Cardiovascular Disease In Familial Hypercholesterolemia Research Articles

Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. Adult patients ( n = 2156, mean age 50 ± 15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Sex‐related differences in premature cardiovascular disease in familial hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is associated with an increased prevalence of premature atherosclerotic cardiovascular disease (ASCVD), however, little is known about sex-specific differences in premature ASCVD and its risk factors. ObjectiveThe present study seeks to assess the burden and risk factors for premature ASCVD among men and women with FH. MethodsIn this study we retrospectively examined sex-specific differences in ASCVD prevalence, risk factor burdens, and lipid treatment outcomes in 782 individuals with clinically or genetically confirmed FH treated in 5 U.S. lipid and genetics clinics. A generalized linear model using Binomial distribution with random study site effect and sex-stratified analysis was used to determine the strongest predictors of premature ASCVD, and lipid treatment outcomes. Covariates included age, sex, diabetes mellitus (DM), hypertension, and current smoking. ResultsAmong the cohort, 98/280 men (35%) and 89/502 women (18%) had premature ASCVD (defined as <55 years in men and <65 years in women). Women with premature ASCVD had higher mean treated total cholesterol (216 vs. 179 mg/dl, p=<0.001) and LDL-C (135 vs. 109 mg/dl, p= 0.005). ConclusionThese data confirm that high percentages of women and men with FH develop premature ASCVD, and suggest that FH may narrow the observed sex difference in premature ASCVD onset. These data support more aggressive prevention and treatment strategies in FH, including in women, to reduce non-lipid risk factors and residual hypercholesterolemia.

Importance of Coagulation Factors as Critical Components of Premature Cardiovascular Disease in Familial Hypercholesterolemia.

For almost a century, familial hypercholesterolemia (FH) has been considered a serious disease, causing atherosclerosis, cardiovascular disease, and ischemic stroke. Closely related to this is the widespread acceptance that its cause is greatly increased low-density-lipoprotein cholesterol (LDL-C). However, numerous observations and experiments in this field are in conflict with Bradford Hill’s criteria for causality. For instance, those with FH demonstrate no association between LDL-C and the degree of atherosclerosis; coronary artery calcium (CAC) shows no or an inverse association with LDL-C, and on average, the life span of those with FH is about the same as the surrounding population. Furthermore, no controlled, randomized cholesterol-lowering trial restricted to those with FH has demonstrated a positive outcome. On the other hand, a number of studies suggest that increased thrombogenic factors—either procoagulant or those that lead to high platelet reactivity—may be the primary risk factors in FH. Those individuals who die prematurely have either higher lipoprotein (a) (Lp(a)), higher factor VIII and/or higher fibrinogen compared with those with a normal lifespan, whereas their LDL-C does not differ. Conclusions: Many observational and experimental studies have demonstrated that high LDL-C cannot be the cause of premature cardiovascular mortality among people with FH. The number who die early is also much smaller than expected. Apparently, some individuals with FH may have inherited other, more important risk factors than a high LDL-C. In accordance with this, our review has shown that increased coagulation factors are the commonest cause, but there may be other ones as well.

The promising novel therapies for familial hypercholesterolemia.

BackgroundThe incidence of premature atherosclerotic cardiovascular disease in familial hypercholesterolemia (FH) is high. In recent years, novel therapeutic modalities have shown significant lipid‐lowering ability. In this paper, we summarize the recent developments in novel therapies for FH via the treatment of different targets and discuss the characteristics of each targeted therapy. Based on the process of protein synthesis, we attempt to summarize the direct‐effect targets including protein, RNA, and DNA.MethodsFor this systematic review, relevant studies are assessed by searching in several databases including PubMed, Web of Science, Scopus, and Google Scholar. The publications of original researches are considered for screening.ResultsMost drugs are protein‐targeted such as molecule‐based and monoclonal antibodies, including statins, ezetimibe, alirocumab, evolocumab, and evinacumab. Both antisense oligonucleotide (ASO) and small interfering RNA (siRNA) approaches, such as mipomersen, vupanorsen, inclisiran, and ARO‐ANG3, are designed to reduce the number of mRNA transcripts and then degrade proteins. DNA‐targeted therapies such as adeno‐associated virus or CRISPR–Cas9 modification could be used to deliver or edit genes to address a genetic deficiency and improve the related phenotype.ConclusionWhile the therapies based on different targets including protein, RNA, and DNA are on different stages of development, the mechanisms of these novel therapies may provide new ideas for precision medicine.

The Effect of LRP-1 Gene and Mir-205 on Cardiovascular Disease in Iraqi Patients with Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder characterized by autosomal inheritance in genes related to LDL-C metabolism, with the major clinical features of hyper-LDL-cholesterolemia and premature coronary artery disease. (LRP-1) is a member of the LDLR family. It is a membrane receptor with scavenging and signaling properties. LRP-1 interacts with a wide range of extracellular ligands as well as intracellular scaffolding and signaling proteins, which makes it important in crucial clinical circumstances like cardiovascular disease, cancer, and neurological illnesses. Mir-205 uses these molecules as biomarker for cardiovascular diseases. This study aims to measure gene expression for the LPR-1 gene and its relationship to the development of cardiovascular disease in familial hypercholesterolemia and non-familial hypercholesterolemia. Also, it studies the indication whether mir-205 regulates the action of the LRP-1 gene in terms of increasing or decreasing gene expression. However, the available methods for measuring LRP1 levels are direct and quantitative using Poly Chain Reaction (RT-PCR) in real time, not at its ends. In the present study, blood was isolated from 150 individuals distributed into three groups: Group 1 included: 50 samples from a healthy group; Group 2: 50 samples from non-Familial hypercholesterolemia patients; Group 3:50 samples Familial hyperchol-esterolemia patients. The results showed that LRP1 protein expression was significantly reduced in patients with F.H compared with normal control in a small cohort from an Iraqi population. This pilot study suggests that the reduced LRP1 protein expression may be associated with cardiovascular disease progression.

PCSK9 as predictor for recurrent cardiovascular disease in familial hypercholesterolemia.

PCSK9 as predictor for recurrent cardiovascular disease in familial hypercholesterolemia.

LPA genotype is associated with premature cardiovascular disease in familial hypercholesterolemia

In recent years, lipoprotein (a) (Lp(a)) has been recognized as an important risk factor for cardiovascular disease (CVD). A variant in the LPA gene, rs10455872, has been associated with higher concentrations of Lp(a), as well as an increased risk of CVD in the general population. The objective of the present study is to compare the predictive value of an LPA variant, rs10455872, as well as Lp(a) concentration on the prevalence of CVD and on the age of the first CVD event in a cohort of genetically confirmed heterozygous patients with familial hypercholesterolemia (FH). Lp(a) total particle mass was measured by an enzyme-linked immunoassay kit. The rs10455872 genotype has been obtained via an exome chip genotyping method. The cohort comprised 88 carriers and 580 noncarriers of the rs10455872. The Lp(a) concentration (g/L) was significantly higher in carriers than in noncarriers (0.41 [0.33-0.60] vs 0.12 [0.05-0.27], respectively, P<.0001). There was a significant association between rs10455872 and prevalent CVD in a model corrected for classical CVD risk factors (odds ratio 1.97, 95% confidence interval 1.05-3.68, P=.04). There was a significant association between rs10455872 and the age of the first CVD event in a model corrected for all cardiovascular risk factors including Lp(a) levels (39.7 vs 43.9years in carriers vs noncarriers, respectively, P=.02). Our results suggest that the LPA variant rs10455872 is a good predictor of premature CVD risk in FH. This also suggest that targeting Lp(a) in FH subjects could be associated with further reduction in CVD risk.

SLC22A3 is associated with lipoprotein (a) concentration and cardiovascular disease in familial hypercholesterolemia

Background and aimsSeveral clinical and genetic factors have been shown to modulate the cardiovascular risk in subjects affected by familial hypercholesterolemia (FH). Genome wide association studies (GWAS) in the general population have identified several single nucleotide polymorphisms (SNPs) significantly associated with the risk of cardiovascular disease (CVD). This include the rs2048327 variant in the SLC22A3 gene. However, the effect of this SNP in FH subjects is unknown. The objectives of this study are to investigate the association between rs2048327 and the prevalence of CVD as well as with the concentration of lipoprotein (a) (Lp (a)), in a cohort of genetically-confirmed heterozygous FH patients. MethodsAn enzyme-linked immunoassay kit was used to assess the Lp (a) concentration, whereas an exome chip genotyping method was used to impute the rs2048327 genotype. ResultsThe cohort comprised 287 non-carriers (TT), 305 heterozygous carriers (TC) and 76 homozygous carriers of the rs2048327 variant. In a model corrected for traditional cardiovascular risk factors, rs2048327 was significantly associated with Lp (a) level (median value of 12, 16 and 29 mg/dL in TT, TC and CC carriers, respectively, p < .0001). In a model corrected for cardiovascular risk factors and Lp(a) value, carrying the C allele was associated with a 2-fold increased risk of CVD (OR 1.96, 95%CI 1.21–3.19, p = .007). ConclusionsIn this study, we demonstrated that the rs2048327 SNP of the SLC22A3 gene was significantly associated with Lp(a) as well as with CVD events in FH subjects. Further studies are required in order to investigate the mechanisms behind these associations.

Risk factors for cardiovascular disease in heterozygous familial hypercholesterolemia: A systematic review and meta-analysis

Current data from individual studies present conflicting evidence about the relationship between risk factors and cardiovascular disease (CVD) in heterozygous familial hypercholesterolemia (FH). We conducted a systematic review and meta-analysis to quantify the association between various CVD risk factors and CVD in FH. We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, and PubMed for English-language studies reporting adjusted-associations between cardiovascular, behavioral, or clinical risk factors and CVD with ≥ 100 participants. We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs) for selected risk factors with random-effects meta-analysis, from which we derived attributable risk estimates. We identified 27 studies representing 41,831 unique participants and 6629 CVD events. Age (OR: 1.07; 95% CI: 1.03, 1.10), male sex (OR: 1.95; 95% CI: 1.68, 2.23), hypertension (OR: 2.11; 95% CI: 1.64, 2.58), diabetes (OR: 1.95; 95% CI: 1.33, 2.57), body mass index (OR: 1.04; 95% CI: 1.03, 1.05), smoking (OR: 1.71; 95% CI: 1.30, 2.12), elevated lipoprotein(a) (OR: 1.90; 95% CI: 1.10, 2.71), low high-density lipoprotein cholesterol (OR: 1.39; 95% CI: 1.24, 1.53), and a family history of CVD (OR: 1.83, 95% CI: 1.58, 2.07) were found to be significant CVD risk factors in FH. Smoking, hypertension, and diabetes accounted for more than a quarter of CVD risk in FH individuals, whereas low-density lipoprotein cholesterol > 4.0mmol/L accounted for 1 in 3 CVD cases. Meta-regression analyses found associations between low-density lipoprotein cholesterol (P=.045) and total cholesterol (P<.001) and CVD. Results were broadly consistent in sensitivity analyses. Several clinical risk factors are significantly and independently associated with CVD risk in patients with FH and should be targeted for modification. These data can also inform the selection of variables for prediction models to aid in risk stratifying patients.

Predicting cardiovascular disease in familial hypercholesterolemia.

Familial hypercholesterolemia is a frequent genetic disease associated with a high lifetime risk of cardiovascular disease (CVD). Statins are the cornerstone of treatment of familial hypercholesterolemia; however, with the advent of novel LDL-cholesterol lowering therapies, it has become necessary to identify familial hypercholesterolemia subjects presenting a significant residual CVD risk. The aim of this review is to provide an update on the recent literature concerning cardiovascular risk stratification in familial hypercholesterolemia. Recently, several clinical and genetic factors have been shown to be independent predictors of CVD in familial hypercholesterolemia. These include clinical scores such as the Montreal-FH-SCORE, novel protein biomarkers, carotid plaque score and genetic predictors such as genetic risk scores as well as single-nucleotide polymorphisms. Although there has been recent progress in cardiovascular risk stratification in familial hypercholesterolemia, there is still a need to further refine our knowledge concerning phenotype modifiers in this disease. Indeed, current known predictors do not explain the entirety of cardiovascular risk. More precise individual risk stratification in familial hypercholesterolemia could help to better tailor the proper therapy for each patient.

Familial hypercholesterolemia: experience from the French-Canadian population.

There has recently been renewed interest in the study of the various facets of familial hypercholesterolemia, a severe monogenic disease associated with elevated LDL-cholesterol and premature cardiovascular disease (CVD). In the present review, novel data presenting the frequency of familial hypercholesterolemia as well as factors modulating the cardiovascular risk in familial hypercholesterolemia will be discussed. Recent studies have showed that familial hypercholesterolemia is much more prevalent than initially thought. Classically, it was estimated that familial hypercholesterolemia affected one in 500 people worldwide, but a recent large-scale meta-analysis has shown a prevalence closer to one in 250. In the French-Canadian population, this disease is even more frequent reaching one in 81 in certain regions of the Province of Quebec. Several novel studies in the French-Canadian population have shown that the clinical outcomes in familial hypercholesterolemia seem to be greatly influenced by risk factors other than LDL-cholesterol. Also, scores to predict CVD in familial hypercholesterolemia have been recently proposed. Familial hypercholesterolemia is more frequent than initially thought and the phenotype of this disease can be variable. Indeed, both clinical and genetic variables can modulate the CVD risk in this population.

Sex differences in cholesterol levels from birth to 19 years of age may lead to increased cholesterol burden in females with FH

The increased risk of cardiovascular disease in familial hypercholesterolemia (FH) is caused by increased cholesterol burden from birth. Even small elevation in cholesterol level accumulates over time and aggravates atherosclerosis. The aim of the present study was to describe the lipid profile across sex and age in a large cohort of untreated children and adolescents with FH, as this have not clearly been described. FH children (438 girls, 452 boys) not receiving lipid-lowering therapy, aged 0 to 19years were included and divided into 4 age groups (<5, 5-9, 10-14, and 15-19years). Information was retrieved from the medical records. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) were studied in relation to sex and age by multiple linear regression analysis. Girls with FH as compared to boys had significantly higher TC, LDL-C, and non-HDL-C (P<.001 for all) levels with mean (95% confidence interval) differences of 0.48mmol/L (0.28, 0.68) (18.6g/dL), 0.39mmol/L (0.19, 0.59) (15.08mg/dL), and 0.42mmol/L (0.22, 0.63) (16.24mg/dL), respectively. These estimates did not change after adjustment for age. We also observed sex differences for HDL-C; girls had higher HDL-C in the youngest (<5years, P=.05) and oldest age groups (15-19years, P<.001). FH girls have higher levels of TC, LDL-C, and non-HDL-C levels than boys from birth up to 19years of age. This may contribute significantly to the total lifelong cholesterol burden in FH women.

Main cardiovascular risk factors and HDL rather than LDL and LP(a) levels predict premature atherosclerotic cardiovascular disease in familial hypercholesterolemia

Main cardiovascular risk factors and HDL rather than LDL and LP(a) levels predict premature atherosclerotic cardiovascular disease in familial hypercholesterolemia

Cardiovascular disease in familial hypercholesterolemia: Validation and refinement of the Montreal-FH-SCORE

Familial hypercholesterolemia (FH) is a disease characterized by increased low-density lipoprotein cholesterol and premature cardiovascular disease (CVD) but there is marked individuality in the occurrence of CVD events. Recently, the Montreal-FH-SCORE (MFHS) has been shown to stratify CVD frequency in FH subjects, but this score has not yet been validated. The aims of the present study were to conduct an independent external validation of the MFHS in a retrospective cohort of heterozygous FH and to identify additional variables that could significantly improve the prediction of prevalent CVD. The MFHS calculation is based on 5 variables: age, high-density lipoprotein cholesterol, gender, hypertension, and smoking status. This score was validated in a cohort of 718 adult FH using receiver operating characteristic (ROC) curves analysis to determine the discriminatory ability of the MFHS. The performance of the MFHS was compared to a novel Combined-FH-SCORE in 1388 FH. The MFHS had an excellent discrimination for prevalent CVD events in the validation cohort, with an area under the receiver operating characteristic curve of 0.799 (0.766-0.832, P<.0001). Patients with a high MFHS score presented a significant 8.8-fold increased odd of CVD events compared with patients with a low score (95% confidence interval 5.8-13.3, P<.0001). The addition of lipoprotein(a) to the score did not improve the prediction of CVD events (area under the receiver operating characteristic curve 0.823 vs 0.817, P=.11). This study confirmed that the MFHS is a strong predictor of prevalent CVD in FH and that the addition of lipoprotein(a) offers a minor improvement in the discrimination of the score.

Polygenic risk score predicts prevalence of cardiovascular disease in patients with familial hypercholesterolemia

Although familial hypercholesterolemia (FH) is a severe monogenic disease, it has been shown that clinical risk factors and common genetic variants can modify cardiovascular disease (CVD) risk. The aim of the study was to evaluate the polygenic contribution to lipid traits and CVD in FH using genetic risk scores (GRSs). Among the 20,434 subjects attending the lipid clinic, we identified and included 725 individuals who carried an FH causing mutation in this retrospective cohort study. We evaluated the association of GRSs for several traits including coronary artery disease (CAD; GRSCAD) as well as plasma concentrations of low-density lipoprotein cholesterol (LDL-C; GRSLDL-C), high-density lipoprotein cholesterol (GRSHDL-C) and triglycerides (GRSTG). A total of 32% (n=231) of FH subjects presented a CVD event before their first visit. Patients in the highest GRSLDL-C tertile presented an LDL-C 0.4mmol/L (15.5mg/dL) higher than the subjects in the lowest tertile (P=.01). The GRSCAD was strongly associated with CVD events (odds ratio 1.80; 95% confidence interval 1.14-2.85; P=.01) even after adjustment for cardiovascular risk factors. Compared with subjects in the first tertile, those in the third GRSCAD tertile had a significantly higher prevalence of events (40.9% vs 24.7%, P<.0001) and a significantly higher number of events (average 0.97 vs 0.57 [P=.0001] events per individual). These results indicate that even in the context of a severe monogenic disease such as FH, common genetic variants can significantly modify the disease phenotype. The use of the 192-SNPs GRSCAD may refine CVD risk prediction in FH patients and this could lead to a more personalized approach to therapy.

LRP1 Gene Polymorphisms Are Associated With Premature Risk of Cardiovascular Disease in Patients With Familial Hypercholesterolemia

Introduction and objectivesLRP1 gene overexpression in atherosclerotic plaque is associated with increased lipid uptake through the vascular wall. The aim of the study was to analyze whether LRP1 modulates the genetic risk of developing premature cardiovascular disease in familial hypercholesterolemia, using single nucleotide polymorphism association analysis. MethodsTen polymorphisms of the LRP1 gene (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164, and rs35282763) were genotyped in 339 patients (77 with premature cardiovascular disease and 262 without) in the SAFEHEART study. ResultsThe c.677C>T (rs1799986) polymorphism showed a significant association with premature cardiovascular disease after adjusting by sex, age, body mass index, and the effect of the low-density lipoprotein receptor mutation in the dominant model (CT+TT vs CC: odds ratio=1.94; 95% confidence interval, 1.08-3.48; P=.029). Similar results were observed after increasing the sample to 648 subjects (133 with premature cardiovascular disease vs 515 without [odds ratio=1.83; 95% confidence interval, 1.16-2.88; P=.011]). ConclusionsThe c.677C>T polymorphism is associated with increased rates of premature cardiovascular disease in familial hypercholesterolemia. Although we were unable to show that this polymorphism was involved in the alteration of normal mRNA splicing patterns, the possibility that it is in strong linkage disequilibrium with another functional polymorphism cannot be ruled out and would explain the cause-effect relationship with cardiovascular disease risk in this population. Further studies are needed to replicate the results and to localize the putative genetic variants associated with this polymorphism.

Los polimorfismos del gen LRP1 se asocian al riesgo prematuro de enfermedad cardiovascular en pacientes con hipercolesterolemia familiar

Introduction and objectivesLRP1 gene overexpression in atherosclerotic plaque is associated with increased lipid uptake through the vascular wall. The aim of the study was to analyze whether LRP1 modulates the genetic risk of developing premature cardiovascular disease in familial hypercholesterolemia, using single nucleotide polymorphism association analysis. MethodsTen polymorphisms of the LRP1 gene (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164, and rs35282763) were genotyped in 339 patients (77 with premature cardiovascular disease and 262 without) in the SAFEHEART study. ResultsThe c.677C>T (rs1799986) polymorphism showed a significant association with premature cardiovascular disease after adjusting by sex, age, body mass index, and the effect of the low-density lipoprotein receptor mutation in the dominant model (CT+TT vs CC: odds ratio=1.94; 95% confidence interval, 1.08-3.48; P=.029). Similar results were observed after increasing the sample to 648 subjects (133 with premature cardiovascular disease vs 515 without [odds ratio=1.83; 95% confidence interval, 1.16-2.88; P=.011]). ConclusionsThe c.677C>T polymorphism is associated with increased rates of premature cardiovascular disease in familial hypercholesterolemia. Although we were unable to show that this polymorphism was involved in the alteration of normal mRNA splicing patterns, the possibility that it is in strong linkage disequilibrium with another functional polymorphism cannot be ruled out and would explain the cause-effect relationship with cardiovascular disease risk in this population. Further studies are needed to replicate the results and to localize the putative genetic variants associated with this polymorphism.Full English text available from:www.revespcardiol.org

Familial hypercholesterolemia and lipoprotein(a) hyperlipidemia as independent and combined cardiovascular risk factors

Abstract The phenotypic diversity of familial hypercholesterolemia (FH) and lipoprotein(a) hyperlipidemia (Lp(a)-HLP), as defined risks for coronary artery disease with genetic background, and their frequent co-incidence with additional cardiovascular risk factors require a critical revisiting of the current diagnostic and screening criteria as well as therapeutic recommendations established for FH or isolated Lp(a)-HLP, since there is no clear guidance for patient stratification and disease management for combined cases. Further evaluation of the recent biomarkers and establishment of novel biomarkers are necessary for extended risk assessment of cardiovascular disease in FH or Lp(a)-HLP and to better understand the pathophysiology of these syndrome complexes. Lipoprotein apheresis is used as long-term treatment to reduce circulating lipoproteins in patients with severe FH and/or Lp(a)-HLP, particularly with multiple cardiovascular risks who are intolerant or insufficiently responsive to lipid-lowering drugs. Recent sophisticated analyses of molecular lipid species (lipidome) extended with transcriptomic and/or proteomic approaches may provide further lipid biomarkers for disease management of FH and/or Lp(a)-HLP, and relevant data for optimization of apheresis treatment. This review summarizes current studies investigating FH and Lp(a)-HLP as independent and combined cardiovascular risk factors, and some promising biomarker candidates for these entities.

ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia

Elevated plasma plant sterol concentrations may be a risk factor of cardiovascular disease (CVD). Polymorphisms in the ABCG8 gene have been identified that contribute to the variation in plasma concentrations of plant sterols. However, data on the direct relationship of ABCG8 gene polymorphisms with CVD are lacking. Therefore, we examined associations between the D19H and T400K polymorphisms in the ABCG8 gene and CVD in a large cohort study of 2012 patients with heterozygous familial hypercholesterolemia (FH). A total of 244 individuals carried one or two alleles of the D19H variant and 568 individuals the T400K variant. During 94,809 person years, 648 (32.2%) individuals developed CVD of which coronary heart disease (CHD) was the most frequent cardiovascular event ( N = 553). In a Cox proportional hazard regression model adjusted for relevant cardiovascular risk factors, the D19H polymorphism was not associated with total CVD risk ( p = 0.2), but there was evidence of an association with higher risk of CHD (RR 1.42, CI 1.04–1.95; p = 0.03). We observed no relationship between the T400K polymorphism and cardiovascular endpoints ( p > 0.1). However, FH individuals carrying the risk genotype for both ABCG8 variants had an increased risk of CVD (RR 1.57, 95% CI 1.13–2.18; p = 0.01) and CHD (RR 1.72, 95% CI 1.23–2.41; p = 0.002). In conclusion, our data suggest that genetic variation in the ABCG8 gene may influence the burden of atherosclerosis.

Altered hemostatic balance and endothelial activation in pregnant women with familial hypercholesterolemia

Introduction Patients with familial hypercholesterolemia (FH) are prone to premature cardiovascular disease. During pregnancy plasma lipids reach higher absolute values in FH than in healthy women. Pregnancy is associated with activation of coagulation and possibly also of vascular endothelium, which might further increase the risk of cardiovascular disease in FH. However, whether hemostatic and endothelial activation markers are increased in pregnant FH women compared with non-FH pregnancies, is unknown. Materials and methods Activation markers of hemostasis and endothelium were analyzed in blood samples collected prospectively from 22 heterozygous FH women during pregnancy and compared with those of a reference group of 149 healthy, pregnant women. Results A procoagulant pattern was detected in both groups, but was more evident among FH women at least partly due to their enhanced thrombin generation, and because tissue factor pathway inhibitor type 1 increased in the reference group only. Furthermore, plasminogen activator inhibitor type 2 antigen increased more in FH than in the reference group. Whereas C-reactive protein, intercellular adhesion marker-1 and E-selectin did not change appreciably, vascular endothelial cell adhesion molecule 1 rose markedly in FH. Conclusion Increased lipid levels as well as a net procoagulant activity and an enhanced endothelial activation possibly confer additional risks of cardiovascular disease among pregnant FH women.