Heterozygous Familial Hypercholesterolemia Subjects Research Articles

Abstract 19911: Markers of Survival in Septuagenarians and Octogenarians With Heterozygous or Homozygous Familial Hypercholesterolemia

Objective: Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-density lipoprotein-cholesterol (LDL-C) concentrations appearing at birth and is associated with an increased risk of premature atherosclerotic cardiovascular disease (CAD). Some homozygous (Ho) FH subjects survive over 80 years of age and a proportion of heterozygous (He) FH subjects aged over 70 years have never experienced CAD symptoms. The objective of this study consists in identifying genetic, clinical and/or environmental factors associated with survival over 70 years in FH. Methods and Results: The familial analysis of 1,860 French-Canadian FH individuals carrying either the French-canadian Type 1 (15KB deletion) or the French-canadian Type 2, (W66G), which are both FH-causing mutations in the LDLR gene, was performed to identify HoFH and HeFH subjects over 70 years of age. Out of this number, we were able to list a total of 112 subjects (among which 2 HoFH aged 72 and 84 years with baseline cholesterol 18 and 21 mmol/L respectively). Multivariate regression analyses revealed that the gender, high-density lipoprotein-cholesterol (HDL-C) level, the proportion of LDL-C decrease under therapy and the type of mutation in the LDLR gene were significant contributory factors of survival over 80 years or of CAD-free survival over 70 years (p-value under 0.001). In these models, the contribution of HDL-C was independent from that of LDL-C reduction. Notably, HDL-C and gender were shown to be significant covariates of survival among HoFH relatives. Fine phenotyping and exome sequencing analyses are ongoing. Conclusion: Based on a monogenic model of high LDL-C and premature CAD, these results demonstrated that despite the reduction of LDL-C, several other covariates would probably constitute major targets for cardiovascular disease (CVD) risk management.

Lipoprotein metabolism in familial hypercholesterolemia: Serial assessment using a one-step ultracentrifugation method

ObjectivesIt is well known that familial hypercholesterolemia (FH) is a common inherited disorder that can markedly elevate the level of plasma LDL cholesterol. However, little data exists regarding the clinical impact of the plasma triglyceride (TG)-rich lipoprotein fraction, including VLDL and IDL, in FH. Thus, we assessed the hypothesis that the mutations in the LDL receptor modulate lipoprotein metabolism other than the LDL fraction. Design and methodsWe investigated plasma lipoprotein with a one-step ultracentrifugation method for 146 controls (mean age=61.4±17.1yr, mean LDL cholesterol=92.7±61.2mg/dl), 213 heterozygous mutation-determined FH subjects (mean age=46.0±18.0yr, mean LDL cholesterol=225.1±61.2mg/dl), and 16 homozygous/compound heterozygous mutation-determined FH subjects (mean age=26.9±17.1yr, mean LDL cholesterol=428.6±86.1mg/dl). In addition, we evaluated cholesterol/TG ratio in each lipoprotein fraction separated by ultracentrifugation. ResultsIn addition to total cholesterol and LDL cholesterol levels, VLDL cholesterol (19.5±10.4, 25.2±19.3, 29.5±21.4mg/dl, respectively) and IDL cholesterol (8.3±3.7, 16.8±11.5, 40.0±37.3mg/dl, respectively) exhibited a tri-model distribution according to their status in LDL receptor mutation(s). Moreover, the ratios of cholesterol/TG of each lipoprotein fraction increased significantly in heterozygous FH and homozygous/compound heterozygous FH groups, compared with that of controls, suggesting that the abnormality in LDL receptor modulates the quality as well as the quantity of each lipoprotein fraction. ConclusionsOur results indicate that cholesterol in TG-rich lipoproteins, including VLDL and IDL, are significantly higher in FH subjects, revealing a tri-modal distribution according to the number of LDL receptor mutations.

Abstract 9600: Abnormal Lipoprotein Metabolism Other Than LDL Fraction in Familial Hypercholesterolemia: Serial analysis using Ultracentrifugation Method

Background: It is well known that familial hypercholesterolemia (FH) is a common inherited disorder that could cause marked elevation of plasma LDL-C level. However, few data exists regarding the clinical impact of plasma levels of VLDL-C and IDL-C as well as the composition of each lipoprotein fraction in FH. Thus, we assessed the hypothesis that the abnormality in LDLR modulates the quality as well as the quantity of lipoprotein other than LDL fraction. Methods: We investigated the plasma lipoprotein by ultracentrifugation method about 146 controls (mean age=61.4±17.1yr, mean LDL-C=92.7±61.2mg/dl), 213 heterozygous mutation-determined FH subjects (mean age=46.0±18.0yr, mean LDL-C=225.1±61.2mg/dl), and 16 homozygous mutation-determined FH subjects (mean age=26.9±17.1yr, mean LDL-C=428.6±86.1mg/dl). In addition, we evaluated the composition of each lipoprotein fraction by calculated cholesterol ester (CE) / triglyceride (TG) ratio. Results: As shown in the figure, the differences of the levels of TC and LDL-C between these 3 groups as well as those of VLDL-C (19.5±10.4, 25.2±19.3, 29.5±21.4 mg/dl, respectively) and IDL-C (8.3±3.7, 16.8±11.5, 40.0±37.3 mg/dl, respectively) were statistically significant. Moreover, the ratios of CE/TG of each lipoprotein fraction significantly increased in heterozygous FH and homozygous FH group, compared with that of controls, suggesting that the abnormality in LDLR modulate the quality as well as the quantity of each lipoprotein fraction. Conclusions: Our results indicate that LDLR participate not only in metabolism of LDL fraction but also in that of VLDL and IDL fractions. Larger amounts of VLDL-C and IDL-C with worse quality should also be additive risk factor in FH subjects.

Imaging biomarkers to track subclinical atherosclerosis in heterozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (FH) is characterized by high LDL cholesterol levels and premature coronary heart disease onset. Nonetheless, the course of coronary disease events in heterozygous FH subjects is variable. The presence and severity of subclinical atherosclerosis predicts cardiovascular event onset and may help reclassify the risk of clinical events in the general population. In this review, we discuss the possible use of subclinical coronary, carotid and aortic atherosclerosis testing in heterozygous FH subjects for cardiovascular risk stratification and treatment. Many FH subjects present an increased and precocious burden of subclinical vascular disease in comparison to normolipidemic subjects. These subjects may be at higher risk of cardiovascular events and might deserve more aggressive lipid-lowering treatment. Nevertheless, routine screening of imaging biomarkers for FH subjects in clinical practice remains to be determined in prospective trials.

More on Cholesterol Trafficking in the Body!

More on Cholesterol Trafficking in the Body!

Aféresis de lipoproteínas de baja densidad en la hipercolesterolemia familiar resistente al tratamiento médico convencional intensivo

Background and objectiveThe aim of our study is to analyze the effect and security of low-density lipoproteins (LDL) apheresis in familial hypercholesterolemia (FH) subjects who did not response to conventional intensive optimized medical treatment. Patients and methodsSeven heterozygous FH subjects and one homozygous apoB familial defective were studied. All subjects were on secondary prevention with highest statins doses in association with other hypolipemiant drugs; the mean LDL-C reduction was 20%. All of them were treated with LDL apheresis (immunoabsorption) for a mean of 4.25 years. ResultsLDL apheresis resulted in a 68.3% decrease in LDL-C and 58.2% in apoB plasma values (P<.001). After an average of 3 years of follow-up, the cardiovascular events disappeared in 4 out of 5 symptomatic patients while in one patient the events were reduced in 75%. Four moderate side effects were reported in 820 apheresis procedures. ConclusionsLDL apheresis is a well-tolerated and safe treatment in FH patients who do not response to intensive conventional optimized medical treatment. The main limitation is its economical cost and low accessibility.

The removal from plasma of chylomicrons and remnants is reduced in heterozygous familial hypercholesterolemia subjects with identified LDL receptor mutations: Study with artificial emulsions

Chylomicron remnants bind to both their specific receptors (LRP) and to the LDL receptor (LDLR) in the liver. There is controversy whether disturbances of chylomicron metabolism occur in subjects with familial hypercholesterolemia (FH). The aim of this study was to evaluate whether there are defects on the removal from plasma of chylomicrons and their remnants in heterozygous FH patients with determined LDLR mutations. We studied 20 heterozygous FH patients (43.2±12 years old, 60% males) and 50 normolipidemic subjects matched for age and gender. FH subjects were not in use of LDL-lowering drugs for at least 6 weeks. The removal from plasma of chylomicrons and their remnants was measured by isotopic decay after venous injection of a chylomicron-like emulsion radiolabeled with 14C-cholesteryl ester (14C-CE) and 3H-triolein (3H-TO). These track respectively removal from plasma of chylomicrons and remnants and lipolysis. There was a significant reduction in the fractional catabolic rates (FCR in h−1) of 14C-CE in FH in comparison with normolipidemics: 0.048 (1.46.10−7; 0.57) vs. 0.71(0.049; 1.62), [median (25th–75th percentile)], p=0.003. No differences were found in FCR of 3H-TO between FH and controls, respectively 1.62 (1.02; 2.331) and 1.914 (1.34; 2.878), p=0.405. In conclusion heterozygous FH subjects had a significant decrease on the removal from plasma of chylomicrons and their remnants compared with normolipidemics.

Abstract 9712: Lack of Association Between Common p.T111I Variant in the Endothelial Lipase Gene and the Risk for Coronary Artery Disease in Familial Hypercholesterolemia: Insights From the Modulation of Phospholipids in the HDL Particles

Background: endothelial lipase (EL) is a major determinant of high-density lipoprotein cholesterol (HDL-C) metabolism through the lipolysis of the phospholipids (PL) in the HDL particles (HDL-PL). Several studies indicated that common p.T111I variant in EL gene (LIPG: rs2000813) is negatively associated with the risk of coronary artery disease (CAD) independent of HDL-C levels. However, few data exist regarding the influence of this variant on the content of HDL-PL in terms of the association with CAD, especially in familial hypercholesterolemia (FH) subjects. The aim of our study is to elucidate the clinical impact of common p.T111I variant in the EL gene on the content of HDL-PL, and whether this variant could be useful predictor of the risk of CAD in FH subjects, which always exhibit low HDL-C levels. Methods: The p.T111I variant was genotyped in our heterozygous FH subjects (n=80, male=56, mean age=64±18yr, mean TC=340±64mg/dl). All those subjects' plasma lipoproteins were investigated by ultracentrifugation method. Overall HDL-C level, HDL-PL level, and the existence of CAD were investigated for each group (TT group vs. TI and II group). Results: The minor allele frequency in the combined pools of subjects was 0.25. There was no significant association between this variant with overall HDL-C level (42±14 vs. 43±17mg/dl, p=NS) nor with HDL-PL level (86±24 vs. 88±27mg/dl, p=NS). In addition, multiple logistic regression analysis revealed no association between this variant and CAD (odds ratio 0.96, 95%CI:0.88-1.04, p=NS) although significant associations between several coronary risk factors and CAD were observed (figure). Conclusions: These data suggest that common p.T111I variant in LIPG neither plays a role in determining HDL-C as well as HDL-PL levels nor is a useful predictor of the risk of CAD in genetically determined heterozygous FH subjects.

Abstract 8252: Altered Metabolism of Post-Prandial Remnant Lipoprotein Fractions in Autosomal Recessive Hypercholesterolemia

Introduction: Autosomal recessive hypercholesterolemia (ARH) associated with mutations in LDLR adaptor protein 1 (LDLRAP1) gene is extremely rare disorder. Although this defect seems to be a phenocopy of homozygous familial hypercholesterolemia (FH), clinical phenotype of ARH seems less severe, more responsive to statins, the cause of which may be derived from the difference of remnant-like particles (RLP) clearance. Hypothesis: We assessed the hypothesis that the ability of RLP clearance of ARH subject was different from that of FH subject. Methods: OFTT cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (squared meter), blood sampling was performed at 2 hour intervals up to 6 hour. Plasma lipoprotein and RLP fraction were determined by HPLC system in one ARH subject (68yr, LDL-C=286mg/dl), 4 heterozygous FH subjects (58±17yr, LDL-C=241±26mg/dl), and 4 controls (62±17yr, LDL-C=88±6mg/dl). All male subjects were selected to have apolipoprotein E2/E3 phenotype without diabetes. None of the subjects took medication known to affect plasma lipids at the time of this study for at least 4 weeks. The area under curve (AUC) of TG, RLP-TG, and RLP-cholesterol levels were evaluated. Results: After oral fat load, the AUC of TG, RLP-TG, and RLP-cholesterol levels of heterozygous FH subjects were significantly increased compared to those of controls (441±87 mg/dl*hour vs 316±133 mg/dl*hour, p&lt;0.05, 126±60 mg/dl*hour vs 49±11 mg/dl*hour, p&lt;0.05, 34±8 mg/dl*hour vs 23±11 mg/dl*hour, p&lt;0.05, respectively). In contrast to these results, the AUC of TG, RLP-TG, and RLP-cholesterol levels of ARH were within the nomal range (310mg/dl*hour, 23mg/dl*hour, 22mg/dl*hour, respectively). Conclusions: These results suggest that the lack of LDLRAP1 modulates RLP metabolism, activating an alternate pathway which can remove remnant fraction paradoxically. This preferred pathway should contribute to the greater responsiveness to statins. Our results will provide new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1.

New therapies for familial hypercholesterolemia

The development of cholesterol-lowering drugs, including a variety of statins, bile acid binding resins and recently discovered inhibitors of cholesterol absorption has expanded the options for cardiovascular disease prevention. However, existing approaches to the treatment of familial hypercholesterolemia (FH) are still ineffective in halting the progression of coronary artery disease (CAD) in some patients despite combination therapies. Homozygous FH (and many heterozygous FH subjects) are resistant to conventional drug treatment and remain at high-risk for development and progression of atherosclerotic cardiovascular disease, therefore alternative approaches are needed. Novel agents that include inhibitors of the apical sodium-dependent bile acid transporter, cholesteryl ester transfer protein, microsomal triglyceride transfer protein and squalene synthase may play a future role in combination with statins. It is possible that with improvements in vector technology, liver-directed somatic gene therapy would be an effective approach for this disorder.

Elevated serum levels of proinflammatory cytokines and biomarkers of matrix remodeling in never-treated patients with familial hypercholesterolemia

Background Familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism, whose origin involves mutations in the gene coding for the low-density lipoprotein receptor protein. Although FH is monogenic, wide variation occurs in the onset and severity of atherosclerosis in these patients. Methods Since data on levels of inflammatory proteins and/or active factors in FH patients who have never received lipid-lowering treatment are lacking, serum levels of MMP-3, active MMP-9 and TIMP-1 as well as pro-inflammatory cytokines (TNF-α, IL-18) were determined in never-treated homozygous FH Moroccan patients ( n = 4) and compared to those of heterozygous FH subjects ( n = 7) and of healthy control subjects ( n = 5). Results When compared to controls, homozygous FH patients exhibited levels of active MMP-9 and TIMP-1 ( p < 0.05), and of both high sensitive-CRP and IL-18 which were significantly elevated ( p < 0.05 and p < 0.01, respectively). In heterozygous FH patients, intermediate values between FH homozygotes and healthy controls were observed for these markers, with the exception of MMP-9 activity whose levels were significantly elevated ( p < 0.05). Multivariate analysis revealed a positive correlation between apolipoprotein B, TIMP-1 and IL-18 levels, and between hs-CRP and IL-18 ( p < 0.01). Conclusions Although the sample size of this FH group was limited, our data suggest that nontreated homozygous FH patients, and to a lesser degree heterozygous FH patients, exhibit not only a markedly proinflammatory vascular state but also pronounced extracellular matrix remodeling, as reflected by elevated circulating levels of inflammatory cytokines and MMPs.

Guidelines applied in practice in medicare patients with acute myocardial infarction

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). FH is a public health problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% of males and 50% of females with FH will suffer a coronary event before 65 years old if appropriate preventive efforts are not implemented. Early identification of persons with FH and their relatives, and the early start of treatment are essential issues in the prevention of premature cardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from their diagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention to answer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of these patients.

Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). FH is a public health problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% of males and 50% of females with FH will suffer a coronary event before 65 years old if appropriate preventive efforts are not implemented. Early identification of persons with FH and their relatives, and the early start of treatment are essential issues in the prevention of premature cardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from their diagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention to answer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of these patients.

Asociación de factores lipídicos, genotipo de APOE y tipos de mutación del gen del receptor de LDL con el infarto agudo de miocardio en sujetos con hipercolesterolemia familiar heterocigota

Our goal was to analyze the relationship of lipids and lipoproteins, APOE genotype and mutations of the LDL receptor gene with the prevalence of myocardial infarction (MI) in patients with familial hypercholesterolemia (FH) from a Southern European FH population. We studied 108 heterozygous FH subjects aged > 35 years (41 males). It was a cross-sectional study comparing individuals with FH and MI with individuals with FH without MI. In 88 FH subjects, a mutation of the LDL receptor gene was detected. These FH subjects were divided in carriers of null mutation or no null mutations. We compared lipids and lipoproteins and prevalences of LDL receptor type mutation and APOE genotype. Parameters associated with MI were: age, presence of xanthomas and arcus cornealis, plasma concentrations of total cholesterol (TC), LDLc, TC/HDLc ratio > 5.3 and *4 genotype of the APOE gene. Odds ratio for MI were as follows: presence of xanthomas and arcus cornealis, 1.36 (CI 95%, 1.08-1.71; P = 0.01), age > 54 years (50 th of FH group), 1.56 (CI 95%, 1.19-2.04; P = 0.001) and plasma TC values > 332 mg/dl (50 th of FH group), 1.34 (CI 95%, 1.05-1.71; P = 0.019). In the logistic regression model, only age and TC were significantly associated with MI. In FH subjects aged over 35 years from a Southern European population, MI is associated with age, plasma TC and LDLc values, TC/HDLc ratio and the *4 genotype. In addition, MI is related with age and TC plasma levels on an independent basis.

Pl A1/A2 polymorphism of platelet glycoprotein IIIa and risk of acute coronary syndromes in heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal inherited disorder caused by different mutations in the low density lipoprotein (LDL) receptor gene. It has been demonstrated that there is an increased risk of coronary heart disease (CHD) in heterozygous FH subjects, although this excess CHD is not only explained by the LDL-cholesterol concentration or the class of the LDL-receptor mutation. To investigate if a common polymorphism at the platelet glycoprotein (GP) IIIa gene locus could be related to CHD phenotypic variation in heterozygous FH, we have carried out a case-control study. We have studied 40 cases and 40 controls matched for age, sex and genetic defect in the LDL-receptor gene. Allele frequency of Pl A2 polymorphism for cases and controls was 20 and 22.5%, respectively, and the difference was not significant. In conclusion, our data do not support any association between the GP IIIa polymorphism and the increased prevalence of acute coronary syndromes in the heterozygous FH subjects.

Contribution of receptor negative versus receptor defective mutations in the LDL-receptor gene to angiographically assessed coronary artery disease among young (25–49 years) versus middle-aged (50–64 years) men

Elevated plasma LDL-cholesterol (LDL-C) levels are associated with an increased risk of coronary artery disease (CAD). Familial hypercholesterolemia (FH), a monogenic trait due to mutations in the LDL-receptor (R) gene is characterized by raised plasma LDL-C levels and premature CAD. The aim of the present investigation, derived from the study of a population of 1465 unrelated men aged 25 to 64 years, was to compare the expression of CAD assessed by coronary angiography in young (aged 25–49 years) versus middle-aged (50–64 years) heterozygous FH patients of French Canadian descent. Furthermore, the relationship of binding-defective versus receptor negative mutations in the LDL-R to premature CAD (<50 years) was examined and compared with men displaying a normal plasma lipoprotein-lipid profile. From the original study sample, a total of 100 men met the clinical criteria of heterozygous FH. Among them, 30 were carriers of a receptor negative mutation (deletion >15 kb or point mutations Y468X or R329X) whereas 64 were carriers of a receptor defective mutation (W66G, E207K or C646Y). As expected, in both age groups (25–49 years vs. 50–64 years), carriers of a receptor negative mutation had higher plasma cholesterol and LDL-C levels than carriers of a defective allele or men with a normal plasma lipoprotein-lipid profile. In addition, the mean number of diseased vessels (with>50% stenosis) was higher in men aged 50–64 years compared to those aged 25–49 years. In the two age groups, FH patients were characterized by a higher number of stenosed coronary vessels than the normal phenotype group. Within each group (either receptor negative, receptor defective or normal phenotype) plasma cholesterol, LDL-C, HDL-C, triglyceride and apolipoprotein B levels were similar irrespective of age (25–49 years vs. 50–64 years). Finally, multiple logistic regression analyses revealed that compared to non-FH men, the relative odds of being affected by CAD before the age of 50 years was 7.3-fold higher for carriers of a receptor negative mutation and 2.7-fold higher for men with a receptor defective mutation at the LDL-R locus. These results suggest that CAD could be an earlier event among heterozygous FH subjects bearing a receptor negative mutation compared to LDL-R defective patients. It also suggest that the selective screening for mutations in the LDL-R gene may allow a better assessment of the individual risk and facilitate the development of family-based preventive strategies or intervention programs in FH.

Preferential cholesteryl ester acceptors among the LDL subspecies of subjects with familial hypercholesterolemia.

Elevated cholesteryl ester transfer protein-mediated transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) may contribute to the atherogenicity of LDL in subjects with familial hypercholesterolemia (FH). To identify the major CE acceptors among LDL subspecies, we investigated the qualitative and quantitative features of CE transfer and exchange to LDL on incubation of plasma under physiological conditions. LDL subspecies were fractionated by density-gradient ultra-centrifugation. Both mass transfer and exchange of HDL CE to and with very-low-density lipoprotein plus intermediate-density lipoprotein and LDL were linear for the first 6 hours of incubation. Thereafter mass transfer ceased, but exchange continued at a comparable rate. The rate of CE mass transfer to apolipoprotein B-containing lipoproteins was significantly enhanced in heterozygous FH subjects compared with normolipidemic individuals (91.6 +/- 28.2 versus 52.9 +/- 19.6 micrograms CE/h per milliliter plasma, FH versus normal subjects, P < .02). In FH subjects the predominant LDL subspecies (LDL 3 and 4, d = 1.029 to 1.050 g/mL) accounted for 59.7 +/- 9.2% of the total CE transferred to LDL from HDL. By contrast, expression of CE mass transfer relative to the mass of each lipoprotein acceptor showed the triglyceride (TG)-rich (10.7% to 17.3%), light LDL subspecies (LDL 1 and 2, d = 1.019 to 1.029 g/mL) to represent the preferential CE acceptors (LDL 1 and 2, 94.8 to 136.5 micrograms CE/mg LDL mass; LDL 3 through 5 [d = 1.029 to 1.063 g/mL], 47.1 to 64.1 micrograms CE/mg LDL mass).(ABSTRACT TRUNCATED AT 250 WORDS)