Familial Hypercholesterolemia Disease 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.

Cascade genetic counseling and testing in hereditary syndromes: inherited cardiovascular disease as a model: a narrative review.

Inherited cardiovascular diseases cover the inherited cardiovascular disease familial hypercholesterolemia and inherited cardiac diseases, like inherited cardiomyopathies and inherited arrhythmia syndromes. Cascade genetic counseling and testing in inherited cardiovascular diseases have had three decades of academic attention. Inherited cardiovascular diseases affect around 1-2% of the population worldwide and cascade genetic counseling and testing are considered valuable since preventive measures and/or treatments are available. Cascade genetic counseling via a family-mediated approach leads to an uptake of genetic counseling and testing among at-risk relatives of around 40% one year after identification of the causal variant in the proband, with uptake remaining far from complete on the long-term. These findings align with uptake rates among relatives at-risk for other late onset medically actionable hereditary diseases, like hereditary cancer syndromes. Previous interventions to increase uptake have focused on optimizing the process of informing relatives through the proband and on contacting relatives directly. However, despite successful information dissemination to at-risk relatives, these approaches had little or no effect on uptake. The limited research into the barriers that impede at-risk relatives from seeking counseling has revealed knowledge, attitudinal, social and practical barriers but it remains unknown how these factors contribute to the decision-making process for seeking counseling in at-risk relatives. A significant effect on uptake of genetic testing has only been reached in the setting of familial hypercholesterolemia, where active information provision was accompanied by a reduction of health-system-related barriers. We propose that more research is needed on barriers -including health-system-related barriers- and how they hinder counseling and testing in at-risk relatives, so that uptake can be optimized by (adjusted) interventions.

Effectiveness of clinical scores in predicting coronary artery disease in familial hypercholesterolemia: a coronary computed tomography angiography study

PurposeOne of the major challenges in the management of familial hypercholesterolemia (FH) is the stratification of cardiovascular risk in asymptomatic subjects. Our purpose is to investigate the performance of clinical scoring systems, Montreal-FH-score (MFHS), SAFEHEART risk (SAFEHEART-RE) and FH risk score (FHRS) equations and Dutch Lipid Clinic Network (DLCN) diagnostic score, in predicting extent and severity of CAD at coronary computed tomography angiography (CCTA) in asymptomatic FH.Material and methodsOne-hundred and thirty-nine asymptomatic FH subjects were prospectively enrolled to perform CCTA. MFHS, FHRS, SAFEHEART-RE and DLCN were assessed for each patient. Atherosclerotic burden scores at CCTA (Agatston score [AS], segment stenosis score [SSS]) and CAD-RADS score were calculated and compared to clinical indices.ResultsNon-obstructive CAD was found in 109 patients, while 30 patients had a CAD-RADS ≥ 3. Classifying the two groups according to AS, values varied significantly for MFHS (p < 0.001), FHRS (p < 0.001) and SAFEHEART-RE (p = 0.047), while according to SSS only MFHS and FHRS showed significant differences (p < 0.001). MFHS, FHRS and SAFEHEART-RE, but not DLCN, showed significant differences between the two CAD-RADS groups (p < .001).MFHS proved to have the best discriminatory power (AUC = 0.819; 0.703–0.937, p < 0.001) at ROC analysis, followed by FHRS (AUC = 0.795; 0.715–0.875, p < .0001) and SAFEHEART-RE (AUC = .725; .61–.843, p < .001).ConclusionsGreater values of MFHS, FHRS and SAFEHEART-RE are associated to higher risk of obstructive CAD and might help to select asymptomatic patients that should be referred to CCTA for secondary prevention.

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.

Coronary microcirculatory blood flow significantly increases upon acute and chronic cholesterol lowering. Evaluation by cadmium-zinc-telluride cardiac imaging stress test

Background and Aims : Aim of this pilot study was to evaluate, in patients with Familial Hypercholesterolemia disease, the impact of the lipid lowering approach on coronary endothelium, by the quantification of the absolute myocardial blood flow (MBF) and the coronary flow reserve (CFR), before and after treatment.

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.

A variant in the fibronectin (FN1) gene, rs1250229-T, is associated with decreased risk of coronary artery disease in familial hypercholesterolaemia

BackgroundIncreased risk of coronary artery disease (CAD) in familial hypercholesterolaemia (FH) is modified by factors beyond defects in the low-density lipoprotein receptor pathway. The rs1250229-T single nucleotide polymorphism (SNP) in the FN1 gene is associated with CAD in genome-wide association studies and is in linkage disequilibrium with another SNP (rs1250259-T) in FN1 that is associated with decrease fibronectin secretion. ObjectiveWe investigated whether rs1250229-T was also associated with prevalent CAD in patients with genetically confirmed FH. MethodsWe collected clinical data from 256 patients with genetically confirmed FH. The FN1 rs1250229 SNP was genotyped on a SEQUENOM platform. The association between rs1250229-T and prevalent CAD was assessed using simple and multiple regression analyses. ResultsIn patients with FH, the FN1 rs1250229-T (minor) allele was a significant negative predictor of prevalent CAD (odds ratio [OR] 0.353; 95% confidence interval [CI] 0.193 - 0.647; P = 0.001). FN1 rs1250229-T remained a significant predictor of prevalent CAD after adjusting for age, sex, obesity, hypertension, smoking status and lipoprotein(a) concentration (OR 0.200; 95% CI 0.091 - 0.441; P < 0.001). ConclusionThe FN1 rs1250229-T allele is inversely associated with CAD in patients with genetically confirmed FH, independently of traditional risk factors. While this finding requires replication, it suggests that the biology of fibronectin may contribute to variation in the risk of CAD in FH.

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.

A genetic risk score predicts coronary artery disease in familial hypercholesterolaemia: enhancing the precision of risk assessment

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutation-negative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.

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 of Ischemic Stroke and Total Cerebrovascular Disease in Familial Hypercholesterolemia: A Register Study From Norway.

Background and Purpose- Familial hypercholesterolemia (FH) is a common autosomal dominant disease leading to increased level of serum LDL (low-density lipoprotein) cholesterol and risk of coronary heart disease. Whether FH increases the risk of cerebrovascular disease, including ischemic stroke, is debated. Accordingly, we studied the incidence of cerebrovascular disease in a cohort of people with genetically verified FH compared with the entire Norwegian population and examined whether people in this cohort with previous cohort had increased risk of cerebrovascular disease. Methods- Incidence rates of hospitalization for cerebrovascular disease (among 3144 people with FH) and ischemic stroke (among 3166 people with FH) were estimated by linkage of FH people to Cardiovascular Disease in Norway-a nationwide database of cardiovascular disease hospitalizations (2001-2009). We calculated standardized incidence ratios and used Cox regression to estimate hazard ratios. Results- A total of 46 cases (19 women and 27 men) of cerebrovascular disease were observed in the cohort of people with FH, with no increased risk of cerebrovascular disease compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.8-1.4). Total number of ischemic strokes in the cohort of people with FH was 26 (9 women and 17 men), with no increased risk compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.7-1.5). Prior coronary heart disease significantly increased cerebrovascular disease risk in women (hazard ratio, 3.29; 95% CI, 1.20-9.00) but not in men (hazard ratio, 1.03; 95% CI, 0.45-2.37; Pinteraction=0.04). Conclusions- In a large cohort of genetically verified FH, risks of cerebrovascular disease and ischemic stroke were not increased compared with the total Norwegian population.

P6269Remnant-like particles and coronary artery disease in familial hypercholesterolemia

P6269Remnant-like particles and coronary artery disease in familial hypercholesterolemia

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.

Excess risk of peripheral arterial disease in familial hypercholesterolemia

Aim: It is unknown to what degree the risk of peripheral arterial disease (PAD) is increased in familial hypercholesterolemia (FH) and the risk in relation to age and sex is unknown. The aim of this study was to explore the role of LDL in PAD in relation to age and sex using FH as a model disease.

Remnant-like particles and coronary artery disease in familial hypercholesterolemia

BackgroundAlthough remnant-like particle cholesterol (RLP-C) has been associated with coronary artery disease (CAD) in the general population, few data exist regarding this issue in patients with familial hypercholesterolemia (FH). The aim of our study was to investigate the association between RLP-C and the presence of CAD in patients with FH. MethodsWe examined 282 patients with FH (144 males, mean age, 41 ± 17 years) whose RLP-C levels were measured. We assessed the baseline characteristics, including lipid levels, other conventional risk factors for cardiovascular events, the presence of CAD, and the serum RLP-C levels. ResultsSerum RLP-C levels significantly correlated with serum triglyceride (TG) levels (Pearson's r = 0.631, p < 0.001). We observed that a larger proportion of individuals in the higher tertiles of serum RLP-C had a larger number of diseased coronary arteries (p < 0.001 for the trend of multi-vessel disease). Logistic regression analysis, after adjusting for age, sex, hypertension, diabetes, smoking, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein (a) [Lp(a)], revealed that RLP-C was significantly associated with CAD [odds ratio (OR): 1.08, 95% confidence interval (CI): 1.00–1.16, p = 0.046]; however, adding serum TG levels into the logistic regression model nullified this association (OR: 1.07, 95% CI: 0.98–1.17, p = 0.141), whereas Lp(a) was independently associated with CAD (OR: 1.02, 95% CI: 1.00–1.03, p = 0.015). ConclusionsSerum RLP-C levels were significantly associated with the presence and severity of CAD in patients with FH. However, the clinical usefulness of measuring RLP-C levels beyond that of measuring TG levels should be further assessed.

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