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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: 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.)

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.)

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: 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 and Aims: Lipoprotein(a) is an independent risk factor for cardiovascular disease and recurrent ischemic stroke. Lipoprotein(a) levels are known to be associated with carotid artery stenosis, but the relation of lipoprotein(a) levels to carotid atherosclerotic plaque composition and morphology is less known. We hypothesize that higher lipoprotein(a) levels and lipoprotein(a)-related SNPs are associated with a more vulnerable carotid plaque and that this effect is sex-specific., Methods: In 182 patients of the Plaque At RISK study we determined lipoprotein(a) concentrations, apo(a) KIV-2 repeats and LPA SNPs. Imaging characteristics of carotid atherosclerosis were determined by MDCTA (n = 161) and/or MRI (n = 171). Regressions analyses were used to investigate sex-stratified associations between lipoprotein(a) levels, apo(a) KIV-2 repeats, and LPA SNPs and imaging characteristics., Results: Lipoprotein(a) was associated with presence of lipid-rich necrotic core (LRNC) (aOR = 1.07, 95% CI: 1.00; 1.15), thin-or-ruptured fibrous cap (TRFC) (aOR = 1.07, 95% CI: 1.01; 1.14), and degree of stenosis (β = 0.44, 95% CI: 0.00; 0.88). In women, lipoprotein(a) was associated with presence of intraplaque hemorrhage (IPH) (aOR = 1.25, 95% CI: 1.06; 1.61). In men, lipoprotein(a) was associated with degree of stenosis (β = 0.58, 95% CI: 0.04; 1.12). Rs10455872 was significantly associated with increased calcification volume (β = 1.07, 95% CI: 0.25; 1.89) and absence of plaque ulceration (aOR = 0.25, 95% CI: 0.04; 0.93). T3888P was associated with absence of LRNC (aOR = 0.36, 95% CI: 0.16; 0.78) and smaller maximum vessel wall area (β = -10.24, 95%CI: -19.03; -1.44)., Conclusions: In patients with symptomatic carotid artery stenosis, increased lipoprotein(a) levels were associated with degree of stenosis, and IPH, LRNC, and TRFC, known as vulnerable plaque characteristics, in the carotid artery. T3888P was associated with lower LRNC prevalence and smaller maximum vessel wall area. Further research in larger study populations is needed to confirm these results., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: There are indications for tracking of circulating total cholesterol concentration (TC) from childhood to later in life. An increased lifelong TC exposure increases the risk of developing atherosclerosis, however little is known about the determinants of TC early in life. We aimed to describe TC in Norwegian offspring aged 6, 12 and 24 months, and to explore if maternal TC, breastfeeding and offspring diet are associated with offspring TC., Methods: In this cross-sectional study, mothers of offspring aged 6 (n = 629), 12 (n = 258) and 24 (n = 263) months completed a questionnaire of the offspring's diet and took home-based dried blood spot samples from themselves and their offspring. The mothers and offspring participating at age 12 months also participated at age 6 months of the offspring., Results: Offspring TC showed a wide range in all three age groups. Twenty one percent of the offspring had TC ≥ 5.1 mmol/l. There was significant tracking of offspring TC from 6 to 12 months of age (r = 0.42, p < 0.001). Maternal and offspring TC was positively associated in all age groups (0.20 ≤ β ≤ 0.40, p < 0.001 for all). Breastfeeding was positively associated with offspring TC at ages 6 and 12 months (0.05 ≤ β ≤ 0.26, 0.001 ≤ p ≤ 0.03), but not at age 24 months., Conclusions: The wide range in TC and probable tracking of TC from infancy to later in life highlights the importance of early identification of children with elevated TC who can benefit from preventive measures., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Severe preeclampsia increases lifetime-risk for cardiovascular disease (CVD). It remains unclear when this risk translates to subclinical atherosclerosis and whether this is related to cardiovascular health (CVH) after pregnancy. Our aims were (1) to determine CVH after severe preeclampsia, (2) to relate CVH to carotid intima-media thickness (CIMT), as a marker of subclinical atherosclerosis and (3) to relate CVH to chronological and vascular age., Methods: A prospective cohort study was performed in women with previous severe pre-eclampsia. CVH, proposed by the American Heart Association, was assessed one year after pregnancy. The CVH score (range 0-14) includes seven metrics (blood pressure, total-cholesterol, glucose, smoking, physical activity, diet and body mass index [BMI]), each weighted as poor (0), intermediate (1) or ideal (2). Vascular age was determined by CIMT. We related CVH to delta age (chronological age - vascular age)., Results: In 244 women, the median CVH score was 10 (90% range 7.0, 13.0). Low CVH (<10) was associated with a larger CIMT than high CVH (≥12) (median 626.3 μm vs. 567.0 μm, respectively). Higher CVH was also associated with a lower vascular age (-2.0 years, 95%CI -3.3, -0.60). Women with low CVH had a larger delta age (22.5 years [90% range -3.9, 49.6) than women with high CVH (16.5 years [90% range -11.9, 43.3)., Conclusions: CVH is inversely related to subclinical atherosclerosis and to vascular age one year after severe preeclampsia. Especially low CVH is associated with a large difference between chronological age and vascular age. CVH counseling might provide the opportunity for timely cardiovascular prevention., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia (FH) is the most common hereditary lipid disorder requiring life-long treatment to prevent cardiovascular disease. A recent concept in healthcare is not only to focus on outcomes defined by healthcare professionals, but also take Patient-Reported Outcomes Measures (PROMs) into account. The aim of this study is (1) to describe the development and first results of a health-related outcomes set including PROMs for FH patients and (2) investigate the influence of patient knowledge on health-related outcomes., Methods: A multidisciplinary group of FH experts, in collaboration with a sounding board of FH patients (n = 166), developed a health-related outcomes set containing the domains: medication adherence (MARS-5), smoking, self-efficacy and self-management, quality of life (QOL) (EQ-5D-5L), reported adverse drug reactions, lipid outcome measures, and FH and cardiovascular risk factor knowledge. Knowledge scores ranged from 0 to 10. Two groups were created: Insufficient knowledge (INSUF) (<7.5), and Sufficient knowledge (SUF) (≥7.5)., Results: The response rate of the questionnaires was 81.4% (n = 429), implicating acceptance of PROMs. In general, FH patients showed good knowledge, high QOL and were adherent to medication. However, the INSUF group had higher triglycerides levels (1.0 vs 0.9, p < 0.05), lower QOL (0.89 [0.79, 1.00] vs 0.89 [0.85, 1.00], p < 0.05), were more often smokers (14% vs 7%, p < 0.05) and reported more adverse drug reactions (62% vs. 49%, p < 0.05)., Conclusions: A health-related outcomes set for FH patients, including PROMs, has been developed, which shows that insufficient knowledge of FH is negatively related to health outcomes. Improving patients' knowledge of FH may lead to better health., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: An atherogenic lipid profile is a risk factor for the initiation and progression of atherosclerosis. This ultimately leads to cardiovascular disease. Women with a history of hypertensive disorders of pregnancy are at increased risk of sustained hypertension and cardiovascular disease later in life. Currently it is unclear whether dyslipidemia during pregnancy contributes to these risks., Objective: The objective of the study was to determine the associations between early pregnancy maternal lipid profile, hypertensive disorders of pregnancy, and blood pressure during and years after pregnancy., Study Design: We included 5690 women from the Generation R Study, an ongoing population-based prospective birth cohort. Two hundred eighteen women (3.8%) developed gestational hypertension and 139 (2.4%) preeclampsia. A maternal lipid profile consisting of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, remnant cholesterol, and non-high-density lipoprotein cholesterol was determined in early pregnancy (median, 13.4 weeks of gestation). Systolic and diastolic blood pressures were measured in early, mid-, and late pregnancy and 6 and 9 years after pregnancy., Results: Triglycerides and remnant cholesterol in early pregnancy were positively associated with preeclampsia. Maternal lipid levels in early pregnancy were not associated with gestational hypertension. Total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and especially triglycerides and remnant cholesterol were positively associated with blood pressure in pregnancy and 6 and 9 years after pregnancy. Triglycerides and remnant cholesterol are positively associated with sustained hypertension 6 and 9 years after pregnancy., Conclusion: An atherogenic lipid profile in early pregnancy reflecting impaired triglyceride-rich lipoprotein metabolism is independently associated with preeclampsia and blood pressure throughout pregnancy but also with sustained hypertension long term postpartum. Lipid levels in early pregnancy may help to identify women at risk for future hypertension and perhaps also women at risk for future cardiovascular disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: A large proportion of patients with heterozygous familial hypercholesterolemia (heFH) do not reach low-density lipoprotein cholesterol (LDL-c) levels advocated by international guidelines (<70 mg/dL or <100 mg/dL)., Objective: We set out to model which proportion of patients reach targets using conventional and novel therapies., Methods: We performed a cross-sectional analysis in a large cohort of genetically identified heFH patients and calculated the proportion reaching treatment targets in four scenarios: (1) after 50% LDL-c reduction (representing maximal dose statin); (2) after 70% LDL-c reduction (maximal dose statin + ezetimibe); (3) additional 40% LDL-c reduction representing cholesteryl ester transfer protein inhibitor (CETPi); and (4) 60% LDL-c reduction (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9i]), on top of scenario 2. We applied 100% adherence rates and literature-based adherence rates from 62% to 80%., Results: We included 1,059 heFH patients with and 9,420 heFH patients without coronary heart disease (CHD). With maximal dose statin, 8.3% and 48.1% of patients with and without CHD would reach their recommended LDL-c targets, respectively. This increases to 54.3% and 93.2% when ezetimibe is added. Addition of CETPi increases these numbers to 95.7% and 99.7%, whereas adding PCSK9i would result in 99.8% and 100% goal attainment. Using literature-based adherence rates, these numbers decrease to 3.8% and 27.3% for maximal dose statin, 5.8% and 38.9% combined with ezetimibe, 31.4% and 81.2% when adding CETPi, and 40.3% and 87.1% for addition of PCSK9i., Conclusions: Less than 10% with and 50% of heFH patients without CHD would reach treatment targets with maximal dose statin, but this substantially increases on addition of ezetimibe, CETPi, or PCSK9i. However, considering recently published adherence data, this might be lower in real life, especially in heFH patients with CHD., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Gestational hypertensive disorders (GHDs), including gestational hypertension and preeclampsia, are associated with an increased risk of cardiovascular disease in later life, possibly through an atherogenic lipid profile., Objective: The objective of this study is to assess if women with a previous GHD have a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy., Methods: In a population-based prospective cohort study, we included 4933 women during pregnancy, including 302 women with a GHD. Six years after pregnancy, we determined maternal lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein[a], and apolipoprotein B) and glucose levels., Results: Women with a previous GHD had a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy. These atherogenic lipid profiles were a result of higher levels of triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B and lower levels of high-density lipoprotein cholesterol. Differences in lipid profile between women with a previous GHD and women with a previous normotensive pregnancy were attenuated after adjustment for prepregnancy body mass index. Between women from both groups, no differences were observed in total cholesterol, lipoprotein[a], and glucose levels., Conclusion: Women with a previous GHD show a more atherogenic lipid profile 6 years after pregnancy than women with a previous normotensive pregnancy. The increased risk of cardiovascular disease after a GHD might result from an atherogenic lipid profile after pregnancy, primarily driven by prepregnancy body mass index., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Despite lipid-lowering therapy (LLT), some patients with familial hypercholesterolemia (FH) still develop cardiovascular events. Data about the quantification and factors contributing to this residual risk are lacking., Objective: This study assessed how many patients with FH developed a cardiovascular event despite LLT and which factors contribute to this risk., Methods: We performed a time-dependent analysis in a cohort of consecutive heterozygous FH patients using stable LLT to evaluate first and subsequent cardiovascular events. Univariate and multivariate regression analyses were conducted to study the association between clinical characteristics and cardiovascular events., Results: Of 821 FH patients (median age 47.4 [interquartile range (IQR) 35.3-58.3] years) treated with LLT for a median period of 9.5 (IQR 5.1-14.2) years, 102 patients (12%) developed cardiovascular disease (CVD) in 8538 statin-treated person-years. Patients who developed a cardiovascular event had a median age of 52.0 (IQR 43.8-59.3) years. These patients more often had previous cardiovascular events (32% vs 9%, P < .001), a family history of premature CVD (58% vs 40%, P = .001), hypertension (70% vs 22%, P < .001), higher on-treatment low-density lipoprotein cholesterol (162 ± 54 vs 135 ± 58 mg/dL, P < .001), lower on-treatment high-density lipoprotein cholesterol (50 ± 15 vs 54 ± 15 mg/dL, P < .001), and were smokers (32% vs 14%, P < .001), compared to patients without cardiovascular events. In 31 patients (30%), a subsequent cardiovascular event occurred with a median interval of 5.7 (IQR 2.4-9.3) years between events. They were more often smokers (32% vs 10%, P = .01) compared to patients with a single cardiovascular event., Conclusions: Despite LLT, FH patients still develop cardiovascular events and especially subsequent events. Classical risk factors such as smoking and hypertension are driving factors for this risk, indicating the high priority of optimizing risk factor reduction in addition to maximum LLT., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Mast cells have been implicated in the development and progression of atherosclerosis in animal models and human autopsy studies. However, it is unknown whether long-term exposure to excess of mast cells is associated with cardiovascular disease (CVD) in humans. Our objective was to compare the prevalence of CVD and cardiovascular risk factors in patients with systemic mastocytosis (SM) and controls., Methods: In 50 patients with SM and 50 age and sex matched controls, the history of CVD and presence of cardiovascular risk factors were assessed. Carotid ultrasound was performed to assess carotid intima-media thickness (C-IMT) and plaques presence., Results: CVD events were more prevalent in SM patients compared to controls (20% vs. 6%, p = 0.04). The prevalence of C-IMT and carotid plaques was similar between patients with SM and controls. In multivariate analysis, CVD events were significantly associated with SM (OR 7.0 (95% CI 1.3-37.6), p = 0.02) and hypertension (OR 9.5 (95% CI 1.9-48.7), p = 0.01). The prevalence of diabetes, hypertension, obesity and smoking was similar between the two groups. Total cholesterol and LDL-C levels were significantly lower in SM patients than in the control group. (5.1 ± 1.1 vs. 5.9 ± 0.9 mmol/l, p < 0.05 and 2.9 ± 0.8 vs. 3.5 ± 0.7 mmol/l, p < 0.05, respectively)., Conclusions: Despite lower plasma total cholesterol and LDL-C, the prevalence of CVD is higher in patients with SM compared to healthy controls. Beyond the setting of SM, this study can be considered as a proof of concept study, indicating the contribution of mast cells to CVD in humans., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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 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.)

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: 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: 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.)

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.)

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.)

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.)