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Unrecognized myocardial infarction (MI) is an MI that remains undetected in the acute phase and is associated with an unfavourable prognosis. With this systematic review and meta-analysis, we evaluated the burden of cardiovascular risk factors in individuals with unrecognized MI. We searched general population-based cohort studies diagnosing unrecognized MI by electrocardiogram or myocardial imaging up to 24 November 2023. Pooled mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs) were determined, and random-effects meta-analyses were performed. Fourteen cohort studies were included involving 200 450 individuals (mean age 62.8 ± 9.9 years, 56.0% women), among which 4322 (2.2%) experienced unrecognized MI (mean age 66.3 ± 8.2 years, 47.8% women) and 4653 (2.1%) recognized MI (mean age 68.5 ± 7.3 years, 33.8% women). Compared to individuals without MI, those with unrecognized MI had higher body mass index (MD 0.27, 95% CI 0.16-0.39) and systolic blood pressure (MD 4.48, 95% CI 2.81-6.15) levels, and higher prevalence of hypertension (RR 1.27, 95% CI 1.06-1.51) and diabetes mellitus (RR 1.67, 95% CI 1.36-2.06). Furthermore, individuals with unrecognized MI had lower prevalence of hypertension (RR 0.92, 95% CI 0.88-0.97) and diabetes mellitus (RR 0.80, 95% CI 0.70-0.92). Individuals with unrecognized MI are characterized by a substantial burden of metabolic risk factors. Our findings suggest insufficient recognition and management of cardiovascular risk factors among individuals with unrecognized MI., Competing Interests: Conflict of interest: J.R.v.L. received a research grant from Novartis paid to the institution. This funding source had no involvement in the study design, data collection, analysis, interpretation, writing, and submission. The other authors have no conflict of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cardiovascular disease is the leading cause of death in women worldwide. Yet, women are often underrepresented in cardiovascular clinical trials. Trial characteristics may influence the participation of women. For instance, trials are often entitled with an acronym, which might be perceived as gendered. We aimed to investigate if the perceived gender of the acronym and other trial characteristics affect the representation of female patients in cardiovascular trials., Methods: We searched ClinicalTrials.gov for randomized controlled trials in cardiovascular disease named with an acronym. Cardiovascular patients (n = 148) scored the perceived gender of the acronym of 148 identified trials. Prevalence ratios (PR) were calculated with Poisson regression to link trial characteristics to representation of female patients in the trials., Results: In 62 % of trials, female patients were underrepresented relative to the disease population. There was no improvement over time in proportion of trials with adequate representation. A third of acronyms was classified as gendered. The perceived gender did not affect representation of female patients (PR 1.01; 95% CI 0.95 - 1.08; P = 0.68). A woman as first and/or last author (PR 1.22; 95% CI 1.07 - 1.38; P = 0.002) and recruitment in an outpatient setting (PR 1.15; 95% CI 1.02 - 1.29; P = 0.01) were associated with a higher prevalence of adequate representation of female patients., Conclusions: Representation of female patients in cardiovascular trials does not depend on the perceived gender of the trial acronym but is improved in trials under female leadership in out-patient settings. Our findings may direct efforts towards increasing representation of female patients in cardiovascular trials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Aims: Evidence on the impact of screening for cardiovascular diseases (CVDs) on health-related quality of life (HRQoL) is important for policy decisions about screening implementation and to uncover teachable moments to motivate healthy lifestyle choices. It is unknown whether screening by cardiac computed tomography (CT) scan has a stronger impact on HRQoL than screening by traditional risk prediction models. The study aims to investigate differences in HRQoL across the screening process between participants who were randomized to CVD risk estimation by coronary artery calcium score or Systematic COronary Risk Evaluation., Methods and Results: A subset of 2687 ROBINSCA participants filled in questionnaires at (T0) randomization, (T1) invitation, (T2) 1-3 days before screening, (T3) 1-3 days after, and (T4) screening result. Generic HRQoL (SF-12; EQ-5D) and anxiety (STAI-6) were measured. We investigated the differences in changes in HRQoL across the screening process with linear mixed models. We found comparable levels of HRQoL at all screening moments for the two intervention groups. Mental health scores were worse at invitation and randomization than at the later time points, irrespective of screening group (all P < 0.001). A result indicating a heightened CVD risk was associated with increased anxiety in the CT screening group., Conclusion: Computed tomography screening for CVD risk has no detrimental impact on HRQoL and anxiety levels compared to screening by traditional risk assessment. Receiving an invitation to screenning or a result implying increased CVD risk could function as teachable moments for high-risk individuals., Registration: ROBINSCA trial registration number: NTR6471 in Dutch Trial Register (NTR)., Competing Interests: Conflict of interest: D.M. reports grants from European Commission—Horizon 2020, outside the conduct of this study. H.J.K. reports an advanced grant from the European Research Council during conduct of the study and grants from European Commission—Horizon 2020, outside the conduct of the study. M.V. reports supports for attending meetings and travel by the British Society of Cardiovascular Imaging, outside of the conduct of this study. R.V. reports grants from Siemens, the Dutch Heart Foundation, The Netherlands Organisation for Health Research and Development, and the Dutch Cancer Foundation, outside the conduct of this study. C.M.v.d.A. reports grants from the European Research Council during conduct of the study and fiduciary role in the B3 user commitee outside the conduct of the study. The authors have no other conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Brown seaweed is promising for the treatment of type 2 diabetes mellitus (T2DM). Its bioactive constituents can positively affect plasma glucose homeostasis in healthy humans. We investigated the effect of the brown seaweeds Sargassum (S.) fusiforme and Fucus (F.) vesiculosus in their natural form on glucose regulation in patients with T2DM., Methods: We conducted a randomized, double-blind, placebo-controlled pilot trial. Thirty-six participants with T2DM received, on a daily basis, either 5 g of dried S. fusiforme , 5 g of dried F. vesiculosus , or 0.5 g of dried Porphyra (control) for 5 weeks, alongside regular treatment. The primary outcome was the between-group difference in the change in weekly average blood glucose levels (continuous glucose monitoring). The secondary outcomes were the changes in anthropometrics, plasma lipid levels, and dietary intake. The data were analyzed using a linear mixed-effects model., Results: The change in weekly average glucose levels was 8.2 ± 2.1 to 9.0 ± 0.7 mmol/L ( p = 0.2) in the S. fusiforme group (n = 12) and 10.1 ± 3.3 to 9.2 ± 0.7 mmol/L ( p = 0.9) in the F. vesiculosus group (n = 10). The between-group difference was non-significant. Similarly, no between-group differences were observed for the changes in the secondary outcomes., Discussion: A daily intake of 5 g of fresh, dried S. fusiforme or F. vesiculosus alongside regular treatment had no differential effect on weekly average blood glucose levels in T2DM.

Purpose of Review: Accommodating fetal growth and development, women undergo multiple physiological changes during pregnancy. In recent years, several studies contributed to the accumulating evidence about the impact of gestational hyperlipidemia on cardiovascular risk for mother and child. This review aims to provide a comprehensive overview of the current research on lipid profile alterations during pregnancy and its associated (cardiovascular) outcomes for mother and child from a clinical perspective., Recent Findings: In a normal pregnancy, total and LDL-cholesterol levels increase by approximately 30-50%, HDL-cholesterol by 20-40%, and triglycerides by 50-100%. In some women, for example, with familial hypercholesterolemia (FH), a more atherogenic lipid profile is observed. Dyslipidemia during pregnancy is found to be associated with adverse (cardiovascular) outcomes for the mother (e.g. preeclampsia, gestational diabetes, metabolic syndrome, unfavorable lipid profile) and for the child (e.g. preterm birth, large for gestational age, preatherosclerotic lesions, unfavorable lipid profile)., Summary: The lipid profile of women during pregnancy provides a unique window of opportunity into the potential future cardiovascular risk for mother and child. Better knowledge about adverse outcomes and specific risk groups could lead to better risk assessment and earlier cardiovascular prevention. Future research should investigate implementation of gestational screening possibilities., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands., Methods: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom., Results: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score > 4 on a 1-7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions., Conclusion: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts., (© 2024. The Author(s).)

Importance: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH., Objective: To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH., Design, Setting, and Participants: Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023., Main Outcomes and Measures: Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality., Results: Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75)., Conclusions and Relevance: In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.

Objective: To study the impact of premenopausal risk-reducing salpingo-oophorectomy (RRSO), compared with postmenopausal RRSO, on urinary incontinence (UI) ≥10 years later., Design: Cross-sectional study, nested in a nationwide cohort., Setting: Multicentre in the Netherlands., Population: 750 women (68% BRCA1/2 pathogenic variant carriers) who underwent either premenopausal RRSO (≤45 years, n = 496) or postmenopausal RRSO (≥54 years, n = 254). All participants were ≥55 years at the time of the study., Methods: Urinary incontinence was assessed by the urinary distress inventory-6 (UDI-6); a score ≥33.3 indicated symptomatic UI. The incontinence impact questionnaire short form (IIQ-SF) was used to assess the impact on women's health-related quality of life (HR-QoL). Differences between groups were analysed using regression analyses adjusting for current age and other confounders., Main Outcome Measures: Differences in UDI-6 scores and IIQ-SF scores between women with a premenopausal and a postmenopausal RRSO., Results: Women in the premenopausal RRSO group had slightly higher UDI-6 scores compared with women in the postmenopausal RRSO group (P = 0.053), and their risk of symptomatic UI was non-significantly increased (odds ratio [OR] 2.1, 95% confidence interval [95% CI] 0.93-4.78). A premenopausal RRSO was associated with a higher risk of stress UI (OR 3.5, 95% CI 1.2-10.0) but not with urge UI. The proportions of women with a significant impact of UI on HR-QoL were similar in the premenopausal and postmenopausal RRSO groups (10.4% and 13.0%, respectively; P = 0.46)., Conclusions: More than 15 years after premenopausal RRSO, there were no significant differences in overall symptomatic UI between women with a premenopausal and those with a postmenopausal RRSO., (© 2023 John Wiley & Sons Ltd.)

Statins have been de cornerstone for the treatment of hyperlipidaemia for decades now. More recently the introduction of the PCSK9 inhibitors, inclisiran and even more recently bempedoic acid have given us new options for the treatment of hyperlipidaemia. Bempedoic acid is a prodrug which is metabolized in the liver and not in the peripheral tissues like muscles, this means that myalgia does not occur as a side effect. Its effect on the cholesterol synthesis occurs earlier in the chain of events than that of statins which work primarily via HMGcoA reductase. Other than that is has more or less the same effect as a statin. Next to cholesterol lowering effect it has a dampening effect on inflammation another important link in atherosclerosis. Bempedoic acid is cheap making it the drug of choice after statins and ezetimibe.

Background and Objective: Inclisiran is the first-in-class small interfering RNA (siRNA) proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. In clinical trials inclisiran showed effective and sustained low-density lipoprotein cholesterol (LDL-C) reduction of ± 50 %. As data in clinical setting are scarce, we aim to investigate the efficacy and safety in clinical practice., Methods: We describe a registry of consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled the reimbursement criteria in the Netherlands. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured at 3 and 9 months after initiation of inclisiran. Median change of LDL-C levels was calculated on an individual and group level., Results: We analysed 65 patients (36 women), median [25 th percentile; 75 th percentile] age of 63 [54; 68] years. Of these, 44 patients had both a 3 month and 9 month visit. At 3 months, patients who newly started inclisiran (group 1, n = 45) showed a LDL-C decrease of 38 [-49;-33] %. Patients who used statins as co-medication (n = 15) had a higher median LDL-C decrease compared to those without statin use (n=30; 45 % vs 38 %). However, patients who switched from mAbs to inclisiran (group 2, n = 20) had an increase in LDL-C of 38 [+4; +97] %. Adverse effects associated with inclisiran were mild and consisted of mild injection site reactions. Efficacy was slightly less whereas safety results were similar at 9 months., Conclusion: Our initial experience of inclisiran in a clinical setting showed less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran generally showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSK9 mAbs., (Copyright © 2023. Published by Elsevier Inc.)

Background and Aims: Despite lipid lowering therapy (LLT), reaching LDL-C targets in patients with familial hypercholesterolemia (FH) remains challenging. Our aim was to determine attainment of LDL-C target levels and reasons for not reaching these in female and male FH patients., Methods: We performed a cross-sectional study of heterozygous FH patients in five hospitals in the Netherlands and Norway. Clinical characteristics and information about LLT, lipid levels and reasons for not being on LDL-C treatment target were retrospectively collected from electronic medical records., Results: We studied 3178 FH patients (53.9% women), median age 48.0 (IQR 34.0-59.9) years. Median LDL-C before treatment and on-treatment was higher in women compared to men (6.2 (IQR 5.1-7.3) and 6.0 (IQR 4.9-7.2) mmol/l (p=0.005) and 3.0 (IQR 2.4-3.8) and 2.8 (IQR 2.3-3.5) mmol/L (p<0.001)), respectively. A minority of women (26.9%) and men (28.9%) reached LDL-C target. In patients with CVD, 17.2% of women and 25.8% of men reached LDL-C target. Women received less often high-intensity statins and ezetimibe. Most common reported reasons for not achieving the LDL-C target were insufficient effect of maximum LLT (women 17.3%, men 24.3%) and side effects (women 15.2%, men 8.6%)., Conclusions: In routine practice, only a minority of women and men with FH achieved their LDL-C treatment target. Extra efforts have to be made to provide FH patients with reliable information on the safety of statins and their long-term effects on CVD risk reduction. If statin treatment is insufficient, alternative lipid lowering therapies such as ezetimibe or PCSK9-inhibitors should be considered., Competing Interests: Declaration of competing competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: This review aims to summarize the existing research on sex differences in familial hypercholesterolemia (FH) across the lifespan., Recent Findings: From childhood onward, total- and low-density lipoprotein cholesterol (LDL-C) levels in girls are higher than those in boys with FH. By the age of 30 years, women with FH have a higher LDL-C burden than men. In adulthood, women are diagnosed later than men, receive less lipid-lowering treatment, and consequently have higher LDL-C levels. An excessive atherosclerotic cardiovascular disease risk is reported in young female compared to male FH patients. The periods of pregnancy and breastfeeding contribute to treatment loss and increased cholesterol burden. Earlier initiation of treatment, especially in girls with FH, and lifelong treatment during all life stages are important. Future research should aim to recruit both women and men, report sex-specific data, and investigate the impact of the female life course on cardiovascular outcomes. Future guidelines should include sex-specific aspects., (© 2023. The Author(s).)

Background and Aims: Proprotein convertase subtilisin/kexin 9 monoclonal antibodies (PCSK9 mAbs) reduce low-density lipoprotein (LDL-c) with a favourable safety profile. Available data from PCSK9 antibody trials suggest LDL-c reduction is lower in women compared to men. Data in real-world setting is scarce. The aim of this study was to assess sex differences in efficacy and safety of PCSK9 antibodies in clinical care., Methods: All patients starting with evolocumab or alirocumab in our lipid clinic were included in a prospective registry. We collected clinical information, including baseline and follow-up mean LDL-C levels after initiation of PCSK9 mAbs treatment. In addition, side effects and PCSK9 mAbs discontinuation were recorded., Results: We analysed 436 patients (209 women), mean age 58 ± 11 years. Women had higher baseline LDL-c levels compared to men (4.7 ± 1.6 mmol/L vs 4.1 ± 1.4 mmol/L, p < 0.01). PCSK9 mAbs resulted in less relative LDL-c reduction in women compared to men (50% vs 61% p<0.01), but equal absolute LDL-c reduction (respectively 2.3 ± 1.3 mmol/L vs 2.5 ± 1.1 mmol/L, p = 0.087). Women less often reached LDL-c target levels than men (50% vs 72%). No sex differences were observed in reporting of side effects (women 32% vs men 27% p = 0.26) or PCSK9 mAbs discontinuation (women 13% vs men 10%, p = 0.46)., Conclusions: In clinical practice, PCSK9 mAbs are less effective in reducing LDL-c levels in women compared to men and equally safe, implying the importance of sex differences in PCSK9 metabolism., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JGB received funding from Sanofi outside the submitted work for education purposes. JRVL received research grants from Novartis and Amryt. JM and KS do not have any disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Inflammatory bowel disease (IBD) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). We compared cardiovascular disease (CVD) risk factors and 10-year risk in IBD patients to the general population., Methods and Results: In this cross-sectional study, consecutive IBD patients ≥45 years were included. History of ASCVD and CVD risk factors (smoking, hypertension, overweight, hypercholesterolaemia, diabetes, and metabolic syndrome) were assessed. The Systematic COronary Risk Evaluation (SCORE2) algorithm was used to estimate 10-year CVD risk. One to four age/sex-matched controls were derived from the prospective population-based Rotterdam Study cohort. In total, 235 IBD patients were included {56% women, median age 59 years [interquartile range (IQR) 51-66]} and matched to 829 controls [56% women, median age 61 years (IQR 56-67)]. Inflammatory bowel disease patients experienced ASCVD events more often compared with matched controls [odds ratio (OR) 2.01, 95% confidence interval (CI) 1.23-3.27], specifically heart failure (OR 2.02, 95% CI 1.02-4.01) and coronary heart disease (OR 2.01, 95% CI 1.7-3.13). Inflammatory bowel disease patients showed lower odds of overweight (OR 0.48, 95% CI 0.35-0.66) and hypercholesterolaemia (OR 0.45, 95% CI 0.31-0.65) and higher odds of hypertension (OR 1.67, 95% CI 1.19-2.32), as well as higher waist circumference (+4 cm, P = 0.006) and triglyceride levels (+0.6 mmol/L, P < 0.001) as compared with controls. Mean 10-year CVD risk was 4.0% [standard deviation (SD) ±2.6] in 135 IBD patients vs. 6.0% (SD ±1.6) in 506 controls., Conclusion: The increased CVD risk in IBD is discrepant with the 10-year CVD risk estimate. Systematic COronary Risk Evaluation may underestimate CVD risk in IBD patients due to differing CVD risk profiles compared with the general population, including a lower prevalence of hypercholesterolaemia and overweight and a higher prevalence of hypertension, abdominal obesity, and hypertriglyceridaemia., Competing Interests: Conflict of interest: J.A.M.S. has nothing to declare. J.E.R.v.L. has nothing to declare. P.J.P.V. has nothing to declare. E.A. has nothing to declare. M.K. has nothing to declare. C.J.v.d.W. served as an advisory board member of Celltrion, Takeda, and Abbvie. A.C.d.V. served as an advisory board member of Jansen, Abbvie, and Takeda., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown., Objective: To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition., Methods: Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE., Results: PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41-59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29-63%; and VLDL-TG 20%, 95%CI 6.3-41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons., Conclusion: PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated., Competing Interests: Declaration of Competing Interest BEH declares no conflicts of interest ADM declares no conflict of interest MM declares no conflicts of interest FV declares no conflict of interest JRvL has received a research grant by Amryt Ad-board speaker fees have been paid to institution of ES by: Amgen, Sanofi, Esperion, Novo-Nordisk, Akcea/Ionis, Regeneron NR declares no conflict of interest LvZ declares no conflicts of interest DMB declares no conflict of interest CK declares no conflicts of interest, (Copyright © 2023. Published by Elsevier Inc.)

Objective: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO., Design: A cross-sectional study with prospective follow-up, nested in a nationwide cohort., Setting: Multicentre in the Netherlands., Population or Sample: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment., Methods: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression., Main Outcome Measures: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO., Results: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years)., Conclusions: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition., (© 2023 John Wiley & Sons Ltd.)

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide., Competing Interests: Conflict of interest Potential conflicts of interest outside the submitted work are summarized as follows. The following authors report participation in trials; receipt of fellowships, or grants for travel, research or staffing support; and/or personal honoraria for consultancy or lectures/speaker’s bureau from: Abbott (K.A.-R., M.K., K.K.R., R.D.S., L.S.T.); Abdi-Ibrahim (M.K., L.S.T.); Acasti (D.G., R.A.H.); Ache (R.D.S.); Actelion (L.S.T.); Aegerion (M.A., E.B., D.G., M.H.-S.); Akcea (M.A., E.B., A.L.C., D.G., R.A.H., K.G.P.); Alexion Pharma France (E.B.); Alfasigma (M.A.); Amarin (M.A., M.Av., A.L.C., L.M.); Amgen (M.A., M.Av., E.B., T.F., D.G., M.H.-S., R.A.H., M.K., L.M., K.G.P., F.J.R., K.K.R., R.D.S., L.S.T., G.F.W., A.W.); Amryt (M.A., M.Av., MC, M.K., L.M., J.E.R.v.L., R.D.S., A.W.); Arrowhead (R.A.H., G.F.W.); Ascent Development (M.H.-S.); Astellas (M.H.-S.); AstraZeneca (A.L.C., D.G., M.K., K.K.R., R.D.S., G.F.W.); Bayer (M.K., L.S.T.); Biolab (R.D.S.); Boehringer Ingelheim (D.G., M.H.-S., K.K.R.); Cerenis (D.G.); CRISPR Therapeutics (K.K.R.); Daiichi-Sankyo (M.Av., E.B., A.L.C., M.H.-S., M.K., L.M., K.G.P., K.K.R., L.S.T.); Dalcor Pharma (D.G.); Danone (E.B.); Deva (M.K.); Esperion (A.L.C., D.G., K.K.R., R.D.S., G.F.W.); Gemphire (D.G.); Genfit (E.B.); Genzyme (A.L.C.); Getz Pharma (R.D.S.); GlaxoSmithKline (D.G.); HDL Therapeutics (D.G.); HLS Therapeutics (R.A.H.); Ionis Pharmaceuticals (E.B., A.L.C., D.G., M.K.); Ironwood (D.G.); Jansen (M.K.); Kowa (A.L.C., D.G., M.H.-S., K.K.R., R.D.S.); LIB Therapeutics (R.A.H., M.K., F.J.R.); Libbs (R.D.S.); Eli Lilly/Lilly (A.L.C., D.G., M.K., K.K.R.); Medpace (M.H.-S., M.K.); Menarini (A.L.C.); Merck (A.L.C., M.K., R.D.S., L.S.T.); MSD (E.B., M.H.-S., K.G.P.); Mylan (M.A., E.B., A.L.C.); Nestlé (D.G.); New Amsterdam (K.K.R.); Novartis (K.A.-R., M.A., M.Av., E.B., A.L.C., T.F., D.G., M.H.-S., R.A.H., M.K., L.M., K.G.P., K.K.R., J.E.R.v.L., F.J.R., R.D.S., L.S.T., G.F.W., A.W.); NovoNordisk (M.K., K.K.R., R.D.S., L.S.T.); Pfizer (M.A., A.L.C., D.G., R.A.H., M.K., K.K.R., R.D.S., L.S.T., G.F.W.); PTC (R.D.S.); Recordati (A.L.C., M.H.-S., M.K., L.S.T.); Regeneron (M.A., A.L.C., MC, D.G., R.A.H., K.G.P., F.J.R., K.K.R., A.W.); REGENXBIO (M.C.); Resverlogix (K.K.R.); Sandoz (A.L.C.); Sanofi (K.A.-R., M.A., A.L.C., T.F., D.G., M.H.-S., R.A.H., M.K., L.M., K.G.P., F.J.R., K.K.R., R.D.S., L.S.T., G.F.W.); Sanofi/Genzyme (M.Av.); Sanofi-Regeneron (E.B.); SCIBE Therapeutics (K.K.R.); Servier (E.B., L.M., L.S.T.); Sigma Tau (A.L.C.); Silence Therapeutics (E.B., K.G.P., K.K.R., G.F.W., A.W.); Sobi Takeda (M.Av.); The Medicine Company (D.G., M.H.-S.); Ultragenyx (R.A.H.); UniQure (D.G.); and Vaxxinity (K.K.R.). ESG Stroes reports honoraria for lectures/advisory board R.D.S. paid to his institution from Amarin, Amgen, Daiichi-Sankyo, Esperion, IONIS/Akcea, Novartis, Novo-Nordisk, and Sanofi-Regeneron. Manuscripts have been published in collaboration with non-academic co-authors by L.S.T. (Fitbit), and G.F.W. (Amgen). T.F. is supported by the project National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104)—Funded by the European Union—Next Generation EU. D.G. is supported by Canadian Cardiovascular Research Network and the Institut de cardiologie de Montréal. Equity interests are reported by K.K.R. (Cargene Therapeutics and Pemi31 Therapeutics) and J.K.S. (AstraZeneca and GSK). K.K.R. is President of the European Atherosclerosis Society. L.S.T. is Past-President of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal. L.C.H. has no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Dyslipidemia may be an important modifiable risk factor contributing to the increased cardiovascular risk in inflammatory bowel disease (IBD). The lipid metabolism is subject to both systemic inflammation and drug therapy; however, it is unclear if this effect is drug-class dependent. Our aim was to assess lipid changes after IBD induction therapy and evaluate associated factors with a particular focus on drug class and disease activity., Methods: In this prospective study, consecutive IBD patients starting systemic therapy (eg, corticosteroids, thiopurines, methotrexate, anti-TNF-α agents, vedolizumab, ustekinumab, and tofacitinib) were included. Primary outcomes were changes in total cholesterol, high density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglycerides at week 10., Results: One hundred ninety-eight IBD patients (107 women [54%], median age 36 years; interquartile range [IQR], 27-47) were included: 137 Crohn's disease (67%), 61 ulcerative colitis (29%), and 8 IBD-unclassified (4%). Median C-reactive protein and fecal calprotectin at baseline were 5.1 mg/L (IQR, 1.6-12.0) and 1040 ug/g (IQR, 383-1800), respectively. Relative increases in total cholesterol, HDL-c, and LDL-c were significant after prednisone (+26%, +31%, +12%) and tofacitinib therapy (+20%, +25%, +26%), respectively. Results remained after adjusting for concomitant corticosteroids, cholestyramine, and PSC diagnosis. Changes in clinical scores were inversely correlated with total cholesterol changes (R -186, P = .014), as was CRP with total cholesterol and LDL-c (R -0.292 and R -0.259, P < .001). No correlation was found with FCP. Lipid changes remained after adjusting for age and CRP., Conclusions: Prednisone and tofacitinib induction therapy significantly increase serum lipid levels, whereas no changes were observed in other drug classes. The observations seem drug-specific inasmuch as adjustment for systemic inflammation did not alter the results., (© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure 1 to 3 years after a premenopausal oophorectomy. However, the long-term effects of premenopausal oophorectomy on sexual functioning are unknown., Objective: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group) or after the age of 54 years (postmenopausal group). Subgroup analyses were performed in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy., Study Design: Between 2018 and 2021, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses, adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes or no), and body image., Results: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P<.001). The mean age at questionnaire completion was 62.7 years in the premenopausal group, compared with 67.0 years in the postmenopausal group (P<.001). Compared with 48.9% of women in the postmenopausal group, 47.4% of women in the premenopausal group were still sexually active (P=.80). Current sexual pleasure scores were the same for women in the premenopausal group and women in the postmenopausal group (mean pleasure score, 8.6; P=.99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% vs 20.9%; P=.04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse than postmenopausal risk-reducing salpingo-oophorectomy (odds ratio, 3.1; 95% confidence interval, 1.04-9.4). Moreover, after premenopausal risk-reducing salpingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio, 2.6; 95% confidence interval, 1.4-4.7). Women with a risk-reducing salpingo-oophorectomy before the age of 41 years reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45 years., Conclusion: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable with the proportion of sexually active women with a postmenopausal risk-reducing salpingo-oophorectomy. However, after a premenopausal risk-reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To compare LDL-C concentrations using the Friedewald formula, the Martin-Hopkins formula, a direct assay and polyacrylamide gradient gel electrophoresis (PGGE) to the reference standard density gradient ultracentrifugation in patients with Familial Dysbetalipoproteinemia (FD) patients. We also compared non-HDL-cholesterol concentrations by two methods., Methods: For this study data from 28 patients with genetically confirmed FD from the placebo arm of the EVOLVE-FD trial were used. Four different methods for determining LDL-C were compared with ultracentrifugation. Non-HDL-C was measured with standard assays and compared to ultracentrifugation. Correlation coefficients and Bland-Altman plots were used to compare the methods., Results: Mean age of the 28 FD patients was 62 ± 9 years, 43 % were female and 93 % had an ɛ2ɛ2 genotype. LDL-C determined by Friedewald (R 2 = 0.62, p <0.01), Martin-Hopkins (R 2 = 0.50, p = 0.01) and the direct assay (R 2 = 0.41, p = 0.03) correlated with density gradient ultracentrifugation. However, Bland-Altman plots showed considerable over- or underestimation by the four methods compared to ultracentrifugation. Non-HDL-C showed good correlation and agreement., Conclusion: In patients with FD, all four methods investigated over- or underestimated LDL-C concentrations compared with ultracentrifugation. In contrast, standard non-HDL-C assays performed well, emphasizing the use of non-HDL-C in patients with FD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BEH declares no conflicts of interest. CK declares no conflicts of interest. JRvL has received a research grant by Amryt. Ad-board speaker fees have been paid to institution of ES by: Amgen, Sanofi, Esperion, Novo-Nordisk, Akcea/Ionis, Regeneron. NR declares no conflict of interest. MM declares no conflicts of interest LvZ declares no conflicts of interest. DMB declares no conflict of interest. ADM declares no conflict of interest. FV declares no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options., Objectives: To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD., Methods: A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins., Results: In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load., Conclusions: Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients., (Copyright © 2022. Published by Elsevier Inc.)

Background and Aims: Availability of age- and sex-specific reference values for sex steroids and sex steroid-binding globulin (SHBG) levels allows for appropriate interpretation of research findings and their clinical applications. We report the sex-specific distribution and reference levels of sex steroids, including total estradiol, total testosterone and (calculated) free androgen index (cFAI), SHBG and other androgens dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione across age., Methods: Using data from 3291 participants from the prospective population-based Rotterdam Study (2006-2008), we visualised the distribution of sex steroids and SHBG levels by calculating and depicting the 5th, 25th, 50th, 75th and 95th percentiles per year and per age-year across 5-year age bands to provide reference value ranges in men and women. Total estradiol and SHBG were measured using automated immunoassay and androgens using liquid chromatography-mass spectrometry (LC-MS/MS)., Result: Mean age was 56.8 (range 45.6-79.9) years in men and 56.9 (range 45.7-79.9) years in women. Amongst men, total estradiol and SHBG showed an increasing trend from 45 years onwards. In women, total estradiol and SHBG showed a decreasing trend from 45 years until the age of 60. From 60 years onwards, SHBG showed an increasing trend. For total testosterone, a clear declining trend was observed amongst men but not women. Other androgens showed a similar decreasing trend in both sexes from 45 years onwards., Discussion and Conclusion: Our study underlines sex-specific trends in sex steroids and SHBG levels with ageing. This warrants taking into account sex- and age-specific reference values for sex steroids and SHBG when investigating their impact on health outcomes to prevent controversial results and allow for their appropriate clinical application., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Competing Interests: Conflict of interest: J.A.M.S., P.J.P.V., M.V., and M.K. have nothing to declare. J.E.R.v.L. received an investigator-initiated grant by Amryt. M.B.A.v.D. reports grants and has served on the advisory board or as a speaker for Novartis and Janssen-Cilag. He has also has served on the advisory board or as a speaker for Abbvie, Leopharma, BMS, Celgene, Lilly, MSD, Pfizer, and Sanofi-Genzyme outside the submitted work. C.J.v.d.W. served as an advisory board member of Celltrion, Takeda, and Abbvie, and A.C.d.V. served as an advisory board member of Jansen, Abbvie, and Takeda.

Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol-enriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow-up, and family counseling., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Importance: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with different epidemiological and pathophysiological processes for women vs men and a poorer prognosis for women. Further investigation of sex-specific risk factors associated with AF development in women is warranted., Objective: To investigate the linear and potential nonlinear associations between sex-specific risk factors and the risk of new-onset AF in women., Design, Setting, and Participants: This population-based cohort study obtained data from the 2006 to 2010 UK Biobank study, a cohort of more than 500 000 participants aged 40 to 69 years. Participants were women without AF and history of hysterectomy and/or bilateral oophorectomy at baseline. Median follow-up period for AF onset was 11.6 years, and follow-up ended on October 3, 2020., Exposures: Self-reported, sex-specific risk factors, including age at menarche, history of irregular menstrual cycle, menopause status, age at menopause, years after menopause, age at first live birth, years after last birth, history of spontaneous miscarriages, history of stillbirths, number of live births, and total reproductive years., Main Outcomes and Measures: The primary outcome was new-onset AF, which was defined by the use of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code I48., Results: A total of 235 191 women (mean [SD] age, 55.7 [8.1] years) were included in the present study. During follow-up, 4629 (2.0%) women experienced new-onset AF. In multivariable-adjusted models, history of irregular menstrual cycle was associated with higher AF risk (hazard ratio [HR], 1.34; 95% CI, 1.01-1.79). Both early menarche (age 7-11 years; HR, 1.10 [95% CI, 1.00-1.21]) and late menarche (age 13-18 years; HR, 1.08 [95% CI, 1.00-1.17]) were associated with AF incidence. Early menopause (age 35-44 years; HR, 1.24 [95% CI, 1.10-1.39]) and delayed menopause (age ≥60 years; HR, 1.34 [95% CI, 1.10-1.78]) were associated with higher risk of AF. Compared with women with 1 to 2 live births, those with 0 live births (HR, 1.13; 95% CI, 1.04-1.24) or 7 or more live births (HR, 1.67; 95% CI, 1.03-2.70) both had significantly higher AF risk., Conclusions and Relevance: Results of this study suggest that irregular menstrual cycles, nulliparity, and multiparity were associated with higher risk of new-onset AF among women. The results highlight the importance of taking into account the reproductive history of women in devising screening strategies for AF prevention.

Background: Maternal lipid levels in early pregnancy are associated with maternal health and foetal growth. It is however unclear if maternal lipids in early pregnancy can be used to predict childhood lipid levels. The aim of this study is to assess the association between maternal and offspring childhood lipid levels, and to investigate the influence of maternal BMI and diet on these associations., Methods: This study included 2692 women participating in the Generation R study, an ongoing population-based prospective cohort study from early life onwards. Women with an expected delivery date between 2002 and 2006 living in Rotterdam, the Netherlands were included. Total cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL-c) were measured in early pregnancy (median 13.2 weeks [90% range 10.6; 17.1]). Low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated. Corresponding lipid measurements were determined in 2692 children at the age of 6 (median 6.0 years [90% range 5.7; 7.5]) and 1673 children 10 years (median 9.7 years [90% range 9.5; 10.3]). Multivariate linear regression analysis was used to examine the association between maternal lipid levels in early pregnancy and the corresponding childhood lipid measurements at the ages of 6 and 10 years while adjusting for confounders., Results: Maternal lipid levels in early pregnancy are positively associated with corresponding childhood lipid levels 6 and 10 years after pregnancy, independent of maternal body mass index and diet., Conclusions: Maternal lipid levels in early pregnancy may provide an insight to the lipid profile of children years later. Gestational lipid levels may therefore be used as an early predictor of children's long-term health. Monitoring of these gestational lipid levels may give a window-of-opportunity to start early interventions to decrease offspring's lipid levels and possibly diminish their cardiovascular risk later in life. Future studies are warranted to investigate the genetic contribution on maternal lipid levels in pregnancy and lipid levels of their offspring years later., (© 2022. The Author(s).)

Background and Aims: Homozygous familial hypercholesterolemia (HoFH) is characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels leading to extremely premature atherosclerotic cardiovascular disease. Therefore, healthcare professionals consider HoFH to have major impact on patients' life. Remarkably, little is known on how patients deal with their condition. The aim of this study is to investigate how Dutch patients experience and cope with HoFH in daily life., Methods: Adult patients with genetically confirmed HoFH, treated at the 3 specialized HoFH-centers in the Netherlands, were interviewed in-depth. Interview transcripts were analyzed according to grounded theory. Health-related quality of life (QoL) and coping were measured with the EuroQol (EQ)-5D-5L questionnaire and the Threatening Medical Situations Inventory (TMSI), respectively., Results: 20 Dutch HoFH patients were interviewed: 50% women, median age 38 years, 60% with cardiovascular disease, 10% on apheresis. Coding of the transcripts resulted in a conceptual model, with disease perception as the central theme. Individual TMSI-results corresponded to the interviews, with most patients showing both monitoring (information-seeking behavior) and blunting (distractive strategies) coping styles. The median EQ-5D-5L health utility score (0.839) was only 5% below the Dutch population (0.887). Transient anxiety was reported when confronted with the consequences of HoFH in daily life. Patients reported high confidence in treatment by a dedicated HoFH center, which helped them cope with their disease., Conclusions: Dutch HoFH patients use a variety of effective coping mechanisms in such a way that their subjective QoL is only slightly affected. Healthcare professionals can use this knowledge to tailor their care to the specific needs of these patients., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lipids are crucial for fetal growth and development. Maternal lipid concentrations are associated with fetal growth in the second and third trimester of pregnancy and with birth outcomes. However, it is unknown if this association starts early in pregnancy or arises later during fetal development. The aim of this study was to investigate the association between the maternal lipid profile in early pregnancy and embryonic size., Methods: We included 1474 women from the Generation R Study, a population based prospective birth cohort. Both embryonic size and the maternal lipid profile were measured between 10 weeks + 1 day and 13 weeks + 6 days gestational age. The maternal lipid profile was defined as total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), remnant cholesterol, non-high-density (non-HDL-c) lipoprotein cholesterol concentrations and the triglycerides/high-density lipoprotein (TG/HDL-c) ratio. Additionally, maternal glucose concentrations were assessed. Embryonic size was assessed using crown-rump length (CRL) measurements. Associations were studied with linear regression models, adjusted for confounding factors: maternal age, pre-pregnancy body mass index (BMI), parity, educational level, ethnicity, smoking and folic acid supplement use., Results: Triglycerides and remnant cholesterol concentrations are positively associated with embryonic size (fully adjusted models, 0.17 SDS CRL: 95% CI 0.03; 0.30, and 0.17 SDS: 95% CI 0.04; 0.31 per 1 MoM increase, respectively). These associations were not present in women with normal weight (triglycerides and remnant cholesterol: fully adjusted model, 0.44 SDS: 95% CI 0.15; 0.72). Associations between maternal lipid concentrations and embryonic size were not attenuated after adjustment for glucose concentrations. Total cholesterol, HDL-c, LDL-c, non-HDL-c concentrations and the TG/HDL-c ratio were not associated with embryonic size., Conclusions: Higher triglycerides and remnant cholesterol concentrations in early pregnancy are associated with increased embryonic size, most notably in overweight women., Trial Registration: The study protocol has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre (Erasmus MC), Rotterdam (MEC-2007-413). Written informed consent was obtained from all participants., (© 2022. The Author(s).)

Background: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia., Methods: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT 4 ), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585., Findings: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT 4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT 4 concentrations were not associated with the outcomes measured., Interpretation: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies., Funding: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research., Competing Interests: Declaration of interests SB declares consulting fees from Sonic Healthcare. PT reports a travel grant from Society for Endocrinology (leadership development award). EO reports grants from the National Institutes of Health. ENG received speaker's fees and payment for expert testimony from Merck and consulting fees from Brunel Rus. TGMV reports grants from the Netherlands Organization for Health Research and Development. EKA reports consultancy with Roche Diagnostics. LC received travel support by Pfizer. CD reports grants from the Chief Scientist Office (Scotland) and the British Heart Foundation. JERvL declares grant or contract support from the Dutch Heart Foundation and Amryt. SMN has received consultancy, speakers' fees, or travel support from Access Fertility, Beckman Coulter, Ferring Pharmaceuticals, Merck, Modern Fertility, Roche Diagnostics, and The Fertility Partnership. SMN also reports payments for medical–legal work and investment in The Fertility Partnership. TIMK reports lectureship fees from Berlin-Chemie, Goodlife Healthcare, Institut Biochimique SA, Merck, and Quidel. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Our purpose was to perform a systematic review to assess the prevalence of microvascular angina (MVA) among patients with stable symptoms in the absence of obstructive coronary artery disease (CAD). We performed a systematic review of the literature to group the prevalence of MVA, based on diagnostic pathways and modalities. We defined MVA using three definitions: (i) suspected MVA using non-invasive ischaemia tests; proportion of patients with non-obstructive CAD among patients with symptoms and a positive non-invasive ischaemia test result, (ii) suspected MVA using specific modalities for MVA; proportion of patients with evidence of impaired microvascular function among patients with symptoms and non-obstructive CAD, and (iii) definitive MVA; proportion of patients with positive ischaemia test results among patients with an objectified impaired microvascular dysfunction. We further examined the ratio of women-to-men for the different groups. Of the 4547 abstracts, 20 studies reported data on MVA prevalence. The median prevalence was 43% for suspected MVA using non-invasive ischaemia test, 28% for suspected MVA using specific modalities for MVA, and 30% for definitive MVA. Overall, more women were included in the studies reporting sex-specific data. The women-to-men ratio for included participants was 1.29. However, the average women-to-men ratio for the MVA cases was 2.50. In patients with stable symptoms of ischaemia in the absence of CAD, the prevalences of suspected and definitive MVA are substantial. The results of this study should warrant cardiologists to support, promote and facilitate the comprehensive evaluation of the coronary microcirculation for all patients with symptoms and non-obstructive CAD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Efficacy tests of physical activity interventions indicate that many have limited or short-term efficacy, principally because they do not sufficiently build on theory-based processes that determine behaviour. The current study aims to address this limitation., Methods and Analysis: The efficacy of the 8-week intervention will be tested using a three-condition randomised controlled trial delivered through an app, in women with a prior hypertensive pregnancy disorder. The intervention is based on the integrated behaviour change model, which outlines the motivational, volitional and automatic processes that lead to physical activity. The mechanisms by which the behaviour change techniques lead to physical activity will be tested.Following stratification on baseline factors, participants will be randomly allocated in-app to one of three conditions (1:1:1). The information condition will receive information, replicating usual care. Additionally to what the information condition receives, the motivation condition will receive content targeting motivational processes. Additionally to what the motivation condition receives, the action condition will receive content targeting volitional and automatic processes.The primary outcome is weekly minutes of moderate-to-vigorous physical activity, as measured by an activity tracker (Fitbit Inspire 2). Secondary outcomes include weekly average of Fitbit-measured daily resting heart rate, and self-reported body mass index, waist-hip ratio, cardiorespiratory fitness and subjective well-being. Tertiary outcomes include self-reported variables representing motivational, volitional, and automatic processes. Outcome measures will be assessed at baseline, immediately post-intervention, and at 3 and 12 months post-intervention. Physical activity will also be investigated at intervention midpoint. Efficacy will be determined by available case analysis. A process evaluation will be performed based on programme fidelity and acceptability measures., Ethics and Dissemination: The Medical Ethics Committee of the Erasmus MC has approved this study (MEC-2020-0981). Results will be published in peer reviewed scientific journals and presented at scientific conferences., Trial Registration Number: Netherlands trial register, NL9329., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4-week run-in phase in which all patients were treated with the perindopril-based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1-5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55-65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55-65: 2.8 mmHg [95% CI = 1.8-3.7], p < 0.001, >65: 3.7 mmHg [95% CI = 2.7-4.7], p < 0.001). A trend of less blood pressure reduction was seen with ageing in both men and women (p < 0.001). To conclude, we observed that in both women and men the perindopril leads to less SBP reduction with increasing age, whereas the DBP reduction increases with age. More research is needed to determine whether it would be beneficial to use age-adjusted perindopril dosages., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement., Methods: We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged ≥ 21 years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature., Results: In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n = 4) had a history of cataract. The majority, 84% (n = 16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene., Conclusions: This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential., (© 2021 The Association for the Publication of the Journal of Internal Medicine.)

Background: Increase in lipid levels associated with the treatment of inflammatory bowel disease (IBD) has previously been reported. However, it is unknown if this effect is similar for all IBD drug classes., Aim: To precisely assess the effect of different IBD drug classes on lipid profiles METHODS: We performed a systematic literature search of randomised controlled trials and observational cohort studies that assessed lipid levels before and after induction (≤10 weeks) and maintenance (>10 weeks) of IBD treatment. Data of 11 studies (1663 patients) were pooled using random effects models. The influence of patient and disease characteristics on treatment effects on total cholesterol levels was analysed in 6 studies (1211 patients) for which individual data were available, using linear mixed models., Results: A statistically significant increase in total cholesterol was observed after induction treatment with corticosteroids (+1.19 mmol/L, 95% confidence interval [CI 95 ] +0.52 to +2.59), and tofacitinib (+0.66 mmol/L, CI 95 +0.42 to +0.79), but not after anti-TNFα treatment (-0.11 mmol/L, CI 95 -0.26 to +0.36 mmol/L). Similar differences were observed after maintenance treatment. Treatment effects were significantly related to age, but not with other factors. Lipid changes were inversely correlated with but not modified by CRP changes., Conclusions: Increase in total cholesterol levels was strongest for corticosteroids followed by tofacitinib but was not observed for anti-TNFα agents. Whether total cholesterol change associated with IBD treatment has an effect on cardiovascular risk requires further study., (© 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Aims: Prior studies have reported inconsistent results for the association between sex hormone-binding globulin (SHBG) and cardiovascular disease among men and women. Although it is suggested that SHBG levels change with aging, the exact trend of SHBG across age and cardiovascular risk and the underlying mechanisms of these changes remain to be elucidated., Methods: Using data of 3264 men and women from a large population-based cohort study, we first visualized the distribution of serum SHBG levels across age. Second, we computed a cardiovascular risk factor sum score and investigated the mean SHBG levels across categories of the risk factor sum score and stratified per age-category. Next, linear regression models were used to investigate the associations between serum SHBG levels and age and potential regulators of SHBG, including body mass index (BMI), fasting insulin, sex steroids, thyroxine, and triglycerides., Results: Among men, a linear increase in SHBG levels with age and among women a U-shaped pattern was observed. Participants with larger number of cardiovascular risk factors had lower SHBG levels. When stratified by age, older participants had higher SHBG levels. A multivariate model including total testosterone and triglyceride levels in men and total testosterone, triglycerides, BMI, and fasting insulin in women explained, respectively, 46.2% and 31.8% of the variance in SHBG levels., Conclusion: We observed a clear sex-specific pattern for SHBG levels with age. Our findings highlight the importance of taking into account the age-related changes in SHBG levels to avoid controversial results in the assessment of the cardiovascular risk associated with SHBG., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)