Search

• 88 children without FH were followed-up for 20 years. • Lp(a) and cIMT were measured at baseline and after 10- and 20 years. • At baseline, Lp(a) was elevated in 11.1% of the children. • Lp(a) did not contribute significantly to arterial wall thickening (measured by cIMT). Elevated lipoprotein(a) [Lp(a)] is independently associated with cardiovascular disease (CVD). In a recent long-term follow-up study involving children with familial hypercholesterolemia (FH), Lp(a) levels contributed significantly to early atherosclerosis, as measured by carotid intima-media thickness (cIMT). To determine if this holds true for children without FH, we conducted a 20-year follow-up study, examining 88 unaffected siblings (mean age: 12.9 years) of children with FH. No significant association was found between Lp(a) and cIMT during follow-up (ß-adjusted [95% confidence interval] = 0.0001 [-0.008 to 0.008] mm per 50 nmol/L increase Lp(a), p = 0.97). In conclusion, our findings suggest that elevated levels of Lp(a) do not play a significant role in arterial wall thickening among children without FH during the 20-year follow-up period. This leads us to consider the possibility that cIMT may not be a suitable marker for detecting potential subtle changes in the arterial wall mediated by Lp(a) in the young, general population. However, it could also be that elevated Lp(a) is only a significant risk factor for atherosclerosis in the presence of other risk factors such as FH. [ABSTRACT FROM AUTHOR]

• Non-adherence to statin therapy is associated with increased risk for CAD. • This dynamic prediction model identifies patients at risk for non-adherence. • Time since diagnosis, CVD, prescription duration positively predicted adherence. • Pre-treatment LDL-C levels and statin intensity negatively predicted adherence. • Dynamically including past prescription adherence increased precision of the model. Statins are the primary therapy in patient with heterozygous familial hypercholesterolemia (HeFH). Non-adherence to statin therapy is associated with increased cardiovascular risk. We constructed a dynamic prediction model to predict statin adherence for an individual HeFH patient for each upcoming statin prescription. 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. 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. 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. [ABSTRACT FROM AUTHOR]

• Evolocumab did not impair cognitive function in pediatric FH after 24 weeks. • Abnormal cognitive decline was less frequent with evolocumab than with placebo. • Small improvements observed with evolocumab in psychomotor function and attention. Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients. To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH. Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test. At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (–0.2, 0.4), –0.1 (–0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (–0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group. In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition. This study was funded and designed by Amgen. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Familial hypercholesterolemia (FH) is a highly prevalent condition, predisposing individuals to premature cardiovascular disease and with a genetic basis more complex than initially thought. Advances in molecular technologies have provided novel insights into the role of next-generation-sequencing, the assessment and classification of newly found variants, the complex genotype-phenotype correlation, and the position of FH in the context of other dyslipidaemias. Areas covered: Understanding the scope of genetic determinants of FH has expanded substantially. This article reviews the current literature on the complexity that comes with this incremental knowledge and highlights the added value of genetic testing as an addition to phenotypic diagnosis of FH. Moreover, we discuss the broad genetic basis of FH, with a focus on the three main FH genes, but we also pay attention to polygenic hypercholesterolemia as well as minor and modulator genes involved in FH. Expert opinion: Both the availability and the need for genetic analysis of FH are on the rise as costs of sequencing continue to drop and new therapies require a genetic diagnosis for reimbursement. However, greater use of genetic testing requires more education of healthcare professionals, since molecular technologies will allow for rapid and accurate evaluation of large numbers of detected variants. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C–lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile. Methods In this double-blind trial, HeFH patients (LDL-C >160 mg/dL) on maximal tolerated LDL-lowering therapy were randomized to mipomersen 200 mg once weekly (n = 104), mipomersen 70 mg thrice weekly (n = 102), or placebo in matching frequency (n = 103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment. Results Mipomersen 200 mg once weekly and mipomersen 70 mg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p < 0.001). Lipoprotein(a) was significantly lowered by 27.7% (p < 0.001) with thrice-weekly dosing. Injection-site reactions and flu-like symptoms led to discontinuation in 21.2% (200 mg), 17.6% (70 mg), and 5.8% (placebo) of participants. Alanine transaminase was elevated (≥3× upper limit of normal at least once) in 21.2%, 21.6%, and 1.0% of subjects, respectively. Conclusions Mipomersen 200 mg once weekly and 70 mg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits. Graphical abstract Image 1 Highlights • Mipomersen 200 mg once weekly and 70 mg thrice weekly are effective in lowering apoB-containing lipoproteins in patients with heterozygous FH. • This effectiveness is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. • Thrice-weekly dosing is associated with less flu-like symptoms and lower discontinuation rates, but otherwise had no major benefits. [ABSTRACT FROM AUTHOR]

Background Familial hypercholesterolemia (FH) is a dominant genetic disorder associated with elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic events. Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for LDL-C reduction among adult patients with FH, placebo-controlled outcome data among FH patients are scant. Objective Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) program. Methods We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular event rates among 1578 FH patients and 15,959 patients without FH who were selected for comparable lipid levels (on-statin levels of LDL-C >100 mg/dL or non–high-density lipoprotein cholesterol > 130 mg/dL). All patients were randomized by computer generated codes to bococizumab 150 mg subcutaneously every 2 weeks or to matching placebo in the SPIRE clinical trials program and were followed over a median period of 11.2 months for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). Analysis is by intention to treat. The SPIRE trials are closed and registered at ClinicalTrials.gov : NCT01968954 , NCT01968967 , NCT02100514 , NCT01968980 , NCT01975376 , and NCT01975389 . Results Compared to non-FH patients, FH patients enrolled in the SPIRE trials were on average younger (58 vs 63 years), more likely to be women (42 vs 35%), more likely to be primary prevention patients (42 vs 23%), had higher mean baseline LDL-C levels (151 vs 127 mg/dL), and lower rates of diabetes (25 vs 52%) and hypertension (59 vs 82%). FH and non-FH patients both had 55% reductions in LDL-C with bococizumab. Among FH patients, major adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and 22 of 797 allocated to placebo (hazard ratio 0.83; 95% confidence interval 0.44–1.54, P = .55). This best estimate of effect was similar in magnitude to that observed in the much larger group of patients without FH (hazard ratio 0.79, 95% confidence interval 0.64–0.97, P = .023) with no statistically significant evidence of heterogeneity between groups ( P = .87). Incidence rate ratios comparing bococizumab to placebo for adverse events were similar among those with and without FH. The proportion of patients developing antidrug antibodies was higher among those with FH compared to those without FH (43% vs 36%, P < .001). Conclusions In these randomized placebo-controlled data, the subgroup of statin-treated FH patients had a similar magnitude of risk reduction for hard cardiovascular events with the PCSK9 inhibitor bococizumab as did patients without FH, with no evidence of statistical heterogeneity between groups. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Familial hypercholesterolemia (FH) is characterized by severely elevated LDL-cholesterol and up to a 20-fold increase in premature cardiovascular disease (CVD). Objective Mipomersen has been shown to lower the levels of these atherogenic lipoproteins, but whether it lowers major adverse cardiac events (MACEs) has not been addressed. Methods This post hoc analysis of prospectively collected data of three randomized trials and an open-label extension phase included patients that were exposed to ≥12 months of mipomersen. MACE rates that occurred during 24 months before randomization in the mipomersen group were compared to MACE rates after initiation of mipomersen. Data from the trials included in this report are registered in Clinicaltrials.gov ( NCT00607373 , NCT00706849 , NCT00794664 , NCT00694109 ). The occurrence of MACE events, defined as cardiovascular death, nonfatal acute myocardial infarction, hospitalization for unstable angina, coronary revascularization and nonfatal ischemic stroke, was obtained from medical history data pre-treatment and adjudicated by an independent adjudication committee for events occurring post-treatment with mipomersen. Results MACEs were identified in 61.5% of patients (64 patients with 146 events [39 myocardial infarctions, 99 coronary revascularizations, 5 unstable angina episodes, 3 ischemic strokes]) during 24 months before mipomersen treatment, and in 9.6% of patients (10 patients with 13 events [1 cardiovascular death, 2 myocardial infarctions, 6 coronary interventions, 4 unstable angina episodes]) during a mean of 24.4 months after initiation of mipomersen (MACE rate 25.7 of 1000 patient-months vs 3.9 of 1000 patient-months, OR = 0.053 [95% CI, 0.016–0.168], P < .0001 by the exact McNemar test). The reduction in MACE coincided with a mean absolute reduction in LDL-C of 70 mg/dL (−28%) and of non-HDL cholesterol of 74 mg/dL (−26%) as well as reduction in Lp(a) of 11 mg/dL (−17%). Conclusion Long-term mipomersen treatment not only lowers levels of atherogenic lipoproteins but may also lead to a reduction in cardiovascular events in FH patients. [ABSTRACT FROM AUTHOR]

Background Familial hypercholesterolemia (FH) is caused by mutations in LDLR , APOB , or PCSK9 , and in a previous study, we identified a causative mutation in these FH genes in 95% (255 of 269) of children with the FH phenotype. It has been hypothesized that a polygenic form of hypercholesterolemia is present in FH patients in whom no mutation is identified in the 3 FH genes. Objective To address whether a polygenic form of hypercholesterolemia, defined as high-weighted effect of low-density lipoprotein cholesterol (LDL-C) raising SNPs expressed as the genetic risk score (GRS), is present in the remaining 14 children. Methods and results On reassessment of the molecular diagnosis and clinical phenotype, 8 FH kindreds met the criteria for hypercholesterolemia of unknown cause and were included in this study. We calculated a weighted GRS comprising 10 established LDL-C–associated SNPs and the APOE genotype in these index cases and evaluated whether the index cases were characterized by an increased GRS compared to 26 first-degree relatives. Phenotypically affected and unaffected individuals could not be distinguished based on any of the risk scores. Conclusions In this and our previous study, we show that a causal mutation in LDLR , APOB , and PCSK9 can be identified in almost all children with a definite clinical diagnosis of FH. In the small group of patients without a mutation, we did not observe a higher GRS compared with unaffected relatives, which suggests that the FH phenotype is not caused by the aggregate of LDL-C increasing SNPs. Our data imply that application of the GRS is not instrumental as a diagnostic tool to individually define clinically diagnosed FH patients with polygenic hypercholesterolemia in our study population. [ABSTRACT FROM AUTHOR]

Objective Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Guidelines recommend initiating statins early to reduce low-density lipoprotein cholesterol (LDL-C). Studies have evaluated rosuvastatin in children aged ≥10 years, but its efficacy and safety in younger children is unknown. Methods Children with HeFH and fasting LDL-C >4.92 mmol/L (190 mg/dL) or >4.10 mmol/L (>158 mg/dL) with other cardiovascular risk factors received rosuvastatin 5 mg daily. Based on LDL-C targets (<2.85 mmol/L [<110 mg/dL]), rosuvastatin could be uptitrated to 10 mg (aged 6–9 years) or 20 mg (aged 10–17 years). Treatment lasted 2 years. Changes in lipid values, growth, sexual maturation, and adverse events (AEs) were assessed. Results The intention-to-treat analysis included 197 patients. At 24 months, LDL-C was reduced by 43, 45, and 35% vs baseline in patients aged 6–9, 10–13, and 14–17 years, respectively ( P < .001 for all groups). Most AEs were mild. Intermittent myalgia was reported in 11 (6%) patients and did not lead to discontinuation of rosuvastatin treatment. Serious AEs were reported by 9 (5%) patients, all considered unrelated to treatment by the investigators. No clinically important changes in hepatic biochemistry were reported. Rosuvastatin treatment did not appear to adversely affect height, weight, or sexual maturation. Conclusions In HeFH patients aged 6–17 years, rosuvastatin 5–20 mg over 2 years significantly reduced LDL-C compared with baseline. Treatment was well tolerated, with no adverse effects on growth or sexual maturation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Aims Statins are essential for the reduction of risk of coronary heart disease (CHD) in familial hypercholesterolemia (FH). One of many genes influenced by statin treatment is the ATP-binding cassette transporter A1 (ABCA1) gene, which plays an important role in metabolism of high-density lipoprotein (HDL). The present aim was to test if the ABCA1 C69T polymorphism influences CHD risk and response to statin treatment. Methods and results In a large cohort of 1686 FH patients without a history of CHD before 1 January 1990, we analysed statin-ABCA1 C69T polymorphism interaction by comparing treated and untreated patients. We used a Cox proportional hazard model adjusted for sex, birth year, and smoking. In analyses restricted to untreated patients, the TT genotype was associated with 1.7 times higher CHD risk than the CC genotype (hazard ratio (HR) =1.65, 95% confidence interval (95% CI): 1.08–2.53; P = 0.02). Conversely, in statin-treated FH patients, CHD risk in TT individuals was not increased (HR: 0.65, 95% CI: 0.35–1.24; P = 0.2). Formal testing confirmed this interaction (P = 0.03). HDL-cholesterol levels were significantly more raised in statin-treated patients with the TT than with the CC genotype (two-way ANOVA, P = 0.045). Conclusion In untreated FH patients, the TT genotype of the ABCA1 C69T polymorphism was associated with increased CHD risk. However, in statin-treated patients, CHD risk was no longer significantly different between genotypes, at least partially explained by a higher rise in HDL-cholesterol levels during statin treatment in TT individuals. [ABSTRACT FROM PUBLISHER]

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA2 levels in children have not been previously reported. The effect of statin therapy on Lp-PLA2 mass and activity in children with familial hypercholesterolemia (FH) is also not known. Methods: Lp-PLA2 mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA2 mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up. Results: Baseline levels of Lp-PLA2 mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA2 mass (217.8 ± 35.0 vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA2 activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp-PLA2 mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA2 mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years. Conclusion: Lp-PLA2 mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy. [Copyright &y& Elsevier]

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.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.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. [ABSTRACT FROM AUTHOR]

Objective: Dihydropyridine calcium antagonists have been shown to retard atherogenesis in animal models and to prevent the development of early angiographic lesions in human coronary arteries. Endothelial dysfunction is an early event in the pathogenesis of cardiovascular disease. We investigated whether nifedipine could improve endothelial function in hypercholesterolemia, independently of changes in blood pressure or plasma lipids. Methods: First, we compared in vivo forearm vascular responses to the endothelium-dependent and independent vasodilators serotonin (5-HT) and sodium nitroprusside (SNP) in 11 patients with familial hypercholesterolemia before and after 6-weeks treatment with nifedipine GITS (60 mg, OD) and in 12 matched controls. In a subgroup of six control subjects forearm vascular function was also assessed before and after 6-weeks nifedipine GITS treatment. In vitro, we subsequently explored possible mechanisms underlying the effect of nifedipine on endothelial function. We investigated the effects of nifedipine on both NO production by recombinant endothelial NO synthase (eNOS) and endothelial cells, using 3H-arginine conversion, as well as on superoxide generation by endothelial cell lysates, using lucigenin enhanced chemiluminescence. Results: In hypercholesterolemia 5-HT-induced vasodilation was impaired (47±9% increase in forearm bloodflow vs. 99±8% in controls). Treatment with nifedipine completely restored 5-HT-induced vasodilation (113±13%), whereas it did not influence basal forearm vasomotion or SNP-induced vasodilation. Nifedipine did not alter forearm vascular responses in control subjects and did not alter blood pressure or plasma lipids. In vitro, we found no direct effect of nifedipine on NO production by recombinant eNOS or endothelial cells. However, we did observe a reduction in endothelial superoxide generation. Conclusions: Our data show that nifedipine improves endothelial function in hypercholesterolemia. It is suggested from our in vitro experiments that this effect is due to reduced NO degradation. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Background Mutations in the genes for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR , apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 ( LDLRAP1 ), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH. [ABSTRACT FROM AUTHOR]

Background Mutation(s) in genes involved in the low-density lipoprotein receptor (LDLR) pathway are typically the underlying cause of familial hypercholesterolemia. Objective The objective of the study was to examine the influence of genotype on treatment responses with alirocumab. Methods Patients from 6 trials (n = 1191, including 758 alirocumab-treated; Clinicaltrials.gov identifiers: NCT01266876 ; NCT01507831 ; NCT01623115 ; NCT01709500 ; NCT01617655 ; NCT01709513 ) were sequenced for mutations in LDLR , apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), LDLR adaptor protein 1, and signal-transducing adaptor protein 1 genes. New mutations were confirmed by Sanger sequencing. Results One or more specific gene mutations were found in 898 patients (75%): 387 and 437 patients had heterozygous LDLR defective and negative mutations, respectively; 46 had a heterozygous APOB -defective mutation; 8 patients had a heterozygous PCSK9 gain-of-function mutation; 293 (25%) had no identifiable mutation in the genes investigated. LDL cholesterol reductions at Week 24 were generally similar across genotypes: 48.3% (n = 131) and 54.3% (n = 89) in LDLR -defective heterozygotes with alirocumab 75 mg Q2W (with possible increase to 150 mg at Week 12) and 150 mg Q2W, respectively; 49.7% (n = 168) and 60.7% (n = 88) in LDLR -negative heterozygotes; 54.1% (n = 20) and 50.1% (n = 6) in APOB -defective heterozygotes; 60.5% (n = 5) and 94.0% (n = 1) in PCSK9 heterozygotes; and 44.9% (n = 85) and 55.4% (n = 69) in patients with no identified mutations. Overall rates of treatment-emergent adverse events were similar for alirocumab vs controls (placebo in 5 trials, ezetimibe control or atorvastatin calibrator arm in 1 trial), with only a higher rate of injection-site reactions with alirocumab. Conclusions In this large patient cohort, individuals with a wide spectrum of mutations in genes underlying familial hypercholesterolemia responded substantially and similarly to alirocumab treatment. [ABSTRACT FROM AUTHOR]

Background Patients with heterozygous familial hypercholesterolemia (HeFH) are characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. Long-term effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have not been thoroughly investigated in these patients. Objective We evaluated efficacy and safety of alirocumab, a PCSK9 inhibitor, vs placebo in patients with HeFH. Methods In total, 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies from four 78-week ODYSSEY trials were analyzed. In FH I and II, patients with baseline LDL-C levels ≥70/100 mg/dL ( n = 735), depending on documented cardiovascular disease history, received placebo or alirocumab 75 mg every 2 weeks (Q2W; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was ≥70 mg/dL). Separately, data were pooled from HIGH FH (baseline LDL-C ≥160 mg/dL) and patients with HeFH from LONG TERM (baseline LDL-C ≥70 mg/dL), where patients received placebo or alirocumab 150 mg Q2W ( n = 522). Results At week 24, alirocumab reduced LDL-C levels by −48.8% (75/150 mg Q2W; placebo: +7.1%) and −55.0% (alirocumab 150 mg Q2W; placebo: +1.3%) (both P < .0001 vs placebo; intention-to-treat analysis). Least-squares mean LDL-C levels of 69.1 to 75.6 mg/dL (alirocumab 75/150 mg/dL Q2W; baseline: 141.3 mg/dL) and 72.2 to 82.3 mg/dL (alirocumab 150 mg Q2W; baseline: 168.4 mg/dL) were achieved at weeks 24 to 78 (on-treatment analysis). Additional beneficial effects were observed in other lipids. Treatment-emergent adverse event rates were similar in the alirocumab (80.5%) and placebo groups (83.0%). Conclusions In this large cohort of patients with HeFH, alirocumab significantly reduced LDL-C levels. Alirocumab was generally well tolerated. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles. Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model. Out of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97–5.0) to 12.0 (95%CI 5.5–24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively. This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods. [Display omitted] • FH results in a markedly elevated lifetime risk for CAD, yet individual risk profiles are notably heterogeneous. • Dichotomous LDLR variant classification inadequately captures patient variability in LDL cholesterol levels and CAD risk. • This study presents a new classification approach using variant-specific LDL cholesterol percentiles to assess CAD risk. • FH-variant carriers had an overall 5-fold higher CAD risk compared with non-carriers. • A gradual increase in CAD risk of 2.2 to 12-fold was observed across variant-specific LDL cholesterol percentile strata. [ABSTRACT FROM AUTHOR]

In this review, we discuss the screening and treatment of familial hypercholesterolemia (FH), an autosomal dominant inherited disease, characterized by severely increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk for premature coronary heart disease (CHD). Genetic family based cascade screening for FH was shown to be cost-effective and a screening program with such an approach was carried out in the Netherlands from 1994 to 2014. Over 64,000 persons have participated in this program of whom 40.3% were found to carry an FH causing mutation. We will discuss the results of this screening program, as well as the scientific opportunities it has provided. Currently, statins and ezetimibe are the only registered LDL-C lowering treatment options for FH patients. Many of them do not attain the treatment goals that are recommended by treatment guidelines. In this review, we will also provide a comprehensive overview of promising new modalities that could lower LDL-C in FH patients. [ABSTRACT FROM AUTHOR]

Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (Q M = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (Q M = 8.3, df = 4, p = 0.08). Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants. [Display omitted] • Similar LDL-C reductions can be achieved through the two major classes of medications targeting PCSK9 in patients with FH. • Therapies targeting PCSK9 showed no statistical heterogeneity on LDL-C reduction among different types of genetic variants. • Statins and therapies against PCSK9 are a potent combination, which requires only one normal LDLR allele to reduce LDL-C. • The choice of therapy targeting PCSK9 could be based on convenience, patient choice and availability of the therapy. [ABSTRACT FROM AUTHOR]

Background: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing.Objectives: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran.Methods: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed.Results: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval: -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups.Conclusions: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents. [ABSTRACT FROM AUTHOR]

Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype. 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1–4.3% for mortality endpoints, versus 2.5–2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH). The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype. Image 1 • Familial hypercholesterolemia (FH) has not been the focus of large-scale placebo-control lipid-lowering outcome RCTs. • P ost-hoc analyses from 4S RCT (statin vs placebo) on the impact of lipid-lowering on outcomes in subjects with/out FH phenotype. • Subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L, vs <4.9, had similar relative reductions but greater absolute benefits in all-cause and cardiovascular outcomes. • Subjects with FH phenotype appear to associate greater relative and absolute benefit from the same magnitude of LDL-C lowering. • The FH phenotype may identify subjects with a greater vulnerability to LDL-C who may derive greater benefit from LDL-C reduction. [ABSTRACT FROM AUTHOR]

Background: Homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder, is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerotic cardiovascular disease. Statin treatment starts at diagnosis, but no statin has been formally evaluated in, or approved for, HoFH children.Objectives: The authors sought to assess the LDL-C efficacy of rosuvastatin versus placebo in HoFH children, and the relationship with underlying genetic mutations.Methods: This was a randomized, double-blind, 12-week, crossover study of rosuvastatin 20 mg versus placebo, followed by 12 weeks of open-label rosuvastatin. Patients discontinued all lipid-lowering treatment except ezetimibe and/or apheresis. Clinical and laboratory assessments were performed every 6 weeks. The relationship between LDL-C response and genetic mutations was assessed by adding children and adults from a prior HoFH rosuvastatin trial.Results: Twenty patients were screened, 14 randomized, and 13 completed the study. The mean age was 10.9 years; 8 patients were on ezetimibe and 7 on apheresis. Mean LDL-C was 481 mg/dl (range: 229 to 742 mg/dl) on placebo and 396 mg/dl (range: 130 to 700 mg/dl) on rosuvastatin, producing a mean 85.4 mg/dl (22.3%) difference (p = 0.005). Efficacy was similar regardless of age or use of ezetimibe or apheresis, and was maintained for 12 weeks. Adverse events were few and not serious. Patients with 2 defective versus 2 negative LDL receptor mutations had mean LDL-C reductions of 23.5% (p = 0.0044) and 14% (p = 0.038), respectively.Conclusions: This first-ever pediatric HoFH statin trial demonstrated safe and effective LDL-C reduction with rosuvastatin 20 mg alone or added to ezetimibe and/or apheresis. The LDL-C response in children and adults was related to underlying genetic mutations. (A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia [HYDRA]; NCT02226198). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Statins are currently the preferred pharmacological therapy in children with familial hypercholesterolemia (FH) with the aim to prevent premature cardiovascular disease (CVD). However, concerns have been raised that lowering cholesterol levels with statins could interfere with hormone production. In this study hormone concentrations were assessed in young adult FH subjects before and 10 years after the initiation of statins, and compared with their unaffected siblings. Methods All 214 FH children (8–18 years) who were previously randomized into a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, and their 95 unaffected siblings, were eligible. Women using oral contraceptives were excluded. Fasted blood samples were taken to measure lipids and testosterone (males), estradiol (females), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and dehydroepiandosterone (DHEAS). Results After ten years, gonadal steroid and gonadotropin concentrations were within the reference interval and did not differ between FH subjects (n = 88) and unaffected siblings (n = 62). Mean DHEAS concentrations (±standard deviation) in the FH subjects and female siblings were normally distributed within the reference interval, whereas male siblings had a higher mean DHEAS concentration than their FH brothers (12.9 [± 4.9] vs. 8.4 [± 3.0] μmol/L, respectively, p < 0.0001). Conclusion After ten years of statin treatment, testosterone, estradiol, LH and FSH concentrations in young adult FH patients are within the reference interval and comparable to their unaffected siblings. These results strengthen current guidelines that statins in FH subjects could be safely used from childhood onwards to prevent premature CVD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Some recently emerged lipid-lowering therapies are currently restricted to patients with homozygous familial hypercholesterolemia (HoFH), and studies are underway to also assess these therapies in patients with ‘severe heterozygous FH (HeFH)’. However, no uniform definition of ‘severe HeFH’ exists, although untreated low-density lipoprotein cholesterol (LDL-C) levels above 8 mmol/L (309 mg/dl) have been historically used to define this phenotype. Our aim was to define severe HeFH, to establish its prevalence and CVD risk, and to study the relative contribution of classical risk factors to CVD risk in HeFH patients. Methods and results: We analysed a cohort of 14,283 patients with molecularly defined HeFH, identified by the national FH screening programme in the Netherlands. Age and gender specific percentiles of untreated LDL-C were determined. The percentile corresponding to an LDL-C level of 8 mmol/L (309 mg/dL) in men aged 36–40 years (90th percentile) was selected as the cut-off value for severe HeFH. By applying this percentile-criterion to the whole cohort, 11% of the HeFH patients could be considered as having severe HeFH. Combined with an estimated HeFH prevalence of 1:300 in the Netherlands, this would translate into a prevalence of approximately 1:3,000 for severe HeFH. CVD risk was significantly increased in severe HeFH patients compared to non-severe HeFH patients (adjusted hazard ratio: 1.25 [95% CI: 1.05–1.51], p = 0.015). In line, male gender, increased age, increased BMI, smoking, hypertension, diabetes, high LDL-C and low high-density lipoprotein cholesterol were independent CVD risk factors in HeFH per se. Conclusions: We changed the commonly used static LDL-C level of 8 mmol/L for the identification of severe HeFH into an age and gender corrected percentile. This definition would theoretically result in a prevalence of 1:3,000 for severe HeFH. Patients with severe HeFH are at increased CVD risk compared to non-severe HeFH patients, which underscores the need for more aggressive LDL-C lowering these patients. [Copyright &y& Elsevier]

Abstract: Objective: Secretory phospholipase A2 (sPLA2) enzymes are thought to contribute to atherosclerosis. In this study we assessed levels of sPLA2 mass and activity, and their relationship to baseline characteristics of children with familial hypercholesterolemia (FH). Furthermore, we evaluated the effect of two years of pravastatin therapy on sPLA2 levels. Methods and results: sPLA2-IIA mass and sPLA2 activity were measured at baseline and after two years in 187 children with FH (aged 8–18 years) randomized to pravastatin or placebo. At baseline, median [IQR] sPLA2-IIA mass and sPLA2 activity levels were 7.2 [5.8–13.2] ng/ml and 36.4 [29.8–47.1] U/ml, respectively. Both sPLA2-IIA mass and sPLA2 activity were significantly correlated with high-sensitivity C-reactive protein (r = 0.33, p < 0.001 and r = 0.386, p < 0 .001, respectively), but not with other cardiovascular risk factors. Baseline levels of sPLA2-IIA mass and sPLA2 activity were not significantly associated with carotid intima-media thickness (cIMT) at baseline or at the end of follow-up. After two years, sPLA2-IIA mass and sPLA2 activity levels were not significantly reduced in the pravastatin group (p = 0.20 and p = 0.63, respectively), nor in the placebo group (p = 0.17 and p = 0.11, respectively). Changes from baseline did not differ between the treatment groups for sPLA2-IIA mass (p = 0.48) and sPLA2 activity (p = 0.88). Conclusions: sPLA2-IIA mass and sPLA2 activity were not significantly associated with cIMT in our pediatric FH cohort. This could indicate that the potential predictive role of sPLA2 as a biomarker of cardiovascular disease in children with FH is limited. Treatment with pravastatin did not reduce sPLA2-IIA mass or sPLA2 activity levels, as compared to placebo. Further studies with larger samples are required to address these issues. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Abstract: Background: Tendon xanthomas are characteristic for familial hypercholesterolemia (FH), and are associated with a higher risk of coronary heart disease (CHD). They often present with local inflammation. Inflammation may therefore be involved in their pathogenesis, as it is in the pathogenesis of CHD. A key role in the inflammatory pathway is played by the 5-lipoxygenase activating protein (ALOX5AP), which is known to influence the risk of CHD in FH. To test our hypothesis that ALOX5AP contributes to the development of xanthomas, we studied whether variants in the ALOX5AP gene influence the risk of xanthomas. Methods: We examined 945 patients with genetically confirmed heterozygous FH to determine whether they had tendon xanthomas. We genotyped seven polymorphisms in the ALOX5AP gene and constructed haplotypes of these polymorphisms. Results: The A allele of the rs9551963 polymorphism was associated with an increased risk of xanthomas (OR 1.52, 95% CI 1.11–2.07, p =0.01), while the A allele of rs17222842 was protective (OR 0.62, 95% CI 0.43–0.90, p =0.01). These two polymorphisms fully explained the risk estimates of all haplotypes. Individual haplotypes, however, were not significantly associated with xanthomas. Conclusion: Variants in the ALOX5AP gene are associated with the presence of xanthomas in FH patients. This result supports our hypothesis that inflammation is a pathogenetic factor of xanthomas. [Copyright &y& Elsevier]

Abstract: Elevated plasma plant sterol concentrations may be a risk factor of cardiovascular disease (CVD). Polymorphisms in the ABCG8 gene have been identified that contribute to the variation in plasma concentrations of plant sterols. However, data on the direct relationship of ABCG8 gene polymorphisms with CVD are lacking. Therefore, we examined associations between the D19H and T400K polymorphisms in the ABCG8 gene and CVD in a large cohort study of 2012 patients with heterozygous familial hypercholesterolemia (FH). A total of 244 individuals carried one or two alleles of the D19H variant and 568 individuals the T400K variant. During 94,809 person years, 648 (32.2%) individuals developed CVD of which coronary heart disease (CHD) was the most frequent cardiovascular event (N =553). In a Cox proportional hazard regression model adjusted for relevant cardiovascular risk factors, the D19H polymorphism was not associated with total CVD risk (p =0.2), but there was evidence of an association with higher risk of CHD (RR 1.42, CI 1.04–1.95; p =0.03). We observed no relationship between the T400K polymorphism and cardiovascular endpoints (p >0.1). However, FH individuals carrying the risk genotype for both ABCG8 variants had an increased risk of CVD (RR 1.57, 95% CI 1.13–2.18; p =0.01) and CHD (RR 1.72, 95% CI 1.23–2.41; p =0.002). In conclusion, our data suggest that genetic variation in the ABCG8 gene may influence the burden of atherosclerosis. [Copyright &y& Elsevier]

Abstract: Objectives: To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH). Background: The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH. Methods: In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking. Results: HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17–1.89, p =0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20–2.76, p =0.005). HapA was not associated with CHD. Conclusion: We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels. [Copyright &y& Elsevier]

Abstract: Introduction: Myeloperoxidase (MPO), an antimicrobial enzyme of the innate immune system, has been proposed to exert a wide array of pro-atherogenic effects throughout all stages of the atherosclerotic process. In view of the potent anti-inflammatory effects of statins in vitro, we evaluated the impact of statin therapy on plasma MPO levels in patients with heterozygous familial hypercholesterolemia (FH), treated with either intensive or conventional lipid-lowering therapy. Furthermore, we evaluated the relation between MPO levels and atherosclerosis progression, as determined by intima media thickness (IMT). Methods: We measured plasma MPO levels, lipoprotein profiles, high sensitivity-C-reactive protein (hs-CRP) as well as IMT of carotid artery segments in 122 FH patients at baseline and after 2-year treatment with atorvastatin 80mg or simvastatin 40mg QD. Results: Baseline median MPO values were 147pM (interquartile range (IQR) 122–217) and 144pM (IQR 118–216) and these increased significantly to 221pM (IQR 144–290) and 255pM (IQR 152–324) during 2-year follow-up in both the atorvastatin 80mg and simvastatin 40mg group, respectively. There was no correlation between MPO levels and IMT progression, change in lipoproteins or hs-CRP. Conclusion: In FH patients, statins do not prevent an increase in MPO levels during follow-up. Moreover, MPO levels are not associated with atherosclerosis progression in these patients. [Copyright &y& Elsevier]

Abstract: Studies on the clinical consequences of different low-density lipoprotein (LDL) receptor genotypes in adult patients have yielded conflicting results. We hypothesized that children with familial hypercholesterolemia (FH) provide a better model to perform genotype–phenotype analyses than adults. We tested this hypothesis and assessed the effect of LDL receptor genotypes on lipoprotein levels and on parental risk of cardiovascular disease (CVD) in a pediatric FH cohort. We identified 75 different LDL receptor mutations in 645 children with heterozygous FH; in these children, null alleles were clearly associated with more elevated LDL cholesterol levels compared to receptor-defective mutations. Familial factors explained 50.4% of the variation in LDL cholesterol levels of this pediatric cohort compared to only 9.5% in adults. Parental CVD risk was not significantly different between carriers of null alleles and receptor-defective mutations (RR, 1.22; 95% CI, 0.76–1.95; p =0.4). The N543H/2393del9 mutation was associated with a less deteriorated lipid profile and the parents had less often CVD relative to parents with other mutations (RR, 0.39; 95% CI, 0.20–0.78; p =0.008). We could confirm that children with FH provide a better model to perform genotype–phenotype analyses. In particular, children with null alleles had significantly more elevated LDL cholesterol levels than carriers of other alleles but this was not associated with higher risk of CVD in the parents. Nonetheless, a specific LDL receptor mutation was associated with less deteriorated lipoprotein levels and a milder CVD risk. [Copyright &y& Elsevier]

: ObjectivesIn the present study, we investigated the effects of statins on serum levels of soluble CD40 ligand (sCD40L) in patients with familial hypercholesterolemia (FH).: BackgroundAtherosclerotic disease seems to involve inflammatory and immunologic mechanisms, and sCD40L has recently been identified as one of the key players in the atherosclerotic process. HMG-Co A reductase inhibitors, statins, have been recognized as immunomodulators and reduce cardiovascular events and mortality, but the effects of statins on sCD40L has not been clarified.: MethodsIn a randomized, double-blind, clinical trial, as part of the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial, 110 patients with FH were given atorvastatin 80 mg/daily (n = 57) or simvastatin 40 mg/daily (n = 53) for two years.: ResultsOur main findings were: 1) at baseline patients with FH had significantly higher (approximately 27-fold) serum levels of sCD40L than healthy controls; 2) statin therapy markedly decreased serum levels of sCD40L (approximately 40% reduction); 3) this decrease in sCD40L was found during both “aggressive” (i.e., atorvastatin) and “conventional” (i.e., simvastatin) statin therapy and was not correlated with the degree of reduction in cholesterol levels.: ConclusionsOur findings may suggest enhanced CD40L-CD40 interaction in FH and that this inflammatory response may be downregulated by statins. [Copyright &y& Elsevier]

: ObjectivesThis study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH).: BackgroundEndothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD.: MethodsThe study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment.: ResultsAt baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% ± 4.3% vs. 1.2% ± 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% ± 6.8% vs. 15.5% ± 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (−2.16 ± 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (−2.13 ± 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = −0.31, p < 0.05) and LDL-C (r = −0.31, p < 0.05).: ConclusionsOur data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible. [Copyright &y& Elsevier]

Statins decrease low-density lipoprotein cholesterol (LDL-C), and additionally, reduce triglycerides (TG) and raise high-density lipoprotein cholesterol (HDL-C) levels. This study evaluated the frequency of abnormal TG and HDL-C levels in patients with classical familial hypercholesterolemia (FH) and assessed therapeutic response at different baseline levels of these lipoproteins after 1 year of statin therapy. A total of 508 FH patients were included and mean LDL-C levels (8.37±2.12 mmol l−1) were severely elevated. After a washout period of 6 weeks, all patients started monotherapy with 80 mg simvastatin. Remarkably, LDL-C reduction was dependent on baseline LDL-C levels ranging from 51.1 to 45.5% in the top versus the bottom third of the LDL-C distribution. Unexpected in FH, elevated baseline TG levels were seen in 30% and low HDL-C levels in 15% of all patients. Also, changes in these lipoproteins were dependent on baseline levels; TG reduction was 40.7 versus 22.2% in patients with elevated versus normal levels, while HDL-C increase was 29.1 versus 11.4% in patients with low versus normal HDL-C levels. In conclusion, FH patients with the worst lipoprotein profile showed the greatest benefit from high-dose simvastatin treatment, since changes in these parameters were partly determined by baseline lipid levels. [Copyright &y& Elsevier]

Objectives: in patients with familial hypercholesterolemia (FH), the propensity towards atherosclerosis may vary considerably. In the general population, a positive family history is associated with an increased risk for cardiovascular events. Since endothelial dysfunction is predictive for future cardiovascular events, we evaluated whether FH-children with a positive family history of premature cardiovascular disease have more pronounced endothelial dysfunction compared to children with a negative family history. Study design: 50 FH children, 10–18 years, participated in this study. Thirty-one children had a positive family history for cardiovascular events (fh+) and 19 children had no events in the family (fh−). Nineteen matched siblings participated as controls. Endothelial function was assessed by testing the flow mediated dilatation (FMD) of the brachial artery. Results: baseline characteristics were comparable for fh+, fh− and controls. Lipid levels were significantly higher in FH children. In FH, FMD was impaired compared to controls (11.7±4.4 vs. 15.6±6.8%, P<0.03). In addition, FMD was significantly lower in fh+ compared to fh− (10.7±9.9 vs. 13.3±4.6%, P<0.05). Conclusion: In FH-children, endothelial function is impaired compared to matched controls. This impairment is most pronounced in FH children with a positive family history of premature cardiovascular disease. [Copyright &y& Elsevier]