Heterozygous Familial Hypercholesterolemia Research Articles

Attainment of the low-density lipoprotein cholesterol treatment target and prognosis of heterozygous familial hypercholesterolemia

Abstract Background and aims No previous study has investigated the association between attainment of low-density lipoprotein (LDL) cholesterol treatment target and better prognosis in patients with familial hypercholesterolemia (FH). The current research aimed to examine the association between attainment of LDL cholesterol treatment target and major adverse cardiac events (MACEs) in patients with FH to validate the current LDL cholesterol treatment targets in primary (< 100 mg/dL) and secondary (< 70 mg/dL) prevention settings. Methods The data of patients with FH who were admitted to our university hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, unstable angina, and myocardial infarction per 1,000 person-years, was calculated for each stratum for the attainment of LDL cholesterol target. Results The median follow-up duration was 12.6 years. In total, 132 MACEs were recorded during the follow-up period. The numbers of patients who attained the LDL cholesterol target in the primary and secondary prevention groups were 228 (31.9%) and 40 (11.9%), respectively. The event rates per 1,000 person-years for LDL cholesterol levels of < 100 and ≥ 100 mg/dL in the primary prevention group were 2.6 and 4.4, respectively. The event rates per 1,000 person-years for LDL cholesterol levels of < 70 and ≥ 70mg/dL in the secondary prevention group were 15.3 and 27.5, respectively. Conclusion Attainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese.

Plasma proteomics identify fibroblast growth factor 5 as a biomarker for genetically proven Familial Hypercholesterolemia

Abstract Background Subjects affected by genetically proven heterozygous Familial Hypercholesterolemia (FH) present lifelong exposure to high Low Density Lipoprotein Cholesterol ("LDL-C burden") causing premature ACVD. Nevertheless, the diagnosis of FH is still far from being optimal due to shortcomings of the clinical algorithms in detecting this form of severe ACVD since early decades of life (1) and because a significant proportion of FH present comparable LDL-C levels to that of subjects who are hypercholesterolemic but are not diagnosed as FH ("non-FH") (2). Purpose We previously demonstrated that targeted proteomics identify subjects at high Atherosclerotic Cardiovascular Diseases (ACVD) risk in the general populations beyond the known risk factors (3). Hence, we now tested whether targeted proteomics may differentiate FH subjects from the general population and from "non-FH". Methods We compared the plasma relative abundance of 264 proteins (Proximity Extension Assay; Olink) in 133 genetically proven FH with that of 586 normocholesterolemic subjects ("controls") and that of 55 non-FH (LDL-C between 190-220 mg/dL, not on statins). We trained and validated a Machine Learning (ML) boosting prediction model (4) in these cohorts to identify the protein markers representative of FH (Random Forest classifiers). Results Fibroblast Growth Factor 5 (FGF-5) resulted as the most powerful plasma protein in differentiating FH subjects from the controls, with an excellent performance (Area Under the Curve (AUC)=0.995 (0.985-1.000); sensitivity=100%; specificity=99.54%; P<0.0001). FGF-5 also emerged as the top protein in differentiating the FH subjects from non-FH (AUC= 1.000 (0.914-1.000; sensitivity=100%, specificity=100% and P<0.001). Finally, when the two groups were matched for LDL-C, FGF-5 still differentiated the FH from the non-FH subjects, (AUC=1.000 (0.914-1.000), sensitivity=100%, specificity=100%, p<0.001). Conclusions FGF-5 allows a clear-cut identification of FH versus controls and, of even more importance, from non-FH with the same LDL-C. The LDL-C burden might be responsible for our findings.

Abstract 16180: The Adherence and LDL-C Lowering Effect of Inclisiran Among Patients Who Received Treatment at Outpatient Clinics

Introduction: Inclisiran is a novel small interfering RNA (siRNA) indicated as an adjunct to diet and maximally tolerated statin to lower LDL-C among adults with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) in the US. It is administered subcutaneously initially, again at 3 months, and then every six months by an HCP. Subsequent doses may be administered within three months after the scheduled dose without restarting a new dose schedule. Metro Infusion Center (MIC) is one of the largest infusion centers across the US with over 200 centers in 38 states and has clinician oversight over each administration. Hypothesis: To describe the real-world adherence to inclisiran and changes in low-density lipoprotein cholesterol (LDL-C) levels associated with inclisiran use at MICs. Methods: Patient charts for those who initiated inclisiran from March 1, 2022 to November 31, 2022 were reviewed retrospectively. Demographics and clinical characteristics at initiation were collected and patients were followed until May 2023 for the current analysis. The study outcomes included the proportion of eligible patients who received the 2 nd or 3 rd dose and the percent change in LDL-C levels from baseline to the latest available data. Results: A total of 562 patients were included in the analysis from 107 different MICs in over 21 states. Mean (SD) age was 70.6 (9.6) years; 51% were female. The majority of patients (80%) were covered by Medicare. 492 (88%) had a history of ASCVD and 60 (11%) had HeFH. Mean (SD) baseline LDL-C was 147.6 (59.9) mg/dl. Of the 562 patients initiated inclisiran, 531 (95%) received their 2 nd dose, and 91% received the 2 nd dose within ±7 days of the schedule. There were 233 patients eligible to receive a 3 rd dose, 196 (84%) of them had received the 3 rd dose. Among 274 patients who had the LDL-C measured after inclisiran initiation, the average LDL-C reduction from baseline was 46.3%. On average, the first LDL-C measurement was taken at 3 months after receiving at least one dose of Inclisiran. Conclusions: These real-world data demonstrate high adherence to inclisiran with LDL-C reductions of 46.3% at 3 months. This finding was consistent with the ORION clinical development program.

Abstract 18931: A PCSK9 and APOB Double Heterozygote Presenting Phenotypically Similar to Homozygous Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is an inherited disorder associated with mutations in APOB, PCSK9 and LDLR genes. Heterozygous FH (HeFH) generally has one gene mutation. Homozygous FH (HoFH) has two mutations in the same gene and is characterized by vastly elevated plasma LDL-C, accelerated ASCVD and resistance to standard lipid-lowering therapy. Combinations of mutations can present with a phenotype similar to HoFH. We present a double heterozygous patient with unreported mutations in PCSK9 and APOB genes, exhibiting clinical features of HoFH. Hypothesis: Patients with multiple gene mutations for FH can present clinically similar to HoFH and would benefit from novel lipid lowering therapies Methods: 73-year-old female with a history of diabetes and hyperlipidemia presented in 2018 with dyspnea on exertion. Cholesterol (TC) and triglycerides (TG) were 430 and 715 mg/dl respectively, on rosuvastatin 40 mg and omega 3 fatty acids. Physical exam showed arcus senilis. A nuclear stress test showed ST depressions in inferolateral leads but normal scintigraphy. Genetic testing revealed APOB and PCSK9 mutations. She was then treated with rosuvastatin, icosapentyl ethyl, ezetimibe and fenofibrate. TC, LDL, TG and ApoB levels were 463, 236, 747 and >240 mg/dl respectively. Evolocumab was added, with reduction of TC, TG and ApoB levels to 326, 432 and 182mg/dl, despite maximal available therapy. Results: Genetic testing revealed APOB variant NP_000375.2:p.Gln3378His and PCSK9 variant NP_777596.2:pAla544Thr, which were unreported mutations with unknown clinical significance. Genetically, this patient is a double heterozygote but expresses a phenotype similar to HoFH due to a poor response to maximum therapy. Conclusions: Although usually genetically defined, the phenotype of HoFH can present with different genetic variations. Chaudhry et al established genetic diagnosis of HoFH in 0.9% of patients initially diagnosed as HeFH, of which 3 were true homozygotes and 3 were compound heterozygotes. These findings support the idea that various heterozygous combinations of mutations in the genes for LDLR, APOB and PCSK9, may present clinically similar to HoFH. Patients with these mutations could benefit from novel agents such as evinacumab.

Abstract 18696: Berberine as a Supplement to Guideline-Based Lipid Management of a Patient With Heterozygous Familial Hypercholesterolemia: A Case Presentation

Description of Case: A 62-year-old female presented for a lipidology consult. Labs revealed total cholesterol >450 mg/dL, Lp(a) 42 mg/dL, and LDL-P 2938. She was not on any lipid lowering therapy. A clinical diagnosis of heterozygous familial hypercholesterolemia (HeFH) was made. She reported occasional chest pain with both cardiac and noncardiac features. She had no personal history of CAD, and her family history revealed a mother and maternal grandfather with CAD in their 50s. A CCTA was performed, which revealed mild-moderate plaque in the ostial left circumflex (25-49%) and a CAC score of 124 (90-95th percentile). She was started on rosuvastatin 10mg daily and alirocumab with reduction of her LDL-C to 247 mg/dL. Given documented CAD, LDL-C <55 mg/dL was targeted. She had intolerable side effects to combination ezetemibe plus bempadoic acid and lomitapide. Evinacumab or LDL pheresis were offered, and the patient preferred to start evinacumab. Alirocumab was stopped. With rosuvastatin plus evinacumab, her LDL-C improved to 198 mg/dL. Berberine 1000mg was added to her regimen and resulted in further reduction of her LDL-C to 117 mg/dL. Discussion: Long used in Traditional Chinese and Ayurvedic medicine, Berberine is an alkaloid found in plants such as barberry and tree turmeric. Berberine suppresses PCSK9 transcription by regulating hepatocyte nuclear factor 1 alpha, a binding site located upstream from the PCSK9 gene promoter. The role of supplements in lipid management remains unknown. We describe a case of HeFH in which berberine yielded an 81 mg/dL absolute reduction (41% relative reduction) in LDL-C when added to guideline-based therapy. In a dedicated integrative lipidology practice, berberine may be an effective supplement to the pharmaceutical management of severe hyperlipidemia.

Abstract 12945: Six-Month Adherence Among Early Inclisiran Initiators vs. Anti-PCSK9 mAbs Users: A Retrospective Analysis of US Claims Databases

Introduction: Poor adherence with statins is an obstacle in achieving LDL-C targets for patients with atherosclerotic cardiovascular disease (ASCVD). Inclisiran is a first-in-class, long-acting, small-interfering RNA approved as an adjunct to diet and maximally tolerated statin for adults with ASCVD or heterozygous familial hypercholesterolemia who require additional LDL-C lowering. It is initially administered subcutaneously by an HCP, again at 3 months and then twice yearly. Real-world studies assessing adherence of inclisiran are limited. Hypothesis: This study evaluated treatment adherence at 6 months for patients who newly initiated inclisiran, alirocumab (every 2 weeks or 1/month) or evolocumab (every 2 weeks or 1/month) since 2022. Methods: This retrospective, observational study utilized the US Komodo Health database from 1/1/21 - 2/8/23. Komodo Health is a nationally representative longitudinal database that captures 330 million patients in the US from open and closed administrative databases. Patients were aged ≥18 years, had 12 months of continuous enrollment (CE) before the index date, 6 months CE after the index date and a first claim for inclisiran, alirocumab, or evolocumab in the identification period (1/1/22 - 10/31/22). Adherence was defined as the proportion of days covered (PDC): the number of days covered by the drug divided by the observational period (6 months after index date). Poor adherence was defined as PDC <80%. Results: A total of 981 patients had ≥6 months of CE after the index date and were in the inclisiran cohort;11,330 patients were in the alirocumab cohort and 30,515 in the evolocumab cohort. Mean (SD) 6-month adherence was highest for inclisiran at 0.85 (0.22) followed by 0.72 (0.30) for alirocumab and 0.70 (0.30) for evolocumab. The proportion of patients with high adherence (PDC ≥0.8) was 69.9% for inclisiran, followed by 51.0% for alirocumab and 48.6% for evolocumab. Of patients in the inclisiran cohort (n=981), 70.9% received a second dose with a mean time of 90.9 (32.0) days between doses. Conclusions: Early evidence post launch shows patients initiating inclisiran had higher adherence vs anti-PCSK9 mAbs. Inclisiran is a new option for patients with ASCVD who may have difficulty reaching their LDL-C target.

Abstract 11400: Coronary Artery and Carotid Artery Plaques in Patients With Heterozygous Familial Hypercholesterolemia

Background: Little is known regarding the formation coronary and carotid plaques and their impact on cardiovascular disease in patients with familial hypercholesterolemia (FH). Objectives: We aimed to determine 1) when coronary and carotid plaques develop, 2) if the development of coronary and carotid plaques are correlated and 3) if these plaques are associated with major adverse cardiac events (MACEs). Methods: This was a retrospective review of 622 patients with heterozygous FH at Kanazawa University Hospital, assessed coronary and carotid plaque scores using coronary computed tomography and carotid ultrasound within 1 year. Spearman correlation coefficients were assessed among variables. Risk factors for MACEs were determined using the Cox proportional hazard model. Results: These scores were significantly correlated (Spearman’s r=0.82; p <0.001 in males and Spearman’s r=0.87; p <0.001 in females). We observed 132 MACEs during the median follow-up period of 13.2 years. Coronary and carotid plaque scores were significantly associated with the occurrence of MACE (hazard ratio: 3.33; 95% confidence interval: 1.88-4.78; p <0.001, hazard ratio: 2.24; 95% confidence interval: 1.28-3.20; p <0.001, respectively). The regression equations between age and the coronary and carotid artery plaque scores, respectively, were Y=0.358X-9.44 and Y=0.146X-3.68 in males, and Y=0.330X-11.76 and Y=0.121X-3.60 in females ( p <0.001 for all). Conclusion: Coronary and carotid plaque scores were significantly correlated, and both were independently associated with MACEs. Based on the regression equations, the average age of onset of coronary and carotid artery plaque developments, respectively, were 26 and 25 years old in males and 35 and 30 years in females.

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.

Evolocumab in paediatric heterozygous familial hypercholesterolaemia: cognitive function during 80 weeks of open-label extension treatment.

PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. ClinicalTrials.gov identifier: NCT02624869.

Real-World Effectiveness of PCSK9 Inhibitors in Reducing LDL-C in Patients With Familial Hypercholesterolemia in Italy: A Retrospective Cohort Study Based on the AIFA Monitoring Registries.

Background Information on the real-world use of proprotein convertase subtilisin kexin 9 inhibitors (PCKS9is) in familial hypercholesterolemia are limited. We evaluated the pattern of prescription and the long-term efficacy of alirocumab and evolocumab in Italian patients with familial hypercholesterolemia in clinical practice. Methods and Results The data set for analysis was extracted from the PCKS9i Italian Medicines Agency (AIFA) registry and included 2484 patients with heterozygous familial hypercholesterolemia (HeFH) and 62 patients with homozygous familial hypercholesterolemia (HoFH) who were prescribed PCKS9is from February 2017 to December 2021. As the follow-up schedules were not prespecified and could vary, persistence and adherence as well as low-density lipoprotein cholesterol (LDL-C) changes during 2 years of treatment were analyzed in a final cohort of 1299 patients with familial hypercholesterolemia. At baseline, 53.8% of patients with HeFH and 69.4% of patients with HoFH were receiving maximally tolerated lipid-lowering therapies, while 45.9% of patients with HeFH and 30.7% of patients with HoFH reported statin intolerance; mean LDL-C was 197.7±52.3 mg/dL in HeFH and 252.0±106.2 mg/dL in HoFH. The 6-month persistence and adherence to therapy were >85%, and LDL-C reduction reached 58.6% (to 79.7 mg/dL) in HeFH and 57.6% (to 95.1 mg/dL) in HoFH after 24 months of treatment. The European Atherosclerosis Society/European Society of Cardiology LDL-C goals were achieved in 43.3% of patients with HeFH and 37.5% of patients with HoFH. Conclusions PCKS9i prescribed to patients with familial hypercholesterolemia in clinical practice showed LDL-C-lowering efficacy similar to that observed in controlled trials. However, 2 of 5 HeFH cases and 2 of 6 HoFH cases achieved the recommended LDL-C goals. The full achievement of European Atherosclerosis Society/European Society of Cardiology LDL-C goals should require a lower threshold for PCKS9i initiation and a combination of multiple therapies.

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.

A retrospective study of people with familial hypercholesterolaemia in a Belgian lipid clinic

Background Familial hypercholesterolaemia (FH) is a genetic disease characterised by hypercholesterolaemia and premature cardiovascular events. Early diagnosis and treatment can reduce the cardiovascular burden. We describe the characteristics of patients with heterozygous FH followed in a tertiary hospital in Belgium. Methods We retrospectively studied a population of 321 patients with definite heterozygous FH who visited the UZ Leuven lipid clinic at least once between 1 January 2016 and 31 December 2020. Data are represented as mean ± SD. Results The age at time of diagnosis of FH was 39 ± 18 years. Patients with atherosclerotic disease (secondary prevention) were older (p < .001), more often male (p < .001), had a higher body mass index (p < .001), prevalence of (pre)diabetes (p < .001) and hypertension (p < .001) and had lower levels of low-density lipoprotein-cholesterol (LDL-C) (p < .001) than individuals without atherosclerotic disease (primary prevention). The average LDL-C in both primary (109 ± 53 mg/dL) and secondary (81 ± 63 mg/dL) prevention did not meet the targets of LDL-C as proposed by the 2019 ESC/EAS guidelines for the management of dyslipidaemias. However, LDL-C levels in the subgroup of patients treated with PCSK9 inhibition therapy, and especially in the triple therapy group (combination of statin, ezetimibe and PCSK9 inhibitor), were markedly lower (p < .001). Conclusions In this Belgian population, people with heterozygous FH remain undertreated. Reaching treatment targets in FH seems possible, although this requires combination treatment (with PCSK9-targeted therapy) in most patients. Earlier diagnosis of FH, more extensive lipid-lowering treatment and reimbursement options and a more holistic approach are needed to lower LDL-C and cardiovascular risk in patients with FH.

Tafolecimab: First Approval.

Tafolecimab (SINTBILO®), a subcutaneously administered anti-proprotein convertase subtilisin/kexin type 9 enzyme(PCSK9) monoclonal antibody, is being developed by Innovent for the treatment of hypercholesterolemia and mixed hyperlipidemia. Tafolecimab was approved in August 2023 in China as an adjunct to diet, in combination with a statin or statin with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, for the treatment of adults with primary hyperlipidemia [including heterozygous familial hypercholesterolemia (HeFH) and non-familial hypercholesterolemia (non-FH)] and mixed dyslipidemia who have failed to achieve LDL-C goals despite moderate or higher doses of statins, to reduce LDL-C, total cholesterol (TC), and apolipoprotein B (ApoB) levels. This article summarizes the milestones in the development of tafolecimab leading to this first approval for the treatment of adults with primary hyperlipidemia and mixed dyslipidemia.

Compound Heterozygous Familial Hypercholesterolemia in a Child: Successfully Treated by Liver Transplant from Heterozygous Living Donor

Background: Familial hypercholesterolemia (FH), mostly inherited as an autosomal dominant disease, is characterized by decreased low-density lipoprotein cholesterol (LDL-C) clearance from the plasma, due to mutation in the LDL receptor (LDL-R). Untreated or treatment resistant cases can have accelerated atherosclerosis leading to cardiovascular deaths. There are very few reports of liver transplant in children with refractory FH. Clinical Description: A 9-year-old girl was having tendinous xanthomas for last 18 months, which remained undiagnosed until she developed early onset acute coronary syndrome with triple-vessel disease. Treatment with statins was initiated for hypercholesterolemia which was detected only postcoronary artery bypass graft. The child was refractory to medical management. Management and Outcome: Genetic analysis revealed a compound heterozygous variant of FH (cHeFH) with a pathogenic mutation in LDL-R, with parents being heterozygotes. She underwent living donor liver transplantation (LT) from her heterozygote father. Posttransplantation, the lipid profiles improved markedly with gradual reduction in size of the xanthomas. Conclusion: FH, if undiagnosed and untreated, can cause serious complications as early as in the first decade. Simple cutaneous markers like tendon xanthomas should raise a suspicion of this condition and investigations should be carried out without further delay. LT, even from a heterozygous donor, can be rewarding in children with FH refractory to medical management.

Lipoprotein(a) in Familial Hypercholesterolemia

BackgroundLow density lipoprotein (LDL) and Lipoprotein (Lp)(a) are proatherogenic apolipoprotein (apo) B-containing members of the non–high-density lipoprotein (non-HDL) family of particles. Elevated plasma levels of LDL cholesterol (C), non-HDL-C, and apo B are defining features of heterozygous familial hypercholesterolemia (HeFH), but reports of elevated plasma Lp(a) concentration are inconsistent. MethodsWe performed retrospective chart reviews of 256 genetically characterized patients with hypercholesterolemia and 272 control subjects from the Lipid Genetics Clinic at University Hospital in London, Ontario. We evaluated pairwise correlations between plasma levels of Lp(a) and those of LDL-C, non-HDL-C and apo B. ResultsMean Lp(a) levels were not different between individuals with hypercholesterolemia and control subjects. No correlations were found between Lp(a) and LDL-C or non–HDL-C levels in controls or patients with hypercholesterolemia; all r values < 0.079 and all P values > 0.193. Borderline weak correlations between Lp(a) and apo B were identified in patients r = 0.103; P = 0.112) and controls (r = 0.175; P = 0.005). Results were similar across genotypic subgroups. ConclusionsLp(a) levels are independent of LDL-C and non–HDL-C; in particular Lp(a) levels are not increased in patients with hypercholesterolemia and molecularly proven HeFH. Apo B was only weakly associated with Lp(a). Elevated Lp(a) does not cause FH in our clinic patients. Genetic variants causing HeFH that raise LDL-C do not affect Lp(a), confirming that these lipoproteins are metabolically distinct. Lp(a) cannot be predicted from LDL-C and must be determined separately to evaluate its amplifying effect on atherosclerotic risk in patients with hypercholesterolemia.

Coronary Artery and Carotid Artery Plaques in Patients With Heterozygous Familial Hypercholesterolemia

BackgroundLittle is known regarding the formation of coronary and carotid plaques and their impact on cardiovascular disease in patients with familial hypercholesterolemia (FH). ObjectivesThis study aimed to determine: 1) if the development of coronary and carotid plaques is correlated; and 2) if these plaques are associated with major adverse cardiac events (MACEs) defined as cardiovascular-related death, unstable angina, myocardial infarction, or staged revascularization. MethodsThis was a retrospective review of 622 patients with heterozygous FH (HeFH) at Kanazawa University Hospital, assessed coronary and carotid plaque scores using coronary computed tomography and carotid ultrasound within 1 year. Spearman correlation coefficients were assessed among variables. Risk factors for MACEs were determined using the Cox proportional hazard model. ResultsCoronary and carotid plaque scores were significantly correlated in patients with HeFH in both sexes (Spearman’s r = 0.82; P < 0.001 in males and Spearman’s r = 0.87; P < 0.001 in females). We observed 132 MACEs during the median follow-up of 13.2 years. These scores were significantly associated with the occurrence of MACE (HR: 3.33; 95% CI: 1.88-4.78; P < 0.001, HR: 2.24; 95% CI: 1.28-3.20; P < 0.001, respectively). ConclusionsCoronary and carotid plaque scores were significantly correlated, and both were independently associated with MACEs. The assessments for coronary and/or carotid plaque are useful for further risk stratifications in patients with HeFH.

Domino Liver Transplantation for Unresectable Colon Cancer Liver Metastasis From a Donor With Heterozygous Familial Hyperlipidemia: A Case Report

Liver transplantation (LT) is a potential curative treatment for unresectable colorectal cancer liver metastasis (CRLM). Familial hypercholesterolemia (FH) is an inherited condition characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. Liver transplantation is offered for selected cases, and an explanted liver can be used as a domino graft. We report the first report of domino LT for unresectable CRLM using a liver from a patient with heterozygous FH. The domino donor was a 30-year-old female with a history of heterozygous FH. She had failed medical therapies for FH, including plasmapheresis; therefore, she underwent living donor LT as a treatment for FH. The explanted liver was transplanted to the domino recipient. She has been doing well with normal LDL-C levels. The domino recipient was a 44-year-old female with a history of stage 4 sigmoid cancer with liver metastases, for which she underwent laparoscopic sigmoid colectomy and right hepatectomy. She developed unresectable lesions in the remnant left lobe, which were controlled well with chemotherapy; therefore, she underwent domino LT. She is doing well without recurrence at the 31-month follow-up. Domino LT from a donor with heterozygous FH is feasible for strictly selected patients with unresectable CRLM.

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.

Aortic Wall Thickness as a Surrogate for Subclinical Atherosclerosis in Familial and Nonfamilial Hypercholesterolemia: Quantitative 3D Magnetic Resonance Imaging Study and Interrelations with Computed Tomography Calcium Scores, and Carotid Ultrasonography.

We aimed to compare the extent of subclinical atherosclerosis in the ascending and descending aortas by measuring wall area and thickness using 3D cardiovascular magnetic resonance imaging (aAWAI and dAWAI) in patients with asymptomatic familial hypercholesterolemia (FH) and nonfamilial hypercholesterolemia (NFH). We also aimed to establish the interrelations of CMR parameters with other subclinical atherosclerosis measurements, such as calcium scores, obtained using computed tomography in coronary arteries (CCS) and ascending and descending aorta (TCSasc and TCSdsc), as well as the carotid intima-media thicknesses (cIMT) using ultrasonography. A total of 60 patients with FH (29 men and 31 women), with a mean age of 52.3 ± 9.6 years, were analyzed. A subclinical atherosclerosis assessment was also performed on a group consisting of 30 age- and gender-matched patients with NFH, with a mean age of 52.5 ± 7.9 years. We found the ascending and descending aortic wall areas and thicknesses in the FH group to be significantly increased than those of the NFH group. A multivariate logistic regression analysis showed that a positive FH mutation value was a strong predictor of high aAWAI and dAWAI independent of the LDL cholesterol level. Correlations across CMR atherosclerotic parameters, calcium scores, and cIMT in the FH and NFH groups, were significant but low. Most of the atherosclerosis tests with high results belonged to the FH group. We found that patients with documented heterozygous FH had a higher atherosclerosis burden in the aorta compared to patients with severe hypercholesterolemia without FH gene mutation. Atherosclerosis is not severe in asymptomatic patients with FH, but is more pronounced and also more diffuse than in patients with NFH. The etiology of hypercholesterolemia, and not just cholesterol levels, plays a significant role in determining the degree of subclinical atherosclerosis.

Does Genotype Affect the Efficacy of PCSK9 Inhibitors in the Treatment of Familial Hypercholesterolemia?

This review discusses whether patients' genotype affects the efficacy of PCSK9 inhibitors in treating familial hypercholesterolemia and how this might influence clinical management. Currently, available evidence consistently demonstrates and is in good agreement that, in general, the LDL-C-lowering effect of PCSK9 inhibitors is similar across genotypes, except for compound heterozygous and homozygous familial hypercholesterolemia (FH). However, it remains to be seen whether the comparable therapeutic effect in lowering LDL-C level also leads to a comparable degree of cardiovascular risk reduction with different genotypes. Generally, the level of LDL-C reduction following PCSK9 inhibitor treatment is similar within different genotypes. Hence, genotype is a less reliable predictor for further LDL-C level reduction on PCSK9 inhibitor therapy, and attention should be given to other external influences, especially for heterozygous FH.