Adherence to statin treatment in patients with familial hypercholesterolemia: A dynamic prediction model.

BACKGROUND: Statins are the primary therapy in patient with heterozygous familial hypercholesterolemia (HeFH). Non-adherence to statin therapy is associated with increased cardiovascular risk. OBJECTIVE: We constructed a dynamic prediction model to predict statin adherence for an individual HeFH patient for each upcoming statin prescription. METHODS: All patients with HeFH, identified by the Dutch Familial Hypercholesterolemia screening program between 1994 and 2014, were eligible. National pharmacy records dated between 1995 and 2015 were linked. We developed a dynamic prediction model that estimates the probability of statin adherence (defined as proportion of days covered >80%) for an upcoming prescription using a mixed effect logistic regression model. Static and dynamic patient-specific predictors, as well as data on a patient's adherence to past prescriptions were included. The model with the lowest AIC (Akaike Information Criterion) value was selected. RESULTS: We included 1094 patients for whom 21,171 times a statin was prescribed. Based on the model with the lowest AIC, age at HeFH diagnosis, history of cardiovascular event, time since HeFH diagnosis and duration of the next statin prescription contributed to an increased adherence, while adherence decreased with higher untreated LDL-C levels and higher intensity of statin therapy. The dynamic prediction model showed an area under the curve of 0.63 at HeFH diagnosis, which increased to 0.85 after six years of treatment. CONCLUSION: This dynamic prediction model enables clinicians to identify HeFH patients at risk for non-adherence during statin treatment. These patients can be offered timely interventions to improve adherence and further reduce cardiovascular risk.

Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town.

OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant. CONCLUSIONS: In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9. Pathogenicity is established beyond doubt for the G516V variant.

Interpretation of laboratory results after gastric bypass surgery: the effects of weight loss and time on 30 blood tests in a 5-year follow-up program.

BACKGROUND: Long-term follow-up with blood tests is essential for bariatric surgery to be a successful treatment for obesity and related co-morbidities. Adverse effects, deficiencies, and metabolic improvements need to be controlled. OBJECTIVE: We investigated the effects of time and weight loss on laboratory results in each postoperative phase after laparoscopic Roux-en-Y gastric bypass (LRYGB). SETTING: Bariatric center of excellence, general hospital, Netherlands. METHODS: We retrospectively evaluated results of 30 blood tests, preoperatively and at 6 months, 1 year, 2 years, and 5 years after LRYGB. The 2019 Dutch bariatric chart was used to define weight loss responses as outstanding (>p[percentile curve]+1 SD), average (p+1 SD to p-1 SD), and poor (

Statin therapy reduces plasma angiopoietin-like 3 (ANGPTL3) concentrations in hypercholesterolemic patients via reduced liver X receptor (LXR) activation.

BACKGROUND AND AIMS: Statins suppress hepatic mRNA expression of ANGPTL3 encoding angiopoietin-like 3 in healthy subjects, but it is unknown if plasma ANGPTL3 concentrations are affected by statins prescribed to hypercholesterolemic patients in clinical practice. We therefore investigated the effect of statin treatment on plasma ANGPTL3 concentrations in hypercholesterolemic patients. In addition, we explored the underlying mechanism by which statins regulate ANGPTL3 in vitro. METHODS: Plasma ANGPTL3 concentrations were measured in 93 genetically confirmed familial hypercholesterolemia (FH) patients who were using statin therapy and 61 statin naïve FH patients. Moreover, concentrations were measured in 14 hypercholesterolemic patients who discontinued their statin treatment for 4 weeks. In vitro studies were performed with Huh7 human hepatoma cells. RESULTS: Plasma ANGPTL3 concentrations were 15% lower in statin treated FH patients compared to statin naïve FH patients (145 (120-193) vs. 167 (135-220) ng/ml, p = 0.012). Statin discontinuation resulted in a 21% (p<0.001) increase of plasma ANGPTL3 concentrations. Simvastatin reduced ANGPTL3 mRNA expression and ANGPTL3 secretion of Huh7 cells. Liver X receptor (LXR) activation with T0901317 increased ANGPTL3 mRNA expression and ANGPTL3 secretion by 6- and 3-fold, respectively. Adding simvastatin did not mitigate this effect but adding the LXR antagonist GSK2230 to simvastatin-incubated Huh7 cells diminished simvastatin-induced reductions in ANGPTL3 mRNA expression and ANGPTL3 secretion. Simvastatin reduced intracellular oxysterol concentrations. Oxysterols are endogenous LXR ligands, implying that simvastatin suppresses ANGPTL3 secretion via reduced oxysterol-mediated LXR activation. CONCLUSIONS: Statins lower plasma ANGPTL3 concentrations in hypercholesterolemic patients, likely due to decreased oxysterol-mediated LXR activation.

Risk Factors for Cholecystectomy After Laparoscopic Roux-En-Y Gastric Bypass.

BACKGROUND: Patients who have undergone bariatric surgery are at risk for subsequent cholecystectomy. We aimed to identify risk factors for cholecystectomy after laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: We conducted a retrospective case-control study of patients who underwent LRYGB between 2013 and 2015. Cases underwent cholecystectomy because of biliary symptoms after LRYGB. For each case, two controls were selected without subsequent cholecystectomy. Logistic regression analyses were used to identify risk factors. RESULTS: Between 2013 and 2015, 1780 primary LRYGBs were performed. We identified 233 (13.1%) cases who had undergone cholecystectomy after a median (IQR) of 12 (8-17) months, and 466 controls. Female gender (OR (95% CI) 1.83 (1.06-3.17)), Caucasian ethnicity (OR (95% CI) 1.82 (1.10-3.02)), higher percent total weight loss (%TWL) at 12 months (OR (95% CI) 1.06 (1.04-1.09)), and preoperative pain syndrome (OR (95% CI) 2.72 (1.43-5.18)) were significantly associated with an increased risk for cholecystectomy. Older age (OR (95% CI) 0.98 (0.96-0.99)) and preoperative statin use were associated with a reduced risk (OR (95% CI) 0.56 (0.31-1.00)). A dose-effect relationship was found between the intensity of preoperative statin and risk for cholecystectomy. CONCLUSIONS: In our study, higher %TWL and preoperative pain syndrome were associated with an increased risk for cholecystectomy besides the traditional risk factors female gender and Caucasian ethnicity. These factors can be used to identify high-risk patients, who might benefit from preventive measures. Whether statins can protect bariatric patients from developing gallstones should be investigated prospectively.

LDL-cholesterol target achievement in patients with heterozygous familial hypercholesterolemia at Groote Schuur Hospital: Minority at target despite large reductions in LDL-C.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is characterized by markedly increased LDL-cholesterol (LDL-C) and premature cardiovascular disease (CVD). LDL-C lowering is the cornerstone of therapy. The aim of our study was to evaluate LDL-C target achievement and explore reasons for not reaching target in FH patients attending a public-sector lipid clinic at Groote Schuur Hospital in Cape Town, South Africa. METHODS: We reviewed clinical records of patients with genetically confirmed heterozygous FH (heFH) retrospectively. For patients seen after 2013, when new guidelines were published, we determined reasons for use of submaximal therapy. RESULTS: Our study population consisted of 776 adult heFH patients. A substantial proportion (41%) of those younger than 50 years of age had already experienced a cardiovascular event. The mean (±SD) untreated and best achieved LDL-C values during follow up were 8.1 ±â€¯2.1 and 4.0 ±â€¯1.5 mmol/l, respectively. Despite a mean LDL-C reduction of 50%, only 140 (25%) achieved an LDL-C ≤ 3.0 mmol/l. Of the 164 participants with follow up after 2013, 42 did not reach LDL-C < 3.0 mmol/l and did not use maximal therapy (26%). The commonest reasons for not using maximum therapy were statin side-effects (n = 15, 36%) and acceptance by the patient (n = 9, 22%) or the physician (n = 8, 19%) of the control achieved. CONCLUSIONS: The heFH population in Cape Town is characterized by high baseline LDL-C, a high prevalence of CVD at presentation and low rates of achieving an LDL-C target of 3.0 mmol/l.

Achieved LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia: A model that explores the efficacy of conventional and novel lipid-lowering therapy.

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.

Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality.

BACKGROUND: A statin-induced reduction of coronary artery disease (CAD) events and mortality has not been adequately quantified in patients with heterozygous familial hypercholesterolemia (FH). OBJECTIVES: This study estimated the relative risk reduction for CAD and mortality by statins in heterozygous FH patients. METHODS: The authors included all adult heterozygous FH patients, identified by the Dutch screening program for FH between 1994 and 2013, who were free of CAD at baseline. Hospital, pharmacy, and mortality records between 1995 and 2015 were linked to these patients. The primary outcome was the composite of myocardial infarction, coronary revascularization, and death from any cause. The effect of statins (time-varying) was determined using a Cox proportional hazard model, while correcting for the use of other lipid-lowering therapy, thrombocyte aggregation inhibitors, and antihypertensive and antidiabetic medication. The authors applied inverse-probability-for-treatment weighting (IPTW) to account for differences at baseline between statin users and never-users. RESULTS: The authors obtained medical records of 2,447 patients, of whom 888 were excluded on the basis of age <18 years or previous CAD. Simvastatin 40 mg and atorvastatin 40 mg accounted for 23.1% and 22.8% of all prescriptions, respectively. Statin users (n = 1,041) experienced 89 CAD events and 17 deaths during 11,674 person-years of follow-up versus statin never-users (n = 518), who had 22 CAD events and 9 deaths during 4,892 person-years (combined rates 8.8 vs. 5.3 per 1,000 person-years, respectively; p < 0.001). After applying IPTW and adjusting for other medications, the hazard ratio of statin use for CAD and all-cause mortality was 0.56 (95% confidence interval: 0.33 to 0.96). CONCLUSIONS: In patients with heterozygous FH, moderate- to high-intensity statin therapy lowered the risk for CAD and mortality by 44%. This is essential information in all cost-effectiveness studies of this disorder, such as when evaluating reimbursement of new lipid-lowering therapies.

Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia.

BACKGROUND AND AIM: We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family. METHODS: We included heterozygous FH patients identified by genetic cascade screening in the Netherlands from 1994 to 2014. A cascade starts with identification of a genetically proven FH patient ("index patient") followed by testing in first degree relatives. If a mutation carrier is identified, their first degree relatives are tested as well, and so on. The associations between distance-to-index (expressed as family relationship) and both LDL-C levels and CVD risk, were evaluated using multivariable linear and Cox regression models. RESULTS: Distance-to-index could be determined in 13,374 patients. Mean (± standard error) levels of LDL-C did not differ significantly in 1st, 2nd, 3rd, and 4th or more family members: 5.46 (1.42), 5.17 (1.42), 4.89 (1.37), and 4.58 (1.27) mmol/L, respectively (adjusted p-for-trend: 0.104). The adjusted hazard ratio of increasing distance-to-index for CVD was 0.92 (95% CI: 0.82-1.03). CONCLUSION: This study was the first to investigate the association between distance-to-index and the phenotype of a monogenetic disorder. The absence of a decrease of phenotype severity lends support for genetic cascade testing in FH.

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26,406 individuals tested for genetic FH.

BACKGROUND: Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations. METHODS AND RESULTS: Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63 ± 1.44 mmol/L for FH carriers (n=5372) and 2.96 ± 0.96 mmol/L for unaffected relatives (n=15 148); P<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%-87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%-97.1%) and 91.3%, respectively. CONCLUSIONS: In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands.

Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia.

Aims Autosomal dominant hypercholesterolaemia (ADH) is a major risk factor for coronary artery disease. This disorder is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). However, in 41% of the cases, we cannot find mutations in these genes. In this study, new genetic approaches were used for the identification and validation of new variants that cause ADH. Methods and results Using exome sequencing, we unexpectedly identified a novel APOB mutation, p.R3059C, in a small-sized ADH family. Since this mutation was located outside the regularly screened APOB region, we extended our routine sequencing strategy and identified another novel APOB mutation (p.K3394N) in a second family. In vitro analyses show that both mutations attenuate binding to the LDLR significantly. Despite this, both mutations were not always associated with ADH in both families, which prompted us to validate causality through using a novel genetic approach. Conclusion This study shows that advances in genetics help increasing our understanding of the causes of ADH. We identified two novel functional APOB mutations located outside the routinely analysed APOB region, suggesting that screening for mutations causing ADH should encompass the entire APOB coding sequence involved in LDL binding to help identifying and treating patients at increased cardiovascular risk.

Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants.

AIMS: A plethora of mutations in the LDL-receptor gene (LDLR) underlie the clinical phenotype of familial hypercholesterolaemia (FH). For the diagnosis of FH, it is important, however, to discriminate between pathogenic and non-pathogenic mutations. The aim of the current study was to assess whether true pathogenic mutations were indeed associated with the occurrence of coronary artery disease (CAD) when compared with non-functional variants. The latter variants should not exhibit such an association with CAD. METHODS AND RESULTS: We assessed 29 365 individuals tested the 64 most prevalent LDLR variants. First, we determined pathogenicity for each of these sequence variants. Subsequently, a Cox-proportional hazard model was used to compare event-free survival, defined as the period from birth until the first CAD event, between carriers and non-carriers of LDLR mutations. Fifty-four sequence variants in the LDLR gene were labelled as pathogenic and 10 as non-pathogenic. The 9 912 carriers of a pathogenic LDLR mutation had a shorter event-free survival than the 18 393 relatives who did not carry that mutation; hazard ratio 3.64 [95% confidence interval (CI): 3.24-4.08; P< 0.001]. In contrast, the 355 carriers of a non-pathogenic LDLR variant had similar event-free survival as the 705 non-carrying relatives; hazard ratio 1.00 (95% CI: 0.52-1.94; P= 0.999). CONCLUSION: These findings with respect to clinical outcomes substantiate our criteria for functionality of LDLR sequence variants. They also confirm the CAD risk associated with FH and underline that these criteria can be used to decide whether a specific sequence variant should be used in cascade screening.

Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study.

A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of 'DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country.

Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels.

Autosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL-cholesterol (LDL-C) levels below the 50th percentile for age and gender prior to lipid-lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss-of-function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL-C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholesterolemic phenotype were not found. The common variants p.N902N, c.3842+82T>A, p.D2312D, and p.E4181K in APOB, and c.1863+94A>G in PCSK9 were significantly more prevalent in our cohort compared to the general European population. Interestingly, 40% of our probands carried at least one minor allele for all four common APOB variants compared to 1.5% in the general European population. While we found a low prevalence of rare variants in our cohort, our data suggest that regions in proximity of the analyzed loci, and linked to specific common haplotypes, might harbor additional variants that correct an ADH phenotype.

Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality.

OBJECTIVE: Fetal exposure to maternal hypercholesterolemia increases the extent of fatty-streak formation in fetal aortas as well as the rate of progression, and may therefore increase coronary heart disease (CHD) risk later in life. We hypothesized that the risk of CHD in untreated individuals with familial hypercholesterolemia (FH) is more extreme when the disease is transmitted maternally. METHODS: In a large Dutch pedigree carrying the V408M mutation in the low-density lipoprotein (LDL) receptor gene, 161 individuals over seven generations were identified for which FH status and parent of origin of FH were known. We calculated standardized mortality ratios (SMR) and compared the consequences of maternal and paternal inheritance of FH by Poisson regression analysis. RESULTS: Maternally inherited FH was associated with significantly higher excess mortality than FH transmitted by fathers (relative risk 2.2; p = 0.048): the SMR of maternal inheritance was 2.49 (95% confidence interval (CI) 1.45-3.99; p = 0.001), whereas it was not significantly increased in paternally inherited FH (SMR 1.30, 95% CI 0.65-2.32; p = 0.234). CONCLUSION: Mortality rates are more increased when FH is inherited through the mother, supporting the fetal origin of adulthood disease hypothesis with all cause death, the most indisputable outcome measure. Future research should explore safe options for cholesterol-lowering therapy of pregnant women with FH in order to prevent unfavourable (epigenetic) consequences leading to atherosclerosis in their children.

Assessment of carotid atherosclerosis in normocholesterolemic individuals with proven mutations in the low-density lipoprotein receptor or apolipoprotein B genes.

BACKGROUND: Genetic cascade screening for heterozygous familial hypercholesterolemia (FH) revealed that 15% of individuals given this diagnosis do not exhibit elevated low-density lipoprotein cholesterol (LDL-C) levels. We assessed whether cardiovascular risk for these individuals differs from that of hypercholesterolemic FH heterozygotes and unaffected relatives. METHODS AND RESULTS: Individuals aged 18 to 55 years were recruited within 18 months after genetic screening. Three groups were studied: subjects given a molecular diagnosis of FH and with LDL-C levels at genetic screening below the 75th percentile (FH-low), subjects with FH and an LDL-C level above the 90th percentile (FH-high), and subjects without FH (no-FH). We measured carotid intima-media thickness (IMT) by ultrasonography. Differences in carotid IMT among the groups were assessed using multivariate linear regression analyses. Mean carotid IMT of 114 subjects in the FH-low group (0.623 mm; 95% CI, 0.609 to 0.638 mm) was significantly smaller than that of 162 subjects in the FH-high group (0.664 mm; 95% CI, 0.648 to 0.679 mm; P<0.001) and did not significantly differ from the mean carotid IMT in 145 subjects in the no-FH group (0.628 mm; 95% CI, 0.613 to 0.642 mm; P=0.67). CONCLUSIONS: Our findings suggest that the risk of cardiovascular disease in patients with FH to a large extent is related to LDL-C levels and not to the presence of a mutation per se. Consequently, this study cautiously suggests that individuals with an FH genotype without expression of hypercholesterolemia may not require a pharmaceutical intervention that is as aggressive as the standard for subjects with FH.

Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.

BACKGROUND: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes. Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia. METHODS AND RESULTS: We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index >75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation (LDLR, 95%; APOB, 5%). CONCLUSION: In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date.

Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.

BACKGROUND: Familial hypercholesterolemia (FH) has been associated with increased cardiovascular risk when untreated or when normal LDL-C concentrations are not reached. Some patients with FH do not reach LDL-C goals despite intensive combination therapy. OBJECTIVE: This study assessed the efficacy and tolerability of colesevelam added to maximally tolerated, stable-dose combination treatment with a statin + ezetimibe. METHODS: This Phase IV, multicenter, randomized, double-blind, placebo-controlled trial enrolled patients aged 18 to 75 years with FH and an LDL-C concentration >2.5 mmol/L who were receiving a maximally tolerated and stable regimen of a statin + ezetimibe. Patients were randomly assigned to receive colesevelam 3.75 g/d or placebo added to the statin + ezetimibe for 12 weeks. The primary efficacy outcome was the difference in LDL-C between the colesevelam and placebo groups after 6 weeks. Secondary efficacy outcomes were between-group differences in LDL-C, total cholesterol (TC), HDL-C, triglyceride (Tg), apolipoprotein (apo) B, and apoA-I concentrations, as well as apoB/apoA-I ratio after 12 weeks. Tolerability was assessed based on the prevalences of adverse events by organ system class in each treatment group. RESULTS: Eighty-six patients were randomized (45 colesevelam, 41 placebo), of whom 84 (44 colesevelam, 40 placebo) were included in the primary analysis. The mean (SD) age of the participants was 52.8 (10.8) years, and 51 (59%) were men. The difference (95% CI) in LDL-C between colesevelam and placebo after 6 weeks was -18.5% (-25.3 to -11.8). Between-group differences in LDL-C, TC, HDL-C, Tg, and apoB/apoA-I ratio after 12 weeks were -12.0% (-17.8 to -6.3), -7.3% (-12.0 to -2.6), +3.3% (-2.4 to +9.0), +2.8% (-10.4 to +15.9), and -12.2% (-20.2 to -4.2), respectively. Colesevelam was generally well tolerated, with gastrointestinal adverse events in 12 of 45 patients (27%) versus 7 of 40 (18%) in the placebo group (P = NS). CONCLUSION: In these patients with FH, colesevelam added to a combination of a statin + ezetimibe was associated with significantly improved LDL-C concentrations compared with placebo during the 12-week study period and was generally well tolerated.

Carotid atherosclerosis progression in familial hypercholesterolemia patients: a pooled analysis of the ASAP, ENHANCE, RADIANCE 1, and CAPTIVATE studies.

BACKGROUND: Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression. METHODS AND RESULTS: We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33%of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, -0.0003-0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020-0.061]; P<0.05). Patients whose statin therapy could be intensified, as evidenced by an LDL-C decrease after the initiation of on-trial statin therapy, showed cIMT decrease in the first 6 to 12 months and a much lower cIMT increase measured over the full 2 years. In line with this, previously statin-naive HeFH patients showed a lower overall cIMT increase. CONCLUSIONS: Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation.