For Familial Hypercholesterolemia Research Articles

RELATION BETWEEN ACHILLES TENDON THICKENING AND SEVERITY OF CORONARY ARTERY DISEASE DESPITE CLINICALLY DIAGNOSED FAMILIAL HYPERCHOLESTEROLEMIA IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION

Tendon xanthoma, represented as Achilles tendon thickening (ATT), is one of the important diagnostic criteria for familial hypercholesterolemia (FH). However, there are some cases with ATT who do not meet these criteria. This study aimed to investigate the severity of coronary artery disease (CAD)

A PATIENT DECISION AID FOR FAMILIAL HYPERCHOLESTEROLEMIA BASED ON PATIENT AND PROVIDER FEEDBACK

Patient Decision Aids (PDAs) can facilitate shared decision making between patients and healthcare providers. We aimed to develop a PDA for Familial Hypercholesterolemia (FH) based on feedback from patients, physicians and genetic counselors (GCs). We first drafted a paper-version PDA based on the

A comparison of scoring criteria for the prediction of mutations for Familial Hypercholesterolaemia (FH) in a cohort of Welsh lipid index patients and family relatives

Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality.Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study).We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1).A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype.This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress.

Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family

Background and aimsHypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41–0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). MethodsWe utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). ResultsWe did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. ConclusionsTaken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs.

Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil

Background and aimsThere is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. MethodsAll index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. ResultsOverall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704–0.784) and 0.730 (95% CI: 0.687–0.774), respectively, p=0.014. ConclusionsIn our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.

Abstract 434: The Majority of Outpatients With Severe Hypercholesterolemia at an Academic Tertiary Centre Have Not Been Screened for FH

Background: National and International guidelines recommend, as a minimum, that individuals with LDL-C ≥190mg/dL are asked about a family history of ASCVD and hypercholesterolemia to screen for familial hypercholesterolemia (FH), a monogenic condition that carries considerable ASCVD risk. However, FH is grossly underdiagnosed and undertreated in the US. One reason for this may be failure to screen severely hypercholesterolemic individuals for FH. Hypothesis: We evaluated the hypothesis that poor identification of FH might be due to inadequate screening for FH among individuals with severe hypercholesterolemia. Methods: An EHR query was used to identify active adult patients in the University of Pennsylvania outpatient EHR database (N=310 802) with LDL-C≥220mg/dL, excluding secondary causes of hypercholesterolemia. The EHR was then systematically reviewed for structured notation of family history information. Result: The query identified 3,475 individuals with severely elevated LDL-C. Among them, only 47.9% (1666) had family history data relating to ASCVD (968), hypercholesterolemia (336) or both (362) in the EHR. The history was positive in 94.2% (1569) of these cases. Overall, patients with LDL-C ≥220mg/dL were more likely to be screened (OR 1.57; 95% CI 1.47-1.68) than those with LDL &lt;220mg/dL. Within the former group, the odds of being screened were higher in Caucasians (OR 1.52; 95% CI 1.33-1.75), with more severe LDL-C elevation or a history of ASCVD (OR 1.36; 95% CI 1.10 - 1.67). Conversely, the presence of diabetes (OR 0.73; 95% CI 0.61-0.86) or hypertension (OR 0.82; 95% CI 0.72-0.94), made screening less likely to occur. Interestingly, the setting of clinical care was also important; individuals seen in secondary care (OR 1.68; 95% CI 1.41-2.26), general (OR 1.69, 95% CI 1.47-1.95) or preventative cardiology (OR 1.82; 95% CI 1.47-2.25) were more likely to be screened. Finally, statin prescription was more common in those screened (OR 1.39; 95% CI 1.16-1.88), but this did not affect LDL-C goal achievement. Conclusion: At a large academic centre, the majority of outpatients with severe hypercholesterolemia had no record of being screened for FH. This report sheds light on factors that might be relevant to the underdiagnosis of FH in the US.

Five year experience of scoring criteria for familial hypercholesterolaemia (FH) genetic testing in wales: Should the criteria be refined to include age?

Five year experience of scoring criteria for familial hypercholesterolaemia (FH) genetic testing in wales: Should the criteria be refined to include age?

A qualitative study of patients' perceptions of the value of molecular diagnosis for familial hypercholesterolemia (FH).

For many years, familial hypercholesterolemia (FH), an inherited disorder, has been diagnosed using phenotypic features plus family history of early onset cardiovascular disease (CVD), and has been successfully treated using statin therapy. DNA testing is now available and this has been incorporated into familial cascade screening programmes in many parts of Europe. Little is known about patients' perceptions of the value of undergoing molecular diagnosis for FH. In-depth interviews were carried out with patients (n=38) being treated for FH who were the first in their family to undergo DNA testing for FH. Data were analysed thematically. While interviewees regarded DNA testing as an unexceptional event, it was seen as a positive innovation because it confirmed that their family carried a particular disorder, offered an aetiological explanation for their hypercholesterolemia and provided information about their own and family members' future risks. From the patient perspective, the main benefit of molecular diagnosis lies in its ability to provide information which allows (younger) family members to access genetic screening and, thus, timely treatment. The implications for future developments in genetic services and the need to investigate further the provision of molecular testing in mainstream specialties are briefly discussed.

Diagnostic scoring for familial hypercholesterolaemia in practice.

Diagnostic scoring for familial hypercholesterolaemia (FH) can be used either to screen for possible FH or guide the selection of patients for genetic (DNA) testing. We review the published diagnostic criteria and discuss the options for future development. Scoring systems have been developed internationally based on lipid values and various combinations of clinical signs and cardiovascular history. The predictive value varies according to the test population, be it lipid clinic referrals, general population, or relatives of patients with FH. Also, there is increasing recognition of genetic heterogeneity in FH so that criteria are of differing predictive value depending on the genetic variant of FH. These clinical scoring systems are increasingly used to guide selection of patients for FH genetic testing but no single approach has yet emerged as the system of choice. Further refinement of these scoring tools using more sophisticated calculators are superseding the more manual approaches. These are well suited to web-based tools or smartphone applications.

Predictors of cardiovascular events after one year of molecular screening for Familial hypercholesterolemia

Background and aimsThis study reports the first year follow-up of individuals enrolled in Brazil’s genetic cascade screening program for Familial Hypercholesterolemia (FH), Hipercol Brasil. Predictors for the occurrence of cardiovascular (CV) events in individuals screened for FH were studied. Methods: This is an open prospective cohort of individuals who were included in a cascade genetic screening program for FH. The first prospective follow-up was carried out one year after patients received their genetic test result. Individuals included in this study were index cases (probands) and relatives with identified (M +) or not genetic mutations (M −). Logistic regression analysis was performed to determine predictive variables for the occurrence of CV events censored at one-year of follow-up. ResultsA total of 818 subjects were included, 47 first CV events were ascertained, with 14 (29.7%) being fatal. For index cases, the only factor independently associated with increased risk of CV events was the presence of corneal arcus (OR: 9.39; 95% CI: 2.46–35.82). There was an inverse association of CV events with higher HDL-cholesterol levels (OR: 0.95; 95% CI: 0.90–0.99). For M+ relatives, risk factors associated with increased CV events risk were diabetes mellitus (OR: 7.97; 95% CI: 2.07–30.66) and tobacco consumption (OR: 3.70; 95% CI: 1.09–12.50). ConclusionsA high one-year incidence of CV events was found in this cascade-screening cohort. Predictors of events differed between index cases and relatives and can be useful for the development of preventive efforts in this highly susceptible group of individuals.

Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy.

BackgroundThe familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low‐density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype.MethodsWe used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR‐associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype‐phenotype correlation in our previous screening.ResultsWe showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes.ConclusionThe p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.

Web based tools to assess eligibility for genetic testing for Familial Hypercholesterolaemia (FH)

Selection of patients who are appropriate for genetic testing for FH is a balance between diagnostic yield and cost. The Wales FH service has implemented a clinical scoring system to guide the selection of patients based on lipid levels, personal and family history of cardiovascular disease plus physical signs. In an evaluation of 623 patients referred to lipid clinics, the proportion of patients with a mutation ranged from 4% in those scoring 5 or less to 85% in those scoring >15.

Familial Hyperlipidemia Screening, Treatment and New Considerations

We present a case of a 47-year-old male who came to the endocrinology department at the request of his GP. He was noted to have elevated lipid levels, twice the normal range. Genetic testing was performed which showed he was heterozygous for familial hypercholesterolemia (FH). His three children subsequently had their lipid levels tested. They all had elevated lipids (cholesterol and LDL) and tested positive for FH. This case highlights the importance of lipid screening in children as the prevalence of FH is 1 in 200, which is higher than previously thought. This has led to the underdiagnosis of FH in both the pediatric and adult population. Often on initial presentation of the disease, irreversible damage has been done increasing the patients’ morbidity and mortality. With newer drugs being introduced and the persistent push by the National Heart, Lung and Blood Institute Expert Panel towards initiating a child screening protocol, there is hope that this disease will be manageable and less detrimental to

The impact of LDLR function on fibroblast growth factor 21 levels.

Fibroblast growth factor 21 (FGF21) has been described to have beneficial effects on glucose and lipid metabolism, and FGF21 analogs are currently evaluated in phase 1 trials. However, the complete spectrum of effects and regulators of FGF21 is yet partly elucidated. Recent studies have shown that FGF21 plays a role in transmembrane cholesterol transport. We set out to examine the association between FGF21 and LDLR mediated transmembrane cholesterol transport, by comparing FGF21 levels in patients with genetically impaired LDLR function and unaffected relatives. Secondly, we explored whether the severity of the LDLR mutation was associated with FGF21 levels. We performed a cross-sectional study in carriers of an LDLR mutation and their unaffected relatives. Subjects were eligible if they participated in the Dutch national screening program for familial hypercholesterolemia (FH), were 18-55 years old, and were carrier of a pathogenic LDLR mutation with an untreated LDL-C level below the 75(th) or above the 90(th) percentile of the general population, or did not carry an FH mutation. The outcome measure was the level of FGF21, which was assessed using ELISA. We included 224 carriers of an LDLR mutation and 148 unaffected relatives. FGF21 levels were lower in LDLR mutation carriers compared to unaffected relatives (median [interquartile range]: 96.92 [60.80-174.05] versus 136.98 [77.34-219.47] pg/mL, respectively; p=0.08), but after adjusting for potential confounders, there was no association between LDLR mutations and FGF21 levels (p=0.70). Neither, did we find a relationship between the severity of LDLR mutations and FGF21 levels (p=0.51, after adjustment for potential confounders). We showed that levels of FGF21 are not different in patients with and without LDLR mutations, which suggests that decreased LDLR expression does not have a negative effect on FGF21 levels. Given the potential beneficial effects of FGF21 analogs on lipids and lipoproteins in a phase 1 study, we deem this of great interest for future treatment options for FH patients.

Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales

Background/ObjectiveFamilial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. Methods623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. ResultsThe proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. ConclusionThese criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH.

Transmission of LDLR Mutation From Donor Through Liver Transplantation Resulting in Hypercholesterolemia in the Recipient

Donor-transmitted disease in organ transplantation is uncommon, but possible. The LDL receptor (LDLR), a key regulator of lipoprotein metabolism, is abundant in the liver. Mutations in the LDLR gene, leading to reduced LDLR activity, are the main cause for familial hypercholesterolemia (FH). The estimated prevalence of FH is 1/200–1/500 in the population indicating that there are 14–34 million individuals with FH worldwide. We describe a patient who developed severe hypercholesterolemia after liver transplantation (LT). The 42-year-old female, who was transplanted because of hepatic epithelioid hemangioendothelioma with normal liver function, exhibited an increase in plasma total cholesterol from 5.6 mmol/L (217 mg/dL) pretransplant to 11.7 mmol/L (452 mg/dL) at 6 months posttransplant. The respective increase in LDL cholesterol was from 3.30 (128 mg/dL) to 8.99 mmol/L (348 mg/dL). At 1 year, total and LDL cholesterol levels were 11.0 (425 mg/dL) and 7.81 (302 mg/dL), respectively. Sequencing of the coding region of LDLR from a liver graft biopsy revealed a splicing heterozygous mutation of LDLR, whereas no FH-related mutation was found in DNA extracted from the patient’s blood white cells. This confirmed the first reported case of a patient receiving a mutation in LDLR through LT. The case shows that a donor-transmitted disorder should not be overlooked as a possible cause for severe hypercholesterolemia.

A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia.

BackgroundGWAS have consistently revealed that LDLR locus variability influences LDL-cholesterol in general population. Severe LDLR mutations are responsible for familial hypercholesterolemia (FH). However, most primary hypercholesterolemias are polygenic diseases. Although Cis-regulatory regions might be the cause of LDL-cholesterol variability; an extensive analysis of the LDLR distal promoter has not yet been performed. We hypothesized that genetic variants in this region are responsible for the LDLR association with LDL-cholesterol found in GWAS.MethodsFour-hundred seventy-seven unrelated subjects with polygenic hypercholesterolemia (PH) and without causative FH-mutations and 525 normolipemic subjects were selected. A 3103 pb from LDLR (-625 to +2468) was sequenced in 125 subjects with PH. All subjects were genotyped for 4 SNPs (rs17242346, rs17242739, rs17248720 and rs17249120) predicted to be potentially involved in transcription regulation by in silico analysis. EMSA and luciferase assays were carried out for the rs17248720 variant. Multivariable linear regression analysis using LDL-cholesterol levels as the dependent variable were done in order to find out the variables that were independently associated with LDL-cholesterol.ResultsThe sequencing of the 125 PH subjects did not show variants with minor allele frequency ≥ 10%. The T-allele from g.3131C > T (rs17248720) had frequencies of 9% (PH) and 16.4% (normolipemic), p < 0.00001. Studies of this variant with EMSA and luciferase assays showed a higher affinity for transcription factors and an increase of 2.5 times in LDLR transcriptional activity (T-allele vs C-allele). At multivariate analysis, this polymorphism with the lipoprotein(a) and age explained ≈ 10% of LDL-cholesterol variability.ConclusionOur results suggest that the T-allele at the g.3131 T > C SNP is associated with LDL-cholesterol levels, and explains part of the LDL-cholesterol variability. As a plausible cause, the T-allele produces an increase in LDLR transcriptional activity and lower LDL-cholesterol levels.

Detection of variations and identifying genomic breakpoints for large deletions in the LDLR by Ion Torrent semiconductor sequencing

ObjectivesThe aims of this study were to 1) compare LDLR variant detection between Ion Torrent Personal Genome Machine (PGM) sequencing and conventional methods used for familial hypercholesterolaemia (FH) diagnosis i.e. exon-by-exon sequence analysis and multiplex ligation-dependent probe amplification (MLPA) and 2) identify genomic breakpoints for 12 cases of large deletions in LDLR previously identified by MLPA. MethodsThirty FH patient samples were selected, 22 with mutations previously determined. Primers were designed and optimised to generate six amplicons covering the entire LDLR and sequenced on a PGM. An additional twelve samples carrying MLPA variants were sequenced on the PGM followed by Sanger sequencing to establish the breakpoints. ResultsA total of 2179 LDLR variants were identified in the 30 samples, with 383 variants in the region sequenced that was common to both PGM and Sanger methods. Three discrepancies were identified; two of these were identified by visual inspection of the BAM files, whilst the remaining discrepancy was likely an artefact of the PCR approach. Approximate genomic breakpoints for the 12 MLPA variants were identified using PGM sequencing, and Sanger sequencing of these regions established causative breakpoints. Eleven different rearrangements/mutational events were found, with eight out of eleven occurring in Alus. Two of the three samples with exons 2–6del had identical breakpoints. Two samples with exons 11–12del had unique breakpoints, indicating separate ancestral origin or mutational events. ConclusionsThis study showed that Ion Torrent PGM sequencing is an accurate and efficient method to detect LDLR variants while providing additional information such as genomic breakpoints.

A DNA Microarray for the Detection of Point Mutations and Copy Number Variation Causing Familial Hypercholesterolemia in Europe

To facilitate genetic cascade screening for familial hypercholesterolemia (FH) in Europe, two versions (7 and 9) of a DNA microarray were developed to detect the most frequent point mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. The design of these microarrays is based on LIPOchip, version 4, which detects 191 LDLR and APOB mutations identified in Spanish patients with FH. A major improvement of LIPOchip, versions 7 and 9, is the ability to detect copy number variation (deletions or duplications of entire exons) in LDLR, thus abolishing the need to perform multiplex ligase-dependent probe amplification in patients with FH. The aim of this study was to validate a tool capable of detecting point mutations and copy number variations simultaneously and to evaluate its use and the newly developed software for analysis in clinical practice by reanalysis of several patients with known mutations causing FH. With the help of these validations, several aspects were analyzed, improved, and implemented in a newer version, which was evaluated through an internal validation.

The potential of mipomersen, an ApoB synthesis inhibitor, to reduce necessity for LDL-apheresis in patients with heterozygous familial hypercholesterolemia and coronary artery disease

Introduction: LDL-apheresis is a treatment option for familial hypercholesterolemia (FH) with country-specific thresholds for LDL-cholesterol (LDL-C) for initiation. Apheresis also reduces lipoprotein(a) [Lp(a)] and may be used to lower Lp(a) in high-risk patients. Mipomersen, an apolipoproteinB-synthesis-inhibitor, reduces LDL-C and Lp(a). We hypothesized that mipomersen may prevent the necessity for apheresis by reducing the both below thresholds.Methods: Data from a study in 123 patients with heterozygous FH and coronary artery disease on maximally tolerated lipid-lowering therapy were used to evaluate in what percentage adding mipomersen resulted in lipid-levels below apheresis-thresholds. Different thresholds were tested: LDL-C ≥ 2.59 mmol/l, ≥ 3.36 mmol/l, ≥ 4.14 mmol/l, Lp(a) ≥ 60 mg/dl.Results: Mipomersen decreased LDL-C by 28% (baseline 153 mg/dl), Lp(a) by 21% (baseline 45 mg/dl) (placebo no effect). Mipomersen reduced the percentage of patients with LDL-C ≥ 4.14 mmol/l from 39 to 2%, with LDL ≥ 3.36 mmol/l from 62 to 16%, with LDL ≥ 2.59 mmol/l from 98 to 54%, and with Lp(a) ≥ 60 mg/dl from 39 to 23%.Summary: When added to maximally tolerated lipid-lowering therapy, mipomersen may reduce the necessity for apheresis in many of these patients. In Germany, the threshold for apheresis for LDL typically is 2.59 mmol/l, for Lp(a) 60 mg/dl. Almost 50% of the patients could avoid apheresis with the addition of mipomersen. Further studies are warranted to evaluate whether patients who qualify for apheresis could be adequately controlled with mipomersen.