with cholesterol-lowering agents is partly effective but shows variable responses between patients with familial hypercholesterolaemia. Recently, new cholesterol-lowering drugs have been developed. Here we describe the most promising of these new agents for which results from phase 2 or phase 3 trials are available. We will discuss the data regarding lipid-lowering potential and safety issues and speculate about the potential reductions of the residual risk of statin-treated FH patients.

Introduction: Women with a history of preeclampsia have an increased risk of developing cardiovascular disease (CVD) later in life. Classical risk scores are not suitable as risk estimates of CVD in this young population. Recent recommendations from the American Heart Association are aimed to improve cardiovascular health (CVH)., Objectives: Examining CVH by Health Life Check (HLC) (http://mylifecheck.heart.org/) in previously severe preeclamptic women is part of our cardiovascular risk follow-up program. Final score is a scale from 1 to 10, where 10 represents ideal CVH., Results: Since 2011 HLC is offered to all women in this program. So far, 213 women were included, 148 (70%) underwent a CVH assessment by performing HLC between three months and one year after delivery. The overall HLC score was 7.4 (median; range: 0.8-10.0) at 3.6 months after the delivery. Only 2 out of 148 women (1.4%) had an ideal score. HLC score was 7.1 (median; range: 0.8-10.0) for 48 women who had a HLC score within 6 months after delivery versus 8.2 (median; range: 2.6-9.8) in the second half of the first year after delivery., Conclusion: These are the first data on CVH in women after severe preeclampsia. Only 1.4% of these women had an ideal score. Active counselling of these women could be the reason of the improved score over time. We showed that CVH as assessed by HLC is an excellent tool for cardiovascular risk management in this specific group of women., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: Women with a history of preeclampsia have an increased risk of developing cardiovascular disease (CVD) later in life. 24-hour ambulatory blood pressure measurement is considered to be the gold-standard for diagnosing hypertension. Data on 24-hour ambulatory blood pressure measurement in women with a history of preeclampsia are scarce., Objectives: To evaluate hypertension in previously severe preeclamptic women, 24-hour ambulatory blood pressure measurements were performed one year after delivery as part of our cardiovascular risk follow-up program., Results: Since 2011 213 women were included in this program. 24-hour ambulatory blood pressure measurement was performed in 90 out of 121 women (74%) who completed follow-up one year after delivery. Systolic blood pressure was 121 mm Hg (median; range 96-157) and diastolic blood pressure 78mm Hg (median; range 62-114). Twenty-three women (26.0%) used antihypertensive medication one year postpartum. Blood pressure levels were not significantly different between women with and without medication. Five women (5/67, 7.5%) of those not using antihypertensives, were diagnosed as having hypertension by this measurement., Conclusion: These data show that 30% of these previously severe preeclamptic women have persisting hypertension one year postpartum. These data stress the importance of close monitoring of blood pressure in these women., (Copyright © 2013. Published by Elsevier B.V.)

Background: The optimal approach for venous thrombosis (VTE) prophylaxis during pregnancy and postpartum in women with an increased risk of VTE is not established., Objectives: To evaluate the effectiveness, represented as the incidence of pregnancy-related VTE, and safety, represented as incidence of postpartum hemorrhage (PPH), of a protocol recommending prophylaxis with low-dose low-molecular-weight heparin (LMWH) in women at intermediate to high risk of VTE., Patients/methods: In this retrospective cohort study, we analyzed 34 women (44 pregnancies) with intermediate risk of VTE who received low-dose LMWH for 6 weeks postpartum and 57 women (82 pregnancies) with high risk of VTE who received low-dose LMWH during pregnancy and for 6 weeks postpartum. Pregnancy-related VTE was defined as VTE during pregnancy or ≤ 3 months postpartum. PPH was defined as blood loss >500 mL and severe PPH as blood loss > 1000 mL., Results: The incidence of pregnancy-related VTE was 5.5% (95% CI, 2.4-12.3) despite prophylaxis with low-dose LMWH. All events occurred in women at high risk, with a postpartum incidence of 7.0% (95% CI, 2.9-16.7) and antepartum incidence of 1.8% (95% CI, 0.4-9.2). The risk of PPH was 21.6% (95% CI, 14.3-31.3) and severe PPH 9.1% (95% CI, 4.7-16.9), which was not different in women who started LMWH postpartum and those who used LMWH during pregnancy., Conclusions: Although prophylaxis with low-dose LMWH during pregnancy and postpartum proved to be safe, the risk of pregnancy-related VTE is considerable in women with a high risk of VTE. VTE prophylaxis with low-dose LMWH may not be sufficiently effective in these women., (© 2011 International Society on Thrombosis and Haemostasis.)

Objective: To evaluate the efficacy and safety of thromboprophylaxis with a low of low-molecular-weight heparin (LMWH) in women with an intermediate to high risk of pregnancy-related venous thromboembolism (VTE)., Design: Retrospective cohort study., Methods: We collected data from all pregnant women with an intermediate or high risk of VTE in the period 1996-2009. In accordance with protocol, pregnant women with an intermediate risk of VTE were treated with a prophylactic dose of LMWH for 6 weeks post partum, and pregnant women with a high risk were treated with a prophylactic dose of LMWH during the pregnancy and for 6 weeks post partum. Efficacy was defined as the incidence of VTE during pregnancy or < 3 months post partum, and safety as the incidence of post-partum haemorrhage (PPH) (> 500 ml blood loss) or severe PPH (> 1,000 ml blood loss)., Results: We analysed 34 women (44 pregnancies) with an intermediate risk and 57 women (82 pregnancies) with a high risk of VTE. The incidence of pregnancy-related VTE despite thromboprophylaxis was 5.5% (95% CI: 2.4-12.3). All VTEs occurred in high-risk women, and risk was higher post partum than ante partum: 7.0% (95% CI: 2.9-16.7) and 1.8% (95% CI: 0.4-9.2%), respectively. The risk of PPH was 21.6% (95% CI: 14.3-31.3) and of severe PPH 9.1% (95% CI: 4.7-16.9) and was comparable in women who used LMWH during pregnancy and those who started LMWH post partum., Conclusion: There was a considerable risk of pregnancy-related VTE in high-risk women despite a prophylactic dose of LMWH during pregnancy and in the post partum period. For these women thromboprophylaxis with a low, prophylactic dose of LMWH appeared to be insufficient.

Haemophagocytic syndrome is a rare and life-threatening disease, which often goes unrecognised in adults, with high mortality as a consequence. Here we present two adult patients who were diagnosed with haemophagocytosis of distinct underlying causes which, despite treatment, led to fatal outcomes. Measuring ferritin is an easy and cheap resource in diagnosis.

Since the late 1970s there has been a decline in cardiovascular mortality in the Netherlands. In recent years, the number of hospital admissions due to cardiovascular disease has decreased, whereas short-stay admissions and outpatients' visits are increasing. One explanation for this phenomenon, suggested by Koek et al. in this issue, is the limited availability and closure of hospital beds in recent years. However, there are other possible reasons for the decrease in cardiovascular mortality. First of all, there has been a substantial improvement in survival following acute myocardial infarction, mainly as a result of advances in the treatment. As all patients with an acute myocardial infarction are admitted anyway, the observed decrease in hospital admissions due to acute myocardial infarction reflects a decrease in the incidence as opposed to a decrease in the availability of hospital beds. Secondly, primary preventive measures aimed at modifying risk factors have been shown to result in a clear decrease in cardiovascular mortality. Lastly, mortality and morbidity due to chronic cardiovascular disease, such as heart failure, have decreased significantly. The range of options to adequately treat this category of patients has expanded considerably with, for example, the introduction of new drugs and biventricular pacemakers. There are many factors, other than the closure of hospital beds, which could explain the observed decline in the number of admissions due to cardiovascular disease.

It has been recognized over the past years that women form a distinct subpopulation within patients with coronary heart disease. This phenomenon should be acknowledged in the management and in the assessment of coronary heart disease. Over the past years remarkable progress has been made concerning our knowledge of cardiovascular risk factors related to gender. For instance, diabetes, high density lipoproteins and triglycerides levels have been found to have a greater impact on coronary heart disease risk in women compared to men. On the other hand, evidence showing that lipoprotein (a) is a cardiovascular risk factor seems to be stronger in men than in women. For optimal treatment and prevention of coronary heart disease it is necessary to acknowledge that it is not self-evident that women and men show similar responses to risk factors or to treatment. This review article addresses the role of cardiovascular risk factors focusing on the differential impact they might have on men and women.

Recent studies have indicated that women were less likely to receive sophisticated pacemaker devices than men. These differences could not be fully explained by demographic and clinical variables. The purpose of the present study was to assess whether a gender related difference might exist in pacemaker mode selection in patients undergoing their first implantation in The Netherlands. Records of first implants (n = 39,217) collected from 1988 through 1997 covering 95% of all implantations in The Netherlands. From this population 33,564 (85.6%) patients were included for final analysis. We observed no significant sex differences in pacemaker selection in patients with atrioventricular conduction disorders and bundle branch block. In patients with sick sinus syndrome, only very old women (> or = 85 years) had more atrial systems implanted than men of similar age (6.5% vs 3.5%), whereas men received more double chamber pacemakers (12.3% vs 10.3%) (P = 0.002). However, the relative distribution of physiological versus nonphysiological pacemakers in this subgroup was similar for men and women. In patients with chronic atrial fibrillation/flutter associated with bradycardia, sex differences were only apparent in the age group of 75-85 years; women received more dual chamber pacemakers (8.8% vs 5.3%) whereas men received more single chamber ventricular pacemakers (94.2% vs 89.8%) (P = 0.0011). With increasing age, sex differences in pacemaker selection were absent, but there was a considerable drop in implantation rate of dual chamber systems. Our study showed no major sex differences in the selection of pacemaker devices. Physicians select pacemaker devices by age rather than gender, which might be a rational choice.

Aims: The aim of the present clinical study was to evaluate whether gender-related differences existed as regards the extent and localization of coronary artery lesions in patients with angiographically documented coronary artery disease, and whether these angiographic findings would lead to differences in further management., Methods and Results: Over a 16-year period (1981-1997) we evaluated 1894 patients (1526 men, 368 women) with angiographically documented coronary artery disease (luminal stenosis >/=60%). For each patient the coronary angiographic results and subsequent revascularization procedures (percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery) were analysed. The study period was divided into the early angioplasty years (1981 to 1989) and the current angioplasty years (1990-1997). No gender differences in extent and localization of coronary angiographic lesions were observed. In men and women the incidence of single-vessel disease was 42% and 40%, two-vessel disease 27% and 27%, three-vessel disease 26% and 24%, and left main disease 5% and 8%, respectively (P=ns). Localization of disease in men and women was 36% and 39% for the left anterior descending coronary artery, 34% and 32% for the right coronary artery, and 27% and 26% for the left circumflex coronary artery, respectively (P=ns). There was a significant shift from multi-vessel disease towards single-vessel disease in both men and women (both P<0.001). As to subsequent management, a significant gender difference in favour of women was observed (P=0.021). Over time, the number of angioplasty procedures increased significantly from 11.6% to 23.2% for men (P<0.001), and for women from 17.6% to 28.0% (P=0.025), whereas the number of coronary artery bypass procedures decreased in men from 34.9% to 29. 5% (P=0.024) and in women from 42.6% to 30.6% (P=0.019). Referral to angioplasty (n=535) and coronary artery bypass surgery (n=616) in relation to the extent of the disease did not show any gender bias in favour of men., Conclusions: Our angiographic findings did not show significant gender differences as regards the extent and localization of coronary artery disease in patients with angiographically documented coronary artery disease. More importantly, no substantial evidence could be found for under-referral of women to subsequent therapeutic management. Therefore our study questions the presence of Yentl syndrome in the current era., (Copyright 2000 The European Society of Cardiology.)

Background: Several studies have shown that the application of diagnostic and invasive procedures varies between men and women. The purpose of this study was to assess if referral for coronary angiography after technetium-99m tetrofosmin myocardial perfusion scintigraphy in 616 patients with undiagnosed chest pain might demonstrate gender bias., Methods and Results: The primary end point for this study was coronary angiography within 90 days of myocardial perfusion scintigraphy. Women had more normal perfusion images than men (207 [70.9%] vs 160 [50.5%], P < .05). Of 242 patients with abnormal images (157 men, 85 women), 28 men (17.7%) and 17 women (20.0%) were referred for further invasive testing (P = not significant). Referral for coronary angiography increased relative to the number of defects. Univariate analysis showed that reversible and persistent defects were the most predictive variables for referral to coronary angiography (odds ratio [OR] 5.45, 95% confidence interval [CI] 3.10-9.58, P < .001, and OR 2.67, 95% CI 1.52-4.67, P = .001, respectively). More importantly, multivariate analysis showed that reversible perfusion defects (OR 4.77, 95% CI 2.48-9.17, P < .001) and persistent perfusion defects (OR 2.14, 95% CI 1.11-4.14, P = .02) were predictive of subsequent coronary angiography. No significant association between gender and subsequent coronary angiography was found both in univariate and multivariate logistic regression analysis (OR 0.64, 95% CI 0.37-1.12, P = .12, and OR 0.70, 95% CI 0.36-1.36, P = .28, respectively)., Conclusions: Our study reveals that after correction for the presence and the severity of myocardial perfusion abnormalities, men and women were referred to coronary angiography at a similar rate. Thus, based on the results of technetium-99m tetrofosmin myocardial perfusion imaging, no substantial evidence for a gender-related bias could be found in the referral for further invasive testing.