Genetic Familial Hypercholesterolemia Research Articles

Genetic testing increases the likelihood of a diagnosis of familial hypercholesterolaemia among people referred to lipid clinics: Danish national study

Background and aimsIt is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. MethodsFrom September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. ResultsA total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. ConclusionsIn a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

Use of Lipoprotein(a) to improve diagnosis and management in clinical familial hypercholesterolemia

Background and aimsLipoprotein(a) (Lp(a)) is an LDL-like particle whose plasma levels are largely genetically determined. The impact of measuring Lp(a) in patients with clinical familial hypercholesterolemia (FH) referred for genetic testing is largely unknown. We set out to evaluate the contribution of (genetically estimated) Lp(a) in a large nation-wide referral population of clinical FH. MethodsIn 1504 patients referred for FH genotyping, we used an LPA genetic instrument (rs10455872 and rs3798220) as a proxy for plasma Lp(a) levels. The genetic Lp(a) proxy was used to correct LDL-cholesterol and reclassify patients with clinical FH based on Dutch Lipid Criteria Network (DLCN) scoring. Finally, we used estimated Lp(a) levels to reclassify ASCVD risk using the SCORE and SMART risk scores. ResultsLPA SNPs were more prevalent among mutation-negative compared with mutation-positive patients (296/1280 (23.1%) vs 35/224 (15.6%), p = 0.016). Among patients with genetically defined high Lp(a) levels, 9% were reclassified to the DLCN category ‘unlikely FH’ using Lp(a)-corrected LDL-cholesterol (LDL-Ccor) and all but one of these patients indeed carried no FH variant. Furthermore, elevated Lp(a) reclassified predicted ASCVD risk into a higher category in up to 18% of patients. ConclusionsIn patients referred for FH molecular testing, we show that taking into account (genetically estimated) Lp(a) levels not only results in reclassification of probability of genetic FH, but also has an impact on individual cardiovascular risk evaluation. However, to avoid missing the diagnosis of an FH variant, clear thresholds for the use of Lp(a)-cholesterol adjusted LDL-cholesterol levels in patients referred for genetic testing of FH must be established.

The First Report of a Real-world Experience With a PCSK9 Inhibitor in a Large Familial Hyperlipidemia and Very-high-risk Middle Eastern Population

Evolocumab, a monoclonal inhibitor of proprotein convertase subtilisin/kexin 9, has been shown to reduce proatherogenic lipoproteins in patients with or without familial hypercholesterolemia (FH), diabetes mellitus, or atherosclerotic cardiovascular disease (ASCVD). We explored the safety profile and clinical effectiveness of evolocumab in an outpatient population of Emirati individuals with FH diagnosed per Dutch Lipid Clinic Network criteria, previous ASCVD, or statin intolerance. This study was a retrospective review of patients initiating evolocumab treatment for any indication at Imperial College London Diabetes Centre between 2017 and 2020. All individuals followed up for at least 90 days or with at least one lipid panel postinitiation were included. Participants were subclassified into primary prevention (no previous ASCVD event, n=81) and secondary prevention (any prior clinical ASCVD event, n=102) groups. Evolocumab was initiated in 183 individuals (mean [SD] age, 51.5 [12.4] years; 51% male); 108 (59%) had a clinical or genetic FH diagnosis, and 70.5% had diabetes mellitus. Statin intolerance was a treatment indication in 60 (32.8%) individuals. At 90 days, substantial reductions in serum LDL-C, triglycerides (TG), and total cholesterol:HDL-C (TC:HDL-C) were observed in both the primary and secondary prevention groups, and both FH and non-FH individuals. In the primary prevention group, median (interquartile range) reduction in LDL-C was 43.7% (10.8%; 63.0%); TG, 15.0% (7.2%; 35.3%); and TC:HDL-C, 31.5% (11.1%; 46.0%). In the secondary prevention group, median (interquartile range) reduction in LDL-C was 48.3% (22%; 70%); TG, 19.6% (1.2%; 32.5%); and TC:HDL-C, 32.6% (14.6%; 46.3%) (all, P < 0.0001). American College of Cardiology/American Heart Association LDL-C targets were consistently achieved in 114 (62.3%) patients during a follow-up of 359 (79-639) days. Nonattainment of the LDL-C target was attributed to nonadherence in 36 (52.2%) patients and discontinuation of treatment in 14 (20.3%) patients. Evolocumab was discontinued in 4 patients because of adverse events. This study is the first from the Middle East and North Africa region that reports the real-world efficacy of evolocumab in a mixed risk population of individuals with FH and other non-FH indications. Clinically meaningful and sustained reductions in LDL-C, TG, and cholesterol ratios were observed after evolocumab initiation. Few adverse events were reported in this predominantly Arabic population, consistent with previous safety reports for evolocumab. Notable strengths of this study include a relatively large cohort, patient heterogeneity and high retention, and a minimum follow-up of 1 year. Despite these strengths, the study has some limitations, including the selection bias due to the retrospective design and absence of comparative group.

Assessment of practical applicability and clinical relevance of a commonly used LDL-C polygenic score in patients with severe hypercholesterolemia

Background and aimsLow-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype. MethodsFirst, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data. ResultsThe mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10–0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk. ConclusionsThis 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD.

Genetic basis of hypercholesterolemia in adults

We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.

Cardiovascular Events According To Maternal Or Paternal Heritability Of Genetic Mutation In Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic autosomal disease, characterized by high levels of cholesterol since birth, that leads to a very high cardiovascular (CV) risk. In patients with the heterozygous FH (HeFH), in case of a maternal transmission, fetus is exposed to high maternal cholesterol levels during pregnancy. Based on the Developmental Origins of Health and Disease concept, our objective was to study the effect of heritability of genetic FH mutation on the occurrence of CV events in adults with HeFH. We included 138 HeHF patients with a genetic diagnosis and a clear familial history of hypercholesterolemia among 513 patients included in the Marseille's REFERCHOL register. Occurrence of CV events were compared by maternal (MH group, 64 patients) or paternal (PH group, 74 patients) heritability. The logistic regression method was used to determine the predictors of CV events. At inclusion, parameters were comparable between groups except more hypertension (25% vs. 9.4%, P = 0.01), more treatment by anti-PCSK9 (20.3 vs. 5.4%, P = 0.008) and less familial early CV events (28.6 vs. 51.4%, P = 0.007) in the MH group. Regarding CV events, 35.9% of MH patients and 27% of PH patients had a CV event ( P = 0.26). Predictive factors of CV event were sex ( P = 0.0004), age at start of statins ( P = 0.0003), maximal LDL-c ( P = 0.009) and Lp(a) ( P = 0.007). On multivariate analysis, heritability was not statistically associated with CV risk (PH risk vs. MH risk: OR = 0.34, P = 0.076). Sex, age at start of statins and Lp(a) were still associated with CV events occurrence (OR = 0.3, P = 0.044 for female; OR = 1.08, P = 0.001 for a later start of statins; OR = 6.98, P = 0.0096 for Lp(a)). Heritability has no significant effect on the occurrence of CV event during adulthood although paternal heritability seems to be protective. We are recruiting all HeFH patients from French FH register to improve the power of the study and confirm the observed trend.

Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors

Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects. LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27 ± 0.07 vs. 1.59 ± 0.04, P = 0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35 y) (1.34 ± 0.08 vs. 1.64 ± 0.08, P = 0.019); moreover, LTL was shorter in statin-naïve HeFH subjects as compared to controls (1.23 ± 0.08 vs. 1.58 ± 0.04, P = 0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33 ± 0.05 vs. 1.55 ± 0.08, P = 0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls. We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.

Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia

BackgroundLipoprotein(a) is an atherogenic low-density lipoprotein–like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why. ObjectivesThis study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically. MethodsWe investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486). ResultsPatients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH. ConclusionsThese results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.

Extreme Atherosclerotic Cardiovascular Disease (ASCVD) Risk Recognition.

To distinguish extreme and very high atherosclerotic cardiovascular disease (ASCVD) event risk based on prospective epidemiological studies and clinical trial results. Clinical practice guidelines have categorized patients with either a history of one or more "clinical ASCVD" events or "coronary heart disease (CHD) risk equivalency" to be at "very high risk" for a recurrence or a first event, respectively. A 20% or greater 10-year ASCVD risk for a composite 3-point "major" atherosclerotic cardiovascular event (MACE) of non-fatal myocardial infarction (MI), non-fatal stroke, or cardiovascular death can serve as an arbitrary definition of those at "very high risk." Exclusion of stroke may underestimate risk of "hard" endpoint 10-year ASCVD risk and addition of other potential endpoints, e.g., hospital admission for unstable angina or revascularization, a 5-point composite MACE, may overinflate the risk definitions and categorization. "Extreme" risk, a descriptor for even higher morbidity and mortality potential, defines a 30% or greater 10-year 3-point MACE (ASCVD) risk. In prospective, epidemiological studies and randomized clinical trial (RCT) participants with an initial acute coronary syndrome (ACS) within several months of entry into the study meet the inclusion criteria assignment for extreme risk. In survivors beyond the first year of an ASCVD event, "extreme" risk persists when one or more comorbidities are present, including diabetes, heart failure (HF), stage 3 or higher chronic kidney disease (CKD), familial hypercholesterolemia (FH), and poorly controlled major risk factors such as hypertension and persistent tobaccoism. "Extreme" risk particularly applies to those with progressive or multiple clinical ASCVD events in the same artery, same arterial bed, or polyvascular sites, including unstable angina and transient ischemic events. Identifying asymptomatic individuals with extensive subclinical ASCVD at "extreme" risk is a challenge, as risk engine assessment may not be adequate; individuals with genetic FH or those with diabetes and Agatston coronary artery calcification (CAC) scores greater than 1000 exemplify such threatening settings and opportunities for aggressive primary prevention. Heterogeneity exists among individuals at risk for clinical ASCVD events; identifying those at "extreme" risk, a more ominous ASCVD category, associated with greater morbidity and mortality, should prompt the most effective global cardiometabolic risk reduction.

High prevalence of genetic determined familial hypercholesterolemia in premature coronary artery disease.

Background: Premature coronary artery disease (CAD) is a major cause of mortality and morbidity. Increased low-density lipoprotein-cholesterol (LDL-C) level is a major risk factor for CAD and thus the main target for its prevention. Familial Hypercholesterolemia (FH) is a genetic inherited disorder characterized by high LDL-C, and subsequent premature CAD development. Early drug treatment with lipid-lowering medications in FH prevents cardiovascular disease onset.The FH prevalence in the Northern European general population is 0.3%, and it is estimated that it explains 20% of premature CAD cases in individuals with familial clustering. Despite the wide number of papers showing the prevalence of clinical FH in cardiovascular disease, the prevalence of genetic FH in individuals with premature CAD is not yet well known. Here, we examined the prevalence of genetically determined FH in individuals with premature CAD.Patients and methods: 66 patients who underwent coronary angiography with suspected premature acute coronary syndrome (age <50 years for men and <55 years for women) underwent genetic screening to identify FH-causing mutations. All patients underwent physical and clinical examinations. Information about family and personal history, drug therapy and habits were also collected.Results: We found FH-causative mutations in 3/66 (4.5%) screened individuals with premature CAD. When considering individuals with confirmed CAD after coronary angiography, the FH mutation prevalence was 6.1% (3/49). After excluding individuals with classical risk factors for CAD other than hypercholesterolemia, the FH mutation prevalence raised to 15.8% (3/19).Conclusion: In conclusion, we found that individuals with premature CAD have a more than 15-fold increased prevalence of FH mutations compared to the general population.

Role of Apolipoprotein E gene polymorphism in the risk of familial hypercholesterolemia: a case-control study.

Familial Hypercholesterolemia (FH) is characterized by elevated cholesterol and based on biochemical, clinical, and genetic studies and FH disease, which was documented even with limited mutations. Earlier studies focused on Apolipoprotein E (ApoE) in variable diseases. The current study aimed to investigate the genetic association between FH disease and ApoE gene polymorphisms (rs429358 and rs7412) in the Saudi population. This case-control study was a hospital-based study performed in Saudi Arabia. Two hundred and four subjects in total were recruited and consisted of FH participants (n=104) and the controls (n=100). Common polymorphisms of ApoE gene (rs429358 and rs7412) were chosen and subjected to the genotyping using the TaqMan assay. Moreover, the ApoE risk allele E4 was proved significantly associated with FH cases when compared with controls (OR-2.24 (95%CI: 1.06-4.70); p=0.02). Lipid profile parameters were significantly associated (p<0.05); however, the ApoE alleles and lipid profiles were not correlated (p>0.05). In conclusion, the FH case-control study was associated with the E4 allele in the Saudi population. However, E4 allele was appeared as a reliable risk marker for lipid profiles, but not for ApoE alleles.

Association between non-cholesterol sterol concentrations and Achilles tendon thickness in patients with genetic familial hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is a genetic disorder that result in abnormally high low-density lipoprotein cholesterol levels, markedly increased risk of coronary heart disease (CHD) and tendon xanthomas (TX). However, the clinical expression is highly variable. TX are present in other metabolic diseases that associate increased sterol concentration. If non-cholesterol sterols are involved in the development of TX in FH has not been analyzed.MethodsClinical and biochemical characteristics, non-cholesterol sterols concentrations and Aquilles tendon thickness were determined in subjects with genetic FH with (n = 63) and without (n = 40) TX. Student-t test o Mann–Whitney test were used accordingly. Categorical variables were compared using a Chi square test. ANOVA and Kruskal–Wallis tests were performed to multiple independent variables comparison. Post hoc adjusted comparisons were performed with Bonferroni correction when applicable. Correlations of parameters in selected groups were calculated applying the non-parametric Spearman correlation procedure. To identify variables associated with Achilles tendon thickness changes, multiple linear regression were applied.ResultsPatients with TX presented higher concentrations of non-cholesterol sterols in plasma than patients without xanthomas (P = 0.006 and 0.034, respectively). Furthermore, there was a significant association between 5α-cholestanol, β-sitosterol, desmosterol, 24S-hydroxycholesterol and 27-hydroxycholesterol concentrations and Achilles tendon thickness (p = 0.002, 0.012, 0.020, 0.045 and 0.040, respectively).ConclusionsOur results indicate that non-cholesterol sterol concentrations are associated with the presence of TX. Since cholesterol and non-cholesterol sterols are present in the same lipoproteins, further studies would be needed to elucidate their potential role in the development of TX.

CORONARY ANGIOGRAPHY IN PATIENTS WITH PREMATURE ACUTE CORONARY SYNDROME AND FAMILY HYPERCHOLESTEROLEMIA

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder with a prevalence of 1/200-1/500 in the general population. The aim of the study was to assess the specific features of coronary angiography in young patients with acute coronary syndrome (ACS) and FH diagnosed using Dutch Lipid Clinic Network (I) and Simone Broome Register (II) criteria. 224 pts with early onset of ACS who underwent coronary angiography were selected (≤ 55 years of age for men and ≤ 60 years of age for women). Two, three vessel disease/left coronary artery (LCA) impairment was observed in 12 of 13 (92,3%) pts with definite/possible FH (I, p=0,036) and in 28 of 29 (96,6%) pts with probable FH (II, p=0,001). In patients with family history of cardiovascular disease three ves-sel disease or LCA impairment was observed in 54 of 73 (74%) pts (p=0,024). Comparing two groups of patients with LDL over and below 4,6 mmol/l (the concentration was obtained by ROC analysis) it was shown that 20 of 29 (69%) and 58 of 144 (40,3%) pts (p=0,036) respectively had culprit vessel thrombosis. Thus, we can suppose that in pts with higher LDL level atherosclerotic plaque rupture is observed more frequently in case of ACS. Therefore, it has been shown that multivessel and LCA stem impairment in young patients with ACS and FH is associated with both main factors used for not genetic FH diagnosis: high LDL cholesterol level and family history of cardiovascular disease.

Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia.

The impact of positive clinical signs (xanthoma and/or family history) and positive familial hypercholesterolaemia (FH) mutation status on risk of coronary artery disease (CAD) over and above that predicted by low-density lipoprotein (LDL) cholesterol level alone has not been fully determined. We assessed whether positive clinical signs and genetic FH diagnosis affected CAD risk among subjects with significantly elevated LDL cholesterol levels (≥180 mg/dL, or ≥140 mg/dL in subjects <15 years of age). Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 636 patients with severe hypercholesterolaemia (mean age, 45 years; 300 males [47%], CAD diagnosis, 185 [29%]), and the presence of clinical FH signs (xanthoma and/or family history) were assessed. CAD prevalence was compared between four subject groups categorized based on these parameters. Compared with the reference group without FH mutations or clinical signs of FH, subjects with clinical signs of FH or FH mutations had three- to four-fold higher odds of developing CAD (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.5-14.5; P = 0.0011 and OR, 3.4; 95% CI, 1.0-10.9; P = 0.0047, respectively), whereas those with clinical signs of FH and FH mutation(s) had >11-fold higher odds of developing CAD (OR, 11.6; 95% CI, 4.4-30.2; P = 1.1 × 10-5) after adjusting for known risk factors including LDL cholesterol. Our findings revealed an additive effect of positive clinical signs of FH and positive FH mutation status to CAD risk among patients with significantly elevated LDL cholesterol.

ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia

HDL composition rather than HDL-cholesterol (HDL-C) levels seems to be a key determinant of HDL-induced atheroprotection. Heterozygous familial hypercholesterolemia (FH) patients, with lifelong exposure to high LDL levels, show a high prevalence of premature coronary artery disease. We hypothesized that HDL of FH patients might have a modified protein composition and investigated the proteomic signature of HDL obtained from FH patients and their unaffected relatives. HDLs were characterized by 2D electrophoresis/MS in 10 families from the SAFEHEART cohort (3 individuals/family: 2 with genetic FH diagnosis and 1 non-FH relative) clinically characterized and treated as per guidelines. FH patients had lower apoA-I levels and a differential HDL distribution profile of apoL1 and apoA-IV. ELISA validation revealed decreased apoL1 serum levels in FH patients. ApoL1 levels were able to predict presentation of an ischemic cardiac event, and apoL1/HDL-C ratio was associated with the survival rate after the event. FH patients who died because of a fatal cardiac event had lower apoL1 and LCAT content in HDL3 an average of 3.5 years before the event than those who survived. Changes in HDL protein composition could affect patients' prognosis. The proteomic profile of apoL1 is modified in HDLs of high cardiovascular risk patients, and apoL1 plasma levels are significantly lower in serum and in HDL3 of patients that will suffer an adverse cardiac event within 3 years.

Abstract 15779: Quality of Life in a Cohort of Familial Hypercholesterolemia Patients Undergoing Molecular Cascade Screening in Brazil

Introduction:: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated disease associated with elevated risk of early cardiovascular disease (CVD) and thus can reduce quality of life. The present health related quality of life (HRQL) investigation, evaluated patients personal interpretation of morbidity burden in daily life. Methods: The study included a total of 1,032 adult individuals participating in a FH molecular cascade-screening program. The involved individuals were index cases (IC n=363), with genetic diagnosis or FH and their first-degree relatives (FDR, n=669). All patients were evaluated at the first session of the molecular diagnosis process. HRQL measurements, mental (MCS) and physical (PCS) component scores, was carried out with the Medical Outcomes Study (MOS) 12-Item Short-Form Health Survey (SF-12) questionnaire. Results: IC were older (52±13.1 vs. 46±16.2 years, P&lt;0.05) and presented lower PCS than FDR (44.7±9.3 vs. 49.2±8.4, P&lt;0.05). No differences were seen on the MCS component. Overall, generalized linear models showed that smoking habit (11.9% prevalence, P=0.006), previous diagnosis of hyperlipidemia (78.6%, P=0.020) and depression (13.5% prevalence, P&lt;0.000) were significant predictors of MCS. The presence of heart failure (6.5%, P=0.018), angina pectoris (12.9%, P=0.005), previous myocardial infarction (12.3%, P=0.012), hypertension (33.9%, P=0.018) and obesity (12.8%, P&lt;0.000) were all predictors of PCS. The presence of arrhythmias (10.7% prevalence) predicted both MCS and PCS (P=0.042 and P=0.00, respectively). Male gender (42.4%, P&lt;0.000) and education level (&lt; 9 years of background, 28% P&lt;0.000) were social-demographic aspects predictive of differences in MCS and PCS, respectively. Conclusions: Reductions in the individuals’ reported quality of life were explained by differences in social-demographic characteristics but mainly by inadequate health/disease status, such as risk factors and previous CVD. Active FH genetic cascade diagnosis by promoting early and adequate medical care and thus preventing early CVD, may improve substantially the subjective appraisal of HRQL.

Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia

ObjectiveTo determine the utility of secondary stratification measures to improve the ascertainment of index cases of familial hypercholesterolaemia (FH).DesignA retrospective study of genotyped index patients with Simon Broome (SB) FH.SettingUniversity...

Atherosclerosis and Vascular Biology

Atherosclerosis and Vascular Biology

Duplication of exon 7–12 in the low-density lipoprotein receptor gene in three Danish patients with familial hypercholesterolemia

Familial hypercholesterolemia (FH) is one of the most frequent single-gene disorders; nevertheless, it is commonly underdiagnosed and undertreated. To increase the number of individuals diagnosed and treated for FH, an ongoing discovery of novel FH mutations is necessary as a prerequisite to implement good nationwide genetic FH screening strategies. Here we report on the finding of a seldom exon 7-12 duplication in the low-density lipoprotein receptor gene of three Danish patients with FH.

Differential Impact of Familial Hypercholesterolemia and Combined Hyperlipidemia on Vascular Wall and Network Remodeling in Mice

Genetic familial hypercholesterolemia (FH) and combined hyperlipidemia (FCH) are characterized by elevated plasma low-density lipoprotein (LDL) (FH) and LDL/triglycerides (FCH), with mouse models represented by LDL receptor (LDLR) and apolipoprotein E (ApoE) gene deletion mice, respectively. Given the impact of FH and FCH on health outcomes, we determined the impact of FH/FCH on vascular structure in LDLR and ApoE mice. LDLR, ApoE and control mice were utilized at 12-13 and 22-23 weeks when gracilis arteries were studied for wall mechanics and gastrocnemius muscles were harvested for microvessel density measurements. Conduit arteries and plasma samples were harvested for biochemical analyses. Arteries from ApoE and LDLR exhibited blunted expansion versus control, reduced distensibility and left-shifted stress versus strain relation (LDLR > ApoE). Microvessel density was reduced in ApoE and LDLR (ApoE > LDLR). Secondary analyses suggested that wall remodeling in LDLR was associated with cholesterol and MCP-1, while rarefaction in ApoE was associated with tumor necrosis factors-alpha, triglycerides and vascular production of TxA(2). Remodeling in ApoE and LDLR appears distinct; as that in LDLR is preferential for vascular walls, while that for ApoE is stronger for rarefaction. Remodeling in LDLR may be associated with cellular adhesion, while that in ApoE may be associated with pro-apoptotsis and constrictor prostanoid generation.