Familial Hypercholesterolemia Women Research Articles

Women and lipoprotein apheresis: another side of gender medicine.

In heterozygous Familial Hypercholesterolemia (FH) woman atherosclerotic cardiovascular disease occurs 20-years earlier respect woman without FH while homozygous FH women may suffer from atherosclerotic cardiovascular disease even in childhood. Lipoprotein apheresis, a therapeutic "last chance saloon", is a well-tolerated procedure that markedly lowers LDL-cholesterol and Lp(a) levels in patients who do not achieve acceptable levels with maximal lifestyle and drug therapy. The experience of LA treatment in 3 female homozygous FH patients was described. Moreover, an explore analysis on pre and post-LA hormonal levels was performed in 8 HeFH women showing a significant improvement in the atherogenic lipid profile (total cholesterol -56%, LDL cholesterol -71%, triglycerides -72%, Apo B lipoprotein -69%, Lp(a) -59%;) and a reduction of FSH and LH values (FSH - 28%, LH -31%). Women with FH experience specific barriers to care, including underrepresentation in research, significant underestimation of risk, and discontinuation of therapy during pregnancy. Therefore, in this study, we investigated the possible effects of LA treatment on plasma FSH and LH levels.

The Cycle study: a prospective study on cholesterol levels during the menstrual cycle

Abstract Background Previous studies showed fluctuating lipid levels during the menstrual cycle in healthy women with normal cholesterol (nChol). Cycle-related variations in lipid levels in women with familial hypercholesterolemia (FH) have not been studied, while these might have important consequences for lipid management. Purpose To investigate menstrual cycle-related fluctuations in lipid levels in women with FH compared to those with nChol. Methods In the Netherlands and Norway, 20 women with clinical/genetic FH and 63 healthy women with nChol were included - details are presented in the figures. Participants had to have a regular cycle between 21-35 days, while pregnant women, and those using hormone-based contraceptives without hormone free interval (HFI) were excluded. Lipid levels were measured in the follicular (visit 1), ovulation (visit 2), and luteal (visit 3) phases. In women using oral contraceptives (OC) measurements were taken during day 12-14 of the pill period (visit 1) and during day 5-7 of the HFI (visit 2). Results Mean (sd) age of the included subjects was 33 (9) years, BMI 23.9 (4) kg/m2, and cycle duration 28 (2) days. These characteristics were similar in FH and nChol. Women with nChol showed slight, although statistically significant, cycle-related variations in cholesterol levels (mean maximum variation total Chol 0.53, LDL-Chol 0.39 and HDL-Chol 0.22 mmol/L; figure 1). FH women who did not receive statin therapy for various reasons showed largest mean variations (total Chol 0.80, LDL-Chol 0.59 and HDL-Chol 0.23 mmol/L), with the highest lipid levels during the ovulation phase. The women with OC had an increase in total- and LDL-cholesterol (groups combined: mean difference 0.55 and 0.51 mmol/L, respectively) between the two visits (n=9) (figure 2). Conclusions In women with untreated FH and normal cholesterol with a regular menstrual cycle, total- and HDL-cholesterol were highest at ovulation. These menstrual fluctuations were absent in women with FH who used statins. Women with OC showed an increase in total- and LDL-cholesterol from the contraceptive pill period to the HFI. Even though in most women the absolute variation in lipid levels during the menstrual cycle and OC are modest, the moment of measurement can be of clinical value in particular in women with untreated high lipid levels. In these women, it is recommended to measure lipid levels at a fixed time of the menstrual cycle.Figure 1Figure 2

Abstract 13180: Cardiovascular Disease and Cholesterol Lowering Therapy in Women and Men With Molecularly Proven Familial Hypercholesterolemia

Introduction: Familial Hypercholesterolemia (FH) is an autosomal dominant disease affecting women and men on the same proportion. There is scant evidence on cardiovascular disease (CVD) and therapy adequacy on contemporary FH cohorts according to sex. Goals: Evaluate whether there were differences in CVD outcomes and treatment intensity in women and men with molecularly proven FH at a specialized lipid clinic. Methods: Initially a cross-sectional analysis of 801 patients with FH enrolled between 2011 and 2022 on a genetic cascade screening program was done . All had a positive FH molecular diagnosis. Participants were then followed by a median of 5 years (0.08 to 11 years). Clinical, laboratory and, treatment parameters were compared at baseline and during follow-up according to sex. Results: The cohort consisted of 455 women (57%) and 346 men (43%), mean age 47± 15 years. At baseline there were no sex differences regarding LDL-C (196±74 mg/dL men vs 200±75 mg/dL women, p= 0.567) as well as percentage of those with LDL-C < 100 mg/dL (6.8% men vs 6.1% women, p=0.712) or < 70 mg/dL at baseline (0.3% men vs 0% women, p=0.238). Intensive lipid lowering treatment use was similar between men and women at baseline (75.1% vs. 74.4%; p= 0.848) and during follow-up (87.6% vs. 88.3%; p= 0.785). At baseline 23.1% of women and 38.1% of men had a previous history of CVD (p= 0.000). After follow-up, 41 women (9%) and 52 men (15%) had an incident CVD event (p=0.009). Multivariate Cox regression analysis showed that risk factors related to incident events were age (HR=1.028, 95% CI 1.005-1.052 per year, p =0.019), presence of corneal arcus (HR 1.794, 95% CI 1.096-2.937, p= 0.02), current smoking (HR 2.534, 95% CI 1.304-4.927, p=0.006) and a previous CVD event (HR= 1.793, 95%CI 1.041-3.087, p= 0.035). Conclusions: Overall FH men had a greater risk of CVD events than FH women. There was no difference in treatment intensity and CVD outcomes were associated with traditional risk factors or previous CVD.

Female patients with familial hypercholesterolemia have higher cholesterol burden at 19 and 30 years of age: Data from 12-years follow-up

Background and Aims : It is the cumulative exposure to low-density lipoprotein cholesterol (LDL-C) that defines the risk of cardiovascular disease (CVD). Patients with familial hypercholesterolemia (FH) have increased risk of premature CVD, and the highest excess risk is observed in young FH women. The aim of our study was to calculate lifelong LDL-C burden in FH individuals and investigate possible sex differences.

Loss of statin treatment years during pregnancy and breastfeeding periods in women with familial hypercholesterolemia

Background and aimsWomen with heterozygous familial hypercholesterolemia (FH) are recommended to initiate statin treatment at the same age as men (from 8 to 10 years of age). However, statins are contraindicated when pregnancy is planned, during pregnancy and breastfeeding. The aim of the study was to determine the duration of pregnancy-related off-statin periods and breastfeeding in FH women. MethodsA cross-sectional study using an anonymous online self-administered questionnaire was conducted. Women with FH were recruited through Lipid Clinics in Norway and Netherlands and national FH patient organizations. Results102 women with FH (n = 70 Norwegian and n = 32 Dutch) were included in the analysis. Total length of pregnancy-related off-statin periods was estimated for 80 women where data were available, and was median (min-max) 2.3 (0–14.2) years. Lost statin treatment time was estimated for 67 women where data were available, and was median (min-max) 18 (0–100)% at mean (SD) age of 31 (4.3) years at last pregnancy. More women breastfed in Norway (83%) and for longer time [8.5 [1-42] months] compared to the Netherlands [63%, p = 0.03; 3.6 (0–14) months, p < 0.001]. Eighty-six percent of the women reported need for more information on pregnancy and breastfeeding in relation to FH. ConclusionsYoung FH women lose years of treatment when discontinuing statins in relation to pregnancy and breastfeeding periods and should be closely followed up to minimize the duration of these off-statin periods. Whether these periods of interrupted treatment increase the cardiovascular risk in FH women needs to be further elucidated.

Sex differences in cholesterol levels from birth to 19 years of age may lead to increased cholesterol burden in females with FH

The increased risk of cardiovascular disease in familial hypercholesterolemia (FH) is caused by increased cholesterol burden from birth. Even small elevation in cholesterol level accumulates over time and aggravates atherosclerosis. The aim of the present study was to describe the lipid profile across sex and age in a large cohort of untreated children and adolescents with FH, as this have not clearly been described. FH children (438 girls, 452 boys) not receiving lipid-lowering therapy, aged 0 to 19years were included and divided into 4 age groups (<5, 5-9, 10-14, and 15-19years). Information was retrieved from the medical records. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) were studied in relation to sex and age by multiple linear regression analysis. Girls with FH as compared to boys had significantly higher TC, LDL-C, and non-HDL-C (P<.001 for all) levels with mean (95% confidence interval) differences of 0.48mmol/L (0.28, 0.68) (18.6g/dL), 0.39mmol/L (0.19, 0.59) (15.08mg/dL), and 0.42mmol/L (0.22, 0.63) (16.24mg/dL), respectively. These estimates did not change after adjustment for age. We also observed sex differences for HDL-C; girls had higher HDL-C in the youngest (<5years, P=.05) and oldest age groups (15-19years, P<.001). FH girls have higher levels of TC, LDL-C, and non-HDL-C levels than boys from birth up to 19years of age. This may contribute significantly to the total lifelong cholesterol burden in FH women.

Pregnancy Outcomes in Familial Hypercholesterolemia

Background— Women with familial hypercholesterolemia (FH) are prone to early cardiovascular disease and death. It is unknown whether FH adversely affects pregnant women and birth outcomes. We determined whether heterozygous FH women are at higher risk of premature birth (&lt;37 gestational weeks), delivering children with low birth weight (&lt;2500 g) and/or with congenital malformations compared to women in general. Methods and Results— We linked information from the Medical Genetics Laboratory with that of the Medical Birth Registry of Norway. We included 1869 FH women (≥14 years) from the Medical Genetics Laboratory and about 2 million (general population) from the Medical Birth Registry of Norway during the period 1967 to 2006. The registry match resulted in analysis of 2319 births of 1093 women with heterozygous FH. The mean (SD) prepregnancy total cholesterol concentration was 9.59 (2.06) mmol/L (370 [80 mg/dL]), whereas the concentration of total cholesterol was not available during pregnancy. The frequencies of prematurity, low birth weight, and congenital malformations for the 40-year period in the FH population were 6.8, 5.0, and 3.3, respectively. The corresponding values for the general population were 6.2, 5.2, and 3.2. The corresponding odds ratios were 1.11 (95 confidence interval 0.94–1.31; P =0.23), 0.96 (0.79–1.15; P =0.64), and 1.09 (0.87–1.37; P =0.45). Conclusions— Women with FH do not appear to have a higher risk of preterm delivery or of having infants with low birth weight or congenital malformations than women in general, but, although this is unlikely, some undetected bias may obscure the real differences.

Maternal Heterozygous Familial Hypercholesterolemia and Its Consequences for Mother and Child

During a normal pregnancy serum lipids (total, low-density lipoprotein [LDL]-cholesterol and high-density lipoprotein cholesterol, and triglycerides) rise steadily1 and take months to fall postpartum.2 LDL-cholesterol can increase by ≈66% and triglycerides can rise 3-fold, and it has been suggested that elevated cholesterol during pregnancy may be associated with spontaneous preterm delivery.3 Article see p 1606 It is known that women with heterozygous familial hypercholesterolemia (FH) who become pregnant have very high levels of LDL-cholesterol early in pregnancy (260 mg/dL or 6.7 mmol/L) that rise to even higher levels near term (330 mg/dL or 8.6 mmol/L).4 These very high lipid levels raise the question of the potential risks of pregnancy to the mother and fetus. FH is caused by mutations in the low-density lipoprotein receptor. In this issue of Circulation , in a study linking the Medical Birth Registry of Norway (1967–2006) and the Medical Genetics Laboratory at Oslo University Hospital that has established the molecular diagnosis in 4400 patients, 2319 births of 1093 women were identified.5 The serum levels of cholesterol in the nonpregnant, nontreated FH women were 370 mg/dL (9.59 mmol/L). In this study, no maternal cardiovascular deaths were observed. In addition, the children of mothers with FH were no more likely than the general population to be born prematurely, have low birth weight, or have congenital malformations. Furthermore, even though the sample size was small, no congenital malformations were observed in the 19 pregnancies associated with the use of lipid-lowering drugs during pregnancy. Although this is a retrospective, registry-based study, the data likely reflect the birth outcomes of a representative cohort of childbearing FH …

Evidence for impaired physiological decrease in the uteroplacental vascular resistance in pregnant women with familial hypercholesterolemia

Abnormal hyperlipidemia characterizes pregnancy in familial hypercholesterolemia (FH), and is associated with vascular dysfunction. Hence, we compared blood flow in the feto- and uteroplacental circulation in FH and healthy reference women using Doppler velocimetry. The umbilical artery pulsatility index (PI) at gestational weeks 24 and 36, and the concomitant physiological decrease in PI, was similar in FH (n=10) and the reference group (n=143). The decrease in mean PI of both uterine arteries from week 24 to 36 was significant in the reference group, but not among the FH women. Plasma LDL-cholesterol measured between weeks 24 and 36 was not correlated with the decrease in umbilical PI in the FH group, or with the decrease in umbilical or mean uterine PI in the reference group. We conclude that pregnancy in FH might be associated with attenuated physiological decrease in mean PI of uterine arteries, possibly reflecting increased uteroplacental vascular resistance unrelated to plasma LDL-cholesterol levels.

Altered hemostatic balance and endothelial activation in pregnant women with familial hypercholesterolemia

Introduction Patients with familial hypercholesterolemia (FH) are prone to premature cardiovascular disease. During pregnancy plasma lipids reach higher absolute values in FH than in healthy women. Pregnancy is associated with activation of coagulation and possibly also of vascular endothelium, which might further increase the risk of cardiovascular disease in FH. However, whether hemostatic and endothelial activation markers are increased in pregnant FH women compared with non-FH pregnancies, is unknown. Materials and methods Activation markers of hemostasis and endothelium were analyzed in blood samples collected prospectively from 22 heterozygous FH women during pregnancy and compared with those of a reference group of 149 healthy, pregnant women. Results A procoagulant pattern was detected in both groups, but was more evident among FH women at least partly due to their enhanced thrombin generation, and because tissue factor pathway inhibitor type 1 increased in the reference group only. Furthermore, plasminogen activator inhibitor type 2 antigen increased more in FH than in the reference group. Whereas C-reactive protein, intercellular adhesion marker-1 and E-selectin did not change appreciably, vascular endothelial cell adhesion molecule 1 rose markedly in FH. Conclusion Increased lipid levels as well as a net procoagulant activity and an enhanced endothelial activation possibly confer additional risks of cardiovascular disease among pregnant FH women.

Positive family history for coronary heart disease and ‘midband lipoproteins’ are potential risk factors of carotid atherosclerosis in familial hypercholesterolemia

Patients with heterozygous familial hypercholesterolemia (FH) were examined with B-mode ultrasound in order to determine intima-media thickness (IMT) in the common carotid artery, and to uncover potential risk factors responsible for the development of IMT. Ninety seven FH subjects and 132 non FH type IIa hyperlipidemic subjects were involved in the present study. Age was found to correlate positively with IMT in both FH and non FH groups. FH individuals showed a higher IMT, along with elevated low density lipoprotein (LDL) cholesterol levels, compared with age-matched non FH individuals. To clarify potential factors contributing to the formation and development of carotid atherosclerosis, we divided the FH subjects into two subgroups, namely FH with high IMT group (HIG), and those with low IMT group (LIG). We investigated those two subgroups on the presence of angiographically documented coronary heart disease (CHD), of family history of CHD and of ‘midband lipoproteins’ by polyacrylamide gel electrophoresis (PAGE) analysis, by matching for age and LDL-cholesterol (LDL-C) level. Fifty percent of FH men in HIG was found to have CHD, whereas only 14% of those in LIG had CHD ( P<0.05). Thirty-three percent of FH women in HIG was found to have CHD, whereas only 12% of those in LIG had CHD ( P<0.05). Fifty percent of FH men in HIG was found to have ‘midband lipoproteins’, whereas only 7% of those in LIG had ‘midband lipoproteins’ ( P<0.01). Seventy-three percent of FH women in HIG had ‘midband lipoproteins’, whereas only 21% of those in LIG had ‘midband lipoproteins’ ( P<0.0005). Fifty-five percent of FH men in HIG was had positive family history for CHD, whereas only 14% of those in LIG had positive family history for CHD ( P<0.05). Sixty-three percent of FH women in HIG was found to have positive family history for CHD, whereas only 29% of those in LIG had positive family history for CHD ( P<0.05). Based on these findings, we propose that, besides age and elevated levels of LDL-C, positive family history for CHD and ‘midband lipoproteins’ are important determinants for the development of carotid atherosclerosis in FH individuals in Japanese population.

Influence of genetic variability in the nondeletion LDL-receptor allele on phenotypic variation in French-Canadian familial hypercholesterolemia heterozygotes sharing a ‘null’ LDL-receptor gene defect

We investigated the associations between low density lipoprotein (LDL)-receptor gene haplotypes and lipid and lipoprotein levels in French-Canadian individuals with familial hypercholesterolemia (FH). The 112 unrelated patients studied shared the same > 10 Kb deletion in the 5′ region of the LDL-receptor gene, leading to a null allele. Support for the hypothesis that the deletion is carried on only one LDL-receptor restriction fragment length polymorphism (RFLP) haplotype in this sample has previously been demonstrated [1]. We studied associations of genetic variability in DNA polymorphisms of the nondeletion LDL-receptor allele with variation in plasma lipid levels in these patients heterozygous for the deletion. All analyses were done separately in males and females. The traits were adjusted for variation in the concomitants age, height and weight, and for variation in apolipoprotein (apo) E phenotype, and then the association between variability in haplotypes defined by two RFLP loci and variation in trait levels were tested. The results indicated that in this sample of French-Canadian >10 Kb deletion FH heterozygotes, variability at the LDL-receptor gene contributes to quantitative variation in measures of lipid metabolism and that the effects are different in males and females. The results indicated that variability at the LDL-receptor gene defined by two RFLP loci contributes to quantitative variation in high density lipoprotein (HDL)-cholesterol and LDL-cholesterol concentrations in French-Canadian FH women heterozygous for the >10 Kb deletion and not in men.