Heterozygous Familial Hypercholesterolemia Patients Research Articles

Efficacy and outcomes of inclisiran in the management of homozygous and heterozygous familial hypercholesterolemia: a systematic review and meta-analysis

Objective: To find out the efficacy of Inclisiran sodium in heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) patient groups. Methods: PubMed, Embase, and Clinicaltrials.gov databases were searched for the relevant studies. Atherosclerotic parameters considered included LDL-C, total cholesterol, PCSK9, apolipoprotein-B, and non-HDL-C. Primary outcomes were the percentage difference in atherosclerotic parameters at follow-up relative to baseline values. Our study examined these primary outcomes to determine whether there is a statistically significant difference between the HeFH and HoFH groups. The risk of bias was assessed by the Cochrane risk of bias tool. Results: Analysis of four ORION clinical trials unveiled the significant difference in pooled mean differences in LDL-C (HeFH: –48.62%, HoFH: –9.12%; P < 0.05) total cholesterol (HeFH: –30.31%, HoFH: –11.50%; P < 0.05), apolipoprotein-B (HeFH: –39.97%, HoFH: –14.68%, P < 0.05), and non-HDL-C (HeFH: –44.51%, HoFH: –12.22%; P <0.05) between HeFH and HoFH groups. However, the difference in the pooled mean difference in PCSK9 values (HeFH: –68.41%, HoFH: –56.25%; P = 0.2) between the HeFH and HoFH groups was statistically insignificant. Studies were of high quality. Conclusion: There was a significant difference in the reductions in atherosclerotic lipid parameters in heterozygous and homozygous populations after the administration of inclisiran except for the PCSK9 parameter. Further studies are needed to support this conclusion.

Adherence to the Healthy Nordic Food Index is associated with reduced plasma levels of inflammatory markers in patients with heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an inherited disease associated with hypercholesterolemia, and dietary treatment is part of the treatment. We aimed to assess the dietary pattern in relation to the Healthy Nordic Food Index (HNFI) in adults with and without heterozygous FH (HeFH), and to examine the associations between dietary quality and biomarkers related to cardiovascular disease in adults with HeFH. We included 205 adults (≥18 years) with HeFH who received follow-up at the Lipid Clinic in Oslo and compared them to controls (n=228). Dietary intake was assessed using a food frequency questionnaire and dietary quality was assessed using the HNFI. Blood samples were analysed for levels of blood lipids, plasma fatty acids (FAs), and markers of inflammation and platelet activation. The HeFH patients (median 60 years; 50.2% female; 25.9% in secondary prevention) had lower intake of total and saturated fat compared to controls (32.6 energy percent (E%) vs. 34.9 E%, and 9.6E% vs 12.0E%, respectively; p<0.001 for both). In the HeFH patients, increasing dietary quality was associated with increased plasma levels of the n-3 polyunsaturated FAs (PUFAs) eicosapentaenoic acid and docosahexaenoic acid, and the n-6 PUFA linoleic acid, and lower plasma levels of the inflammatory cytokines Tumor Necrosis Factor and interleukin-6, and of the platelet-derived inflammatory cytokines Platelet Factor 4 and Neutrophil-Activating Peptide-2. Norwegian patients with HeFH followed up at a Lipid Clinic eat healthier than controls. Adherence to a healthy dietary pattern is associated with higher plasma levels of n-3 and n-6 PUFA, and lower levels of inflammatory markers, including platelet markers. This may suggest that adherence to an overall healthy dietary pattern might be beneficial for HeFH patients independent of the cholesterol-lowering effect of the diet.

Clinical reality and challenges with familial hypercholesterolemia patients' management. 2024 results from the Regional Center for Rare Diseases (RCRD) Registry in Poland

Despite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients. The registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n=5). We studied 173 consecutive heFH patients, median age for adult population was 40years (range: 27-57), of whom 56.14% were women. Among the population, 82.1% were adults (n=142), and 31 were children (17.92%; median age 9 (8-13), females 58.16%). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6% had an LDL receptor (LDLR) mutation, while 23.4% had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7%), very high (22.1%), and extremely high (7.1%) risk groups. Triple therapy achieved treatment goals in 61.76% of adults and 70.97% of children. At baseline, 36.62% of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33% of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27% of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17% FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141mg/dl (107-184). For triple therapy, median achieved LDL-C was 52.5mg/dL (32-86.5). Overall median achieved LDL-C in the study population was 99.5mg/dl (57.5-145.4). PCSK9 inhibitors reduced LDL-C by 165.6mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p=0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66mg/dl (45% reduction; p=0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors. In Poland, FH patients are often diagnosed too late (usually over 40years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets - even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101.

A contemporary snapshot of familial hypercholesterolemia registries.

Familial hypercholesterolemia (FH) registries can capture unique data on FH concerning real-world practice, clinic epidemiology, natural history, cascade testing, cardiovascular consequences of late diagnosis, and use of healthcare resources. Such registries are also valuable for identifying and bridging the gaps between guidelines and clinical practice. We reviewed recent findings from the principal FH registries. Most adult patients with heterozygous FH (HeFH) are diagnosed late, undertreated, and do not reach guideline-recommended low density lipoprotein-cholesterol (LDL-C) goals. In children and adolescents with HeFH, detection relies principally on genetic testing and measurement of LDL-C levels. Similarly, the majority of patients with homozygous FH (HoFH) receive sub-optimal cholesterol-lowering treatments and do not attain recommended LDL-C goals, gaps being wider in lower income than higher income countries. In HeFH patients, men have a higher risk of atherosclerotic cardiovascular disease than women. The evolving data from FH registries provide real-world evidence for developing implementation strategies to address gaps across the continuum of care of FH worldwide.

Lipidomic profiling in patients with familial hypercholesterolemia: Abnormalities in glycerolipids and oxysterols

This study aimed to identify precise biomarkers and develop targeted therapeutic strategies for preventing premature atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH) by investigating the quantitative and qualitative abnormalities in the metabolic network of lipids in these patients using an advanced lipidomics platform. The study population comprised 18 homozygous (HoFH), 18 heterozygous (HeFH) FH patients, and 20 healthy controls. Cholesterol oxidation products (oxysterol, COPs) and main lipid classes were determined using gas chromatography-mass spectrometry. Results were expressed as percentages of total fat matter for lipid classes and percentages of total COPs for oxysterols. The principal component analysis (PCA) was also carried out, to highlight the correlation between studied parameters and groups investigated. Patients (both HoFH and HeFH) showed lower content of free fatty acids (FFAs) and greater values of triacylglycerols (TAGs) in comparison to controls. HoFH showed lower monoacylglycerols (P<0.01) and higher free cholesterol (FC) (P<0.05) when compared to HeFH and controls. The total content of COPs ranged from 1.96 to 4.25mg/dL, from 2.27 to 4.05mg/dL, and from 0.79 to 4.12mg/dL in healthy controls, HoFH and HeFH groups, respectively, with no significant differences between patients and controls. In general, the 7α-hydroxycholesterol (7α-HC) was greater than other COPs. However, no significant differences were found between the three studied groups. Moreover, an opposite trend was observed between 7α-HC and 7-ketocholesterol (7-KC). Additionally, when PCA was carried out, the first two PCs explained 92.13% of the total variance, of which the PC1 describes 53.94% of variance mainly correlated to TAGs, diacylglycerols (DAGs), and 7-KC. On the other hand, the PC2 was correlated primarily for FFAs, FC and esterified sterols (E-STE). In conclusion, abnormal levels of TAGs, DAGs and 7-KC were associated with HeFH while HoFH was associated with the abnormal amount of E-STE.

Monoclonal Anti-PCSK9 Antibodies: Real-World Data.

Background: Real-world data on the use of lipid-lowering therapy (LLT) in clinical practice show that about 80% of (very) high-cardiovascular (CV)-risk patients disregard the 2019 European Society of Cardiology (ESC) Guidelines' recommendations on dyslipidemias. The availability of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9mAb) should reduce this gap. Our aim was to provide data on PCSK9mAb use in clinical practice, investigating the achievement of the ESC Guidelines' recommendations in the real world. Methods: Between April 2018 and December 2022, patients who started on PCSK9mAb therapy (140 mg of evolocumab or 75 mg or 150 mg of alirocumab, subcutaneous injection every 2 weeks) were included in a prospective registry. Our cohort consisted of 256 patients: 95 (37.1%) were women (mean age: 65.43 ± 11.12 yrs), 53 (20.7%) were at high CV risk, and 203 (79.3%) were at very high CV risk. Results: After one year of PCSK9mAb treatment, nearly 60% of patients demonstrated full adherence to the ESC Guidelines' recommendations, defined as achieving at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C) levels along with reaching LDL-C target levels (≤55 and ≤70 mg/dL for very high and high risk, respectively). Concomitant high-dose statin therapy emerged as the primary predictor of LDL-C target attainment. Heterozygous familial hypercholesterolemia (HeFH), statin intolerance, and female gender were associated with a significant lower probability of achieving LDL-C target levels. Conclusions: Our analysis confirms that PCSK9mAb treatment is safe and effective, enabling 60% of our cohort to fully achieve the LDL-C guideline recommendations. The use of high-intensity statins emerged as a significant predictor of efficacy. Conversely, familial hypercholesterolemia and female gender were identified as predictors of therapeutic failure. Hence, it is crucial to address disparities in cardiovascular disease prevention between genders and to enhance strategies for managing elevated LDL-C in HeFH patients.

Coronary artery event-free or resilient familial hypercholesterolemia: what's in a name?

Familial hypercholesterolemia (FH) is an autosomal semi-dominant condition, characterized by excessive circulating low-density lipoprotein cholesterol (LDL-C) from birth that substantially accelerates the onset and progression of atherosclerotic cardiovascular disease (ASCVD), classically coronary artery disease (CAD). Elevated plasma LDL-C integrated over time is unequivocally the major determinant of ASCVD in heterozygous FH (HeFH); however, the wide variation in incidence and progression of ASCVD suggests a role for a wide spectrum of risk modifiers. We reviewed recent evidence describing the features of an ASCVD-free entity referred to as resilient FH among patients with HeFH. Compared with nonresilient FH patients, resilient patients are more likely to be female, and have a lower prevalence of ASCVD comorbidities, higher levels of HDL-C and larger HDL particles, as well as a lower level of lipoprotein(a). A lower SAFEHEART risk score is also an independent predictor of resilient FH. Gene expression studies also demonstrate that resilient FH patients are associated with a less atherogenic gene expression profile in relation to HDL metabolism and immune responses, as reflected by higher expression of ABCA1 and ABCG1, and lower expression of STAT2 and STAT3, respectively. A group of HeFH patients, referred as resilient FH, can survive to advance ages without experiencing any ASCVD events. Several key contributors to the event-fee CAD in HeFH patients have been identified. This could not only improve risk stratification and management for FH but also be of major importance for the general population in primary and secondary prevention. However, resilient FH remains an under-investigated area and requires further research.

Efficacy of Inclisiran in Patients Having Familial Hypercholesterolemia: Heterozygous Compared to Homozygous Trait, a Systematic Review and Meta-analysis.

To find out whether inclisiran sodium has different efficacy in heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) patient groups. We conducted the systematic review and meta-analysis of ORION clinical trials. PubMed, Embase, and Clinicaltrials.gov databases were searched for the relevant studies. Atheroscalerotic parameters considered for our objective were low-density lipoprotein cholesterol, total cholesterol, proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B, and nonhigh-density lipoprotein cholesterol. Primary outcomes were the percentage difference in atheroscalerotic parameters at follow-up relative to baseline values. Our study examined these primary outcomes to determine whether there is a statistically significant difference between the HeFH and HoFH groups. Risk of bias was assessed by the Cochrane risk of bias tool. Meta-analysis was performed when at least 2 studies reported on the same variable. Four ORION clinical trials provided the data related to the mean difference in the atheroscalerotic parameters at follow-up relative to baseline, of HeFH and HoFH patient populations, after administration of 300 mg inclisiran subcutaneously. We pooled together these mean differences for each group and applied a statistical test to analyze if the values were significantly different between the groups. The results of our study unveiled the significant difference in pooled mean differences in low-density lipoprotein cholesterol (HeFH: -48.62%; HoFH: -9.12%; P < 0.05), total cholesterol (HeFH: -30.31%; HoFH: -11.50%; P < 0.05), apolipoprotein (HeFH: -39.97%; HoFH: -14.68%; P < 0.05), and nonhigh-density lipoprotein (HeFH: -44.51%; HoFH: -12.22%; P < 0.05) between HeFH and HoFH groups. However, the difference in pooled mean difference in PCSK9 values (HeFH: -68.41%; HoFH: -56.25%; P = 0.2) between HeFH and HoFH groups was statistically insignificant. Studies were of high quality. There was a significant difference in the reductions in atherosclerotic lipid parameters in heterozygous and homozygous populations after the administration of inclisiran except for PCSK9 parameter. Further studies are needed to support this conclusion.

Risk Factors and Modifiers for Cardiovascular Disease Assessment of Patients with Heterozygous Familial Hypercholesterolaemia.

Background: The assessment of the risk of cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolemia (HeFH) is determined by conventional risk factors. However, factors modifying CVD, or risk modifiers, beyond conventional risk factors may inform their CVD risk assessment and the subsequent use of new therapies. This work identifies and characterises patients within a lipid clinic cohort with regards to conventional CVD risk factors and risk modifiers with a focus on those with HeFH. Methods: A study of consecutive adult patients attending our specialist lipid clinic was performed over a six-month period. The patient data recorded included demographics, clinical characteristics, risk factors and risk modifiers, biochemical profiles and genetic testing results. Risk modifiers were identified based on ESC/EAS guidance, and those with HeFH were compared to those without. Results: A total of 370 patients were included. Of these, 98 HeFH patients were identified (26%). Then, 52% of HeFH patients were stratified into the very-high risk category due to the presence of CVD risk factors. Risk modifiers were present in 73%. These included a family history of premature CVD (56%), obesity (28%), a sedentary lifestyle (13%) and a major psychiatric disorder (12%). Compared to the rest of the cohort, those with HeFH were less likely to have hypertension and more likely to have a family history of premature CVD. Conclusions: Half of patients with HeFH are categorised as having very high CV risk. Consideration of risk modifiers, particularly a family history of premature CV disease, increases this very-high-risk category further. This may have implications for the clinical application and access to novel treatments.

Lipoprotein(a) is associated with DNA damage in patients with heterozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal-dominant inherited disorder associated with atherosclerotic cardiovascular disease (ASCVD). HeFH subjects have a higher lipoprotein(a), i.e. Lp(a), concentration than the general population. Patients with FH are exposed to elevated levels of LDL from birth and ox-LDL may induce other oxidation pathways. The aim of the study was to determine the levels of markers of oxidative stress and DNA damage in patients with HeFH and describe the effect of Lp(a) on the resulting damage. Higher DNA damage was identified in patients with HeFH compared to the normolipidemic ones, and ASCVD was associated with greater damage. Oxidative stress markers were elevated in HeFH patients; however, only ox-LDL was higher in the ASCVD group and its level correlated with DNA damage. A positive correlation was found between DNA damage and Lp(a) concentration in the HeFH patients. Higher levels of Lp(a) were associated with greater DNA damage, especially in patients with HeFH and ASCVD. In HeFH patients, the optimal Lp(a) cut-off point associated with ASCVD is > 23.45 nmol/L, i.e. much lower than for the general population; however this cut-off point needs validation in a larger group of HeFH patients.

IPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia.

Defects in the low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. LDLR deficiency in hepatocytes leads to elevated blood cholesterol levels, which damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully understood. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSCs) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-ECs), we detected the LDLR protein predominantly in its mature form, whereas iPSC-ECs from FH patients have reduced levels of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of mutant LDLR iPSC-ECs revealed a unique transcriptome profile with downregulated genes related to monocarboxylic acid transport, exocytosis, and cell adhesion, whereas upregulated signaling pathways were involved in cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increase the susceptibility of endothelial cells to inflammation and oxidative stress. In combination with elevated extrinsic cholesterol levels, this may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies associated with FH.

Risk Assessment for Cardiovascular Events using Achilles Tendon Thickness and Softness and Intima-Media Thickness in Familial Hypercholesterolemia

This was a retrospective cohort study that aimed to determine cutoff values for major adverse cardiovascular events (MACEs) in patients with heterozygous FH (HeFH) for Achilles tendon (AT) thickness (ATT) measured by ultrasonography (US-ATT) and radiography (Xp-ATT), AT softness, and intima-media thickness of carotid artery (C-IMT), and to examine the effectiveness of these values as well as AT calcification as indexes in assessing risk for MACEs. The subjects were 391 clinically diagnosed HeFH patients. Kaplan-Meier curves were drawn based on the threshold values for the individual indexes calculated from ROC curves, and multivariate analysis was used to examine whether they were predictors of the development of MACEs. The median observation period was 1,239 days (700-1,827 days). Twenty-one subjects (5%) had MACEs during the observation period. The cutoff values for MACEs for US-ATT were 9.9 mm in males and 7.1 mm in females, and those for C-IMT were 1.6 mm in males and 1.5 mm in females. Subjects were classified into two groups according to whether they were above or below the cutoff values and presence of calcification, and we compared MACE rates between them. MACE rates were significantly increased in groups with AT thickening determined by ultrasonography (P＜0.001), AT softening (P＜0.001), presence of calcification in AT (P=0.016) and greater C-IMT (P＜0.001). However, classification according to Xp-ATT revealed no significant difference in MACE rate (P=0.112). These thresholds and examination for AT calcification will help in risk assessment for patients in Japanese FH practice and encourage stricter and more comprehensive management for patients who exceed the thresholds.

E670G PCSK9 polymorphism in HeFH & CAD with diabetes: is the bridge to personalized therapy within reach?

To assess the distribution of PCSK9 E670G genetic polymorphism and PCSK9 levels in patients with Coronary Artery Disease (CAD) and Heterozygous Familial Hypercholesterolemia (HeFH), based on the presence of type 2 Diabetes Mellitus (T2DM). The study included 201 patients with chronic CAD, including those with HeFH (n=57, group I) and without it (n=144, group II). DLCN was used to diagnose HeFH. The PCSK9 E670G (rs505151) polymorphism was genetically typed using the PCR-RFLP procedure. In both the patient and control groups, the genotype frequency matched the Hardy-Weinberg equilibrium distribution (P>0.05). There were twice more G alleles in group I (13, 11.4%) than in group II (17, 6.0%), and thrice more (1, 3.0%) than in the healthy control group; nevertheless, these differences weren't statistically significant. Simultaneously, PCSK9 levels were higher in HeFH patients (P<0.05) compared to non-HeFH patients not taking statins (n=63). T2DM was equally represented in groups I and II (31.6% vs. 33.3%). But carriers of AG+GG genotypes in group I had a higher chance of having a history of T2DM (RR 4.18; 95%CI 2.19-8.0; P<0.001), myocardial infarction (RR 1.79; 95%CI 1.18-2.73; P<0.05), and revascularization (RR 12.6; 95%CI 4.06-38.8; P<0.01), than AA carriers. T2DM was also more common among G allele carriers (RR 1.85; 95% CI 1.11-3.06; P<0.05) in patients with non-HeFH. T2DM in patients with CAD, both with HeFH and non-HeFH, in the Uzbek population was significantly more often associated with the presence of the "gain-of-function" G allele of the PCSK9 E670G genetic polymorphism.

Decreased Serum Stromal Cell-Derived Factor-1 in Patients with Familial Hypercholesterolemia and Its Strong Correlation with Lipoprotein Subfractions.

Stromal cell-derived factor-1 (SDF-1) is a chemokine that exerts multifaceted roles in atherosclerosis. However, its association with hyperlipidemia is contradictory. To date, serum SDF-1 and its correlations with lipid fractions and subfractions in heterozygous familial hypercholesterolemia (HeFH) have not been investigated. Eighty-one untreated patients with HeFH and 32 healthy control subjects were enrolled in the study. Serum SDF-1, oxidized LDL (oxLDL) and myeloperoxidase (MPO) were determined by ELISA. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly lower serum SDF-1 was found in HeFH patients compared to healthy controls. Significant negative correlations were detected between serum total cholesterol, triglycerides, LDL-cholesterol (LDL-C), apolipoprotein B100 (ApoB100) and SDF-1. Furthermore, serum SDF-1 negatively correlated with VLDL and IDL, as well as large LDL and large and intermediate HDL subfractions, while there was a positive correlation between mean LDL-size, small HDL and SDF-1. SDF-1 negatively correlated with oxLDL and MPO. A backward stepwise multiple regression analysis showed that the best predictors of serum SDF-1 were VLDL and oxLDL. The strong correlation of SDF-1 with lipid fractions and subfractions highlights the potential common pathways of SDF-1 and lipoprotein metabolism, which supports the role of SDF-1 in atherogenesis.

Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial.

Lerodalcibep, a novel small recombinant fusion protein of a PCSK9-binding domain (adnectin) and human serum albumin demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 ml SC dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep was evaluated in heterozygous familial hypercholesterolaemia (HeFH) patients requiring additional LDL-C lowering. Patients were randomized 2:1 to monthly SC injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the percent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. In 478 randomized subjects [mean age (range); 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L] lerodalcibep reduced LDL-C, compared to placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean(SE); 95% CI -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% CI -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < 0.0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended ESC LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. Lerodalcibep, a novel anti-PCSK9 small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with HeFH with a safety profile similar to placebo.

Compliance of heterozygous familial hypercholesterolemia patients: 5-years follow-up of the Russian familial hypercholesterolemia registry

Compliance of heterozygous familial hypercholesterolemia patients: 5-years follow-up of the Russian familial hypercholesterolemia registry

Effect of causative genetic variants on atherosclerotic cardiovascular disease in heterozygous familial hypercholesterolemia patients.

Heterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment. A retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study's participants for the occurrence of ASCVD. A causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305-4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017-1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899-3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups (p = 0.523). In this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.

Nailfold capillaroscopy reveals early peripheral microcirculation abnormalities in children affected by heterozygous familial hypercholesterolemia.

nailfold capillaroscopy (NCF) is a non-invasive imaging technique to seek peripheral microcirculation abnormalities in children and adults. Familial hypercholesterolemia is a genetic disorder caused by mutations capable of increasing blood levels of low-density lipoproteins cholesterol (LDL-C), thus triggering early atherosclerosis. The study aims at evaluating peripheral microcirculation in children with heterozygous familial hypercholesterolemia (HeFH) by means of NFC in comparison with healthy peers and at searching for possible correlations between these abnormalities and patients' lipid panel. thirty-six HeFH patients were enrolled (13 males and 23 females. Mean age 8±3years; age range 3-13years). They had increased levels of total cholesterol (237.9±34.2mg/dl) and LDL-C (154.2±37.6mg/dl). Both values were ≥95th gender and age specific centile. All the subjects in the study underwent NFC. In 69.4% of HeFH children nailfold capillaries were tortuous (p<0.00001 compared to healthy controls). In 41.6% the number of capillaries was markedly reduced (<7 capillaries/mm). The mean number of capillaries was 8.4±2.6/mm in HeFH and 12.2±1.4/mm in healthy controls (p<0.00001). In 100% of the sample size capillary blood flow was slowed down (p<0.00001). In 50% of the sample size a blood "sludge" phenomenon was seen (p<0.00001). No gender differences were detected. Sludge phenomenon was seen only in those with LDL-C over 99th centile (p<0.00001). NCF allows the identification of an early peripheral microvascular dysfunction in HeFH children which is similar to that already seen in atherosclerotic disease. Prompt identification of these capillary abnormalities may be crucial in implementing early prevention measures.

Salivary cholesterol level does not reflect cholesterolemia in children with heterozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia is a common genetic disease responsible for premature atherosclerosis. Therefore, early diagnosis and treatment are recommended to reduce cardiovascular risk. Usually, the screening is based on high plasma LDL-cholesterol. In children, blood testing is often an obstacle for screening. This study aims to evaluate the relevance of a salivary non-invasive LDL dosage in heterozygous familial hypercholesterolemia in a pediatric population. Prospective, case control, monocentric study comparaing the salivary cholesterol of 30 heterozygous familial hypercholesterolemia pediatric patients and 30 healthy age-matched controls with two different enzymatic kits (Amplite™ kit - AAT Bioquest® and Total Cholesterol Assay kit - CELL BIOLABS®, Inc). While the median serum total-cholesterol was significantly different in control and heterozygous familial hypercholesterolemia patients as expected, the median salivary cholesterol concentration was similar between the two groups and 1000 times lower than in serum. No correlation was found between salivary and serum cholesterol concentrations. Although cholesterol is detectable in saliva, our study suggests that the low salivary cholesterol concentrations result mostly from variable gingival bleeding, precluding any reliable use for Heterozygous Familial Hypercholesterolemia screening in children. L’hypercholestérolémie familiale est une maladie génétique fréquente responsable de lésion d’athérosclérose précoce. Ainsi, le diagnostic et le traitement précoce sont recommandés pour réduire le risque cardiovasculaire. Le dépistage actuellement recommandé est réalisé par le dosage sanguin de LDL-cholestérol. Chez l’enfant, le caractère invasif des prises de sang peut être un obstacle à la réalisation du dépistage. Cette étude a pour but d’évaluer la pertinence du dosage salivaire non invasif du LDL-cholestérol chez les enfants atteints d’hypercholestérolémie familiale. Étude prospective, cas-contrôle, monocentrique comparant le cholestérol salivaire chez 30 enfant témoins et chez 30 enfants hypercholestérolémiques apparié en age dosé par deux kits enzymatiques (Amplite™ kit - AAT Bioquest® et Total Cholesterol Assay kit - CELL BIOLABS®, Inc) Le cholestérol total sérique médian est significativement différent entre les deux groupes comme attendu, néanmoins les taux médians de cholestérol salivaire sont similaires entre les deux groupes et 1000 fois inférieures au sérum. Aucune corrélation n’a été retrouvée entre la salive et le cholestérol total sérique. Le cholestérol total est bien détectable dans la salive, notre étude suggère que le faible taux de cholestérol dans la salive résulte en majeur parti d’une contamination par micro-saignement gingival, ne permettant pas de l’envisager comme un outil fiable non invasif pour le dépistage de l’hypercholestérolémie familiale chez l’enfant.

LDL cholesterol targets rarely achieved in familial hypercholesterolemia patients: A sex and gender-specific analysis

Despite lipid lowering therapy (LLT), reaching LDL-C targets in patients with familial hypercholesterolemia (FH) remains challenging. Our aim was to determine attainment of LDL-C target levels and reasons for not reaching these in female and male FH patients. We performed a cross-sectional study of heterozygous FH patients in five hospitals in the Netherlands and Norway. Clinical characteristics and information about LLT, lipid levels and reasons for not being on LDL-C treatment target were retrospectively collected from electronic medical records. We studied 3178 FH patients (53.9% women), median age 48.0 (IQR 34.0-59.9) years. Median LDL-C before treatment and on-treatment was higher in women compared to men (6.2 (IQR 5.1-7.3) and 6.0 (IQR 4.9-7.2) mmol/l (p=0.005) and 3.0 (IQR 2.4-3.8) and 2.8 (IQR 2.3-3.5) mmol/L (p<0.001)), respectively. A minority of women (26.9%) and men (28.9%) reached LDL-C target. In patients with CVD, 17.2% of women and 25.8% of men reached LDL-C target. Women received less often high-intensity statins and ezetimibe. Most common reported reasons for not achieving the LDL-C target were insufficient effect of maximum LLT (women 17.3%, men 24.3%) and side effects (women 15.2%, men 8.6%). In routine practice, only a minority of women and men with FH achieved their LDL-C treatment target. Extra efforts have to be made to provide FH patients with reliable information on the safety of statins and their long-term effects on CVD risk reduction. If statin treatment is insufficient, alternative lipid lowering therapies such as ezetimibe or PCSK9-inhibitors should be considered.