FH Patients Research Articles

Achieving low-density lipoprotein cholesterol targets as assessed by different methods in patients with familial hypercholesterolemia: an analysis from the HELLAS-FH registry

BackgroundFamilial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and increased cardiovascular disease (CVD) risk. FH patients often have increased lipoprotein(a) [Lp(a)] levels, which further increase CVD risk. Novel methods for accurately calculating LDL-C have been proposed.MethodsPatients with FH were recruited by a network of Greek sites participating in the HELLAS-FH registry. LDL-C levels were calculated using the Friedewald (LDL-CF) and the Martin/Hopkins (LDL-CM/H) equations as well as after correcting LDL-CM/H for Lp(a) levels [LDL-CLp(a)corM/H]. The objective was to compare LDL-C levels and target achievement as estimated by different methods in FH patients.ResultsThis analysis included 1620 patients (1423 adults and 197 children). In adults at diagnosis, LDL-CF and LDL-CM/H levels were similar [235 ± 70 mg/dL (6.1 ± 1.8 mmol/L) vs 235 ± 69 mg/dL (6.1 ± 1.8 mmol/L), respectively; P = NS], while LDL-CLp(a)corM/H levels were non-significantly lower than LDL-CF [211 ± 61 mg/dL (5.5 ± 1.6 mmol/L); P = 0.432]. In treated adults (n = 966) both LDL-CF [150 ± 71 mg/dL (3.9 ± 1.8 mmol/L)] and LDL-CM/H levels [151 ± 70 mg/dL (6.1 ± 1.8 mmol/L); P = 0.746] were similar, whereas LDL-CLp(a)corM/H levels were significantly lower than LDL-CF [121 ± 62 mg/dL (3.1 ± 1.6 mmol/L); P < 0.001]. Target achievement as per latest guidelines in treated patients using the LDL-CM/H (2.5%) and especially LDL-CLp(a)corM/H methods (10.7%) were significantly different than LDL-CF (2.9%; P < 0.001).In children, all 3 formulas resulted in similar LDL-C levels, both at diagnosis and in treated patients. However, target achievement by LDL-CF was lower compared with LDL-CM/H and LDL-CLp(a)corM/H methods (22.1 vs 24.8 vs 33.3%; P < 0.001 for both comparisons).ConclusionLDL-CLp(a)corM/H results in significantly lower values and higher target achievement rate in both treated adults and children. If validated in clinical trials, LDL-CLp(a)corM/H may become the method of choice to more accurately estimate ‘true’ LDL-C levels in FH patients.

PCV31 COST-EFFECTIVENESS OF EVOLOCUMAB FOR THE TREATMENT OF PATIENTS WITH HYPERCHOLESTEROLEMIA IN THE KINGDOM OF SAUDI ARABIA

Atherosclerotic cardiovascular disease (ASCVD) represents a major health challenge for the Saudi Arabian population, in which the prevalence of cardiovascular (CV) risk factors including elevated low-density lipoprotein cholesterol (LDL-C) is increasing. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha®) has been demonstrated to reduce the risk of recurrent CV events in patients whose LDL-C levels are not controlled despite statin-based lipid-lowering therapy. Those most likely to experience CV events include patients with clinically evident ASCVD and Familial hypercholesterolemia. This study is conducted to evaluate the cost-effectiveness of evolocumab in the Kingdom of Saudi Arabia and to detail the underlying economic model. The Markov cohort state transition model incorporates efficacy estimates from evolocumab’s outcomes study, FOURIER, and observational research data on baseline CV event rates in actual clinical practice. All analyses are conducted from a public healthcare perspective in the KSA. In patients with clinically evident ASCVD and baseline LDL-C ≥70 mg/dL (1.8 mmol/L) or ≥100 mg/dL (2.6 mmol/L), adding evolocumab to maximally tolerated statin (with or without ezetimibe) is associated, respectively, with an incremental cost per quality-adjusted life year (QALY) gained of 109,274 SAR and 75,163 SAR over a lifetime time horizon. In heterozygous familial hypercholesterolemia (HeFH) patients with baseline LDL-C ≥100 mg/dL, adding evolocumab to background LLT is associated with an incremental cost per QALY gained of 22,391 SAR over a patient’s lifetime compared with background LLT. These findings are robust to changes in the model input parameters and fall below the conventionally applied threshold of up to three times the gross domestic product (GDP) per capita (about 265,000 SAR). In clinically evident ASCVD or FH patients who are unable to control LDL-C levels with conventional LLTs, adding evolocumab reduces unnecessary CV events, partially lessening the substantial impact of ASCVD on the hospital system, patients, and society.

An age-matched computed tomography angiographic study of coronary atherosclerotic plaques in patients with familial hypercholesterolaemia

Background and aimsFamilial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH. MethodsWe undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M–) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis. ResultsWe studied 104 cases and 104 controls (mean age 49.9 ± 10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M– group (7.8 ± 2.1 vs 6.2 ± 1.2 mmol/L, p<0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p<0.05), in the M+ compared with the M– group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p<0.05), but not in the left circumflex. ConclusionsAmong patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques.

Abstract AP17: MOLECULAR AND FUNCTIONAL HETEROGENEITY OF CANCER ASSOCIATED FIBROBLASTS IN HIGH-GRADE SEROUS OVARIAN CANCER

Abstract High grade serous ovarian cancer (HGSC) is typically diagnosed at an advanced stage and the vast majority of patients relapse and die within 5 years of diagnosis. Significant clinical problems in HGSC include wide-spread abdominal dissemination of disease and chemotherapy resistance. Cancer-associated fibroblasts (CAFs) have been shown to play a role in promotion of cancer cell proliferation and invasion, and mediation of chemotherapy resistance. To interrogate the molecular properties of CAFs in HGSC we used fluorescence activated cell sorting to isolate CAFs directly from primary tumor samples and performed gene expression profiling. We found that patients stratify into two classes based on their CAF gene signatures: One with high expression of Fibroblast Activation Protein (FAP-High; FH) and one with low expression of FAP (FAP-Low; FL). FH CAFs express classical CAF genes whereas FL CAFs possesses a preadipocyte-like molecular signature. The FL phenotype has remained largely unnoticed as it is generally out-competed in vitro by FH cells when grown under classical CAF culture conditions. Patients from The Cancer Genome Atlas (TCGA), as well as from our own institute, can be stratified into FH and FL subtypes; in both cohorts patients with FH CAFs have a significantly shorter disease-free and overall survival. In vitro and in vivo functional assays performed with isolated CAFs of both types indicate that FH CAFs aggressively promote proliferation, invasion and therapy resistance of cancer cells, whereas FL CAFs do not. Finally, we identified TCF21, a transcriptional repressor, as a FL-specific transcription factor. Analysis of published TCF21 ChIP-Seq data indicates that TCF21 targets a large number of genes specific to FH CAFs. Overexpression of TCF21 in FH CAFs partially reversed their ability to promote cancer cell invasion and tumor growth. Our discovery of CAF heterogeneity in HGSC highlights the need to personalize patient treatment with respect to both cancer and stromal phenotypes. FH patients may benefit from inhibition of cancer-stroma interactions or from epigenetic modulators that reprogram cancer-promoting FH CAFs into the non-supportive FL state. Citation Format: Ali Hussain, Veronique Voisin, Stephanie Poon, Jalna Meens, Julia Dmytryshyn, Josh Paterson, Marcus Bernardini3, Gary Bader, Benjamin G Neel, Laurie E Ailles. MOLECULAR AND FUNCTIONAL HETEROGENEITY OF CANCER ASSOCIATED FIBROBLASTS IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP17.

Baseline and on-statin treatment lipoprotein(a) levels for predicting cardiovascular events in patients with familial hypercholesterolemia

Background and aimsLipoprotein(a) [Lp(a)] has been considered as a causal risk factor for cardiovascular disease (CVD) in the general population and levels vary in different ethnicities. However, no systemic analysis is currently available regarding the relation of plasma Lp(a) levels to cardiovascular events (CVEs) in Chinese patients with heterozygous familial hypercholesterolemia (HeFH). MethodsThree hundred and ninety-three patients with HeFH undergoing Lp(a) measurement at baseline were consecutively enrolled and followed prospectively for an average of 36.5 months. Lp(a) levels were determined using an immunoturbidimetry assay. Cox regression analysis with adjusted hazard ratios (HRs) and Kaplan-Meier analysis were used to evaluate the prognostic value of Lp(a) on CVEs. ResultsThirty-five events occurred during follow-up. Lp(a) was significantly higher in patients with CVEs (53.3 mg/dL versus 31.7 mg/dL, p < 0.001). In Kaplan-Meier analysis, patients with upper tertile of Lp(a) had a significant lower event-free survival (p = 0.004). After adjusting for confounding risk factors, per log unit increase in baseline Lp(a) was independently associated with CVEs [HR: 2.03(1.28–3.21), p = 0.002]. HRs remained unchanged after accounting for hard endpoints and did not vary too much in several relevant subgroups. Adding Lp(a) to the Cox model led to a significant improvement in C-statistic, net reclassification and integrated discrimination. Moreover, HR for upper versus lower tertile of change in Lp(a) was 2.68 (1.11–6.48) for CVEs after one year. ConclusionsBoth baseline and on-statin treatment Lp(a) levels were associated with an increased risk of CVEs in patients with HeFH, suggesting that Lp(a) measurement might clinically help further risk stratification of FH patients.

Predicting intention to participate in self-management behaviors in patients with Familial Hypercholesterolemia: A cross-national study

RationaleFamilial Hypercholesterolemia (FH) is a genetic condition that predisposes patients to substantially increased risk of early-onset atherosclerotic cardiovascular disease. FH risks can be minimized through regular participation in three self-management. Behaviorsphysical activity, healthy eating, and taking cholesterol lowering medication. ObjectiveThe present study tested the effectiveness of an integrated social cognition model in predicting intention to participate in the self-management behaviors in FH patients from seven countries. MethodConsecutive patients in FH clinics from Australia, Hong Kong, Brazil, Malaysia, Taiwan, China, and UK (total N = 726) completed measures of social cognitive beliefs about illness from the common sense model of self-regulation, beliefs about behaviors from the theory of planned behavior, and past behavior for the three self-management behaviors. ResultsStructural equation models indicated that beliefs about behaviors from the theory of planned behavior, namely, attitudes, subjective norms, and perceived behavioral control, were consistent predictors of intention across samples and behaviors. By comparison, effects of beliefs about illness from the common sense model were smaller and trivial in size. Beliefs partially mediated past behavior effects on intention, although indirect effects of past behavior on intention were larger for physical activity relative to taking medication and healthy eating. Model constructs did not fully account for past behavior effects on intentions. Variability in the strength of the beliefs about behaviors was observed across samples and behaviors. ConclusionCurrent findings outline the importance of beliefs about behaviors as predictors of FH self-management behaviors. Variability in the relative contribution of the beliefs across samples and behaviors highlights the imperative of identifying sample- and behavior-specific correlates of FH self-management behaviors.

P648Screening and treatment of familial hypercholesterolemia in a French sample of ambulatory care: a retrospective longitudinal cohort study

Abstract Background Familial hypercholesterolemia (FH) is largely underdiagnosed as there are typically no clinical symptoms prior to the first cardiovascular (CV) event. We conducted a study which utilised ambulatory care electronic medical record (EMRs) to alert physicians to possible cases of FH. Specifically, physicians were alerted to LDL-C levels &gt;190 mg/dL (suggesting a risk of FH) and invited to complete the Dutch Lipid Clinic Network score (DLCN). Purpose Describe characteristics, comorbidities and clinical management of patients diagnosed with definite or probable FH in an ambulatory care setting. Methods All patients with a DLCN score of definite/probable FH (score higher or equal than 6; index event) between January 2016 and September 2018 were identified in the THIN® database (The Health Improvement Network; an anonymized EMR powered by GERSDATA, a Cegedim Health Data Division). These fully anonymized data were collected by 2000 General Practitioners (GP), 130 cardiologists and 40 endocrinologists, receiving 5.5 million patients regularly in their office. Sociodemographic, laboratory measurements, comorbidities, lipid-lowering therapies (LLT), visits to specialists, LDL-C and hospitalizations were collected and analysed at baseline, and 1, 2, 3, 6 months, and 1 year thereafter. Results From 999 anonymous patients with a DLCN score, 98 (10%) FH patients were identified (38 [39%] definite FH, 60 [61%] probable FH) while remaining fully anonymous, 9 (9%) of whom already had genetic testing. Mean (SD) age was 57.4 (14.3) years; 56 (57%) patients were female, half (51/98 [52%]) were diagnosed with pure hypercholesterolemia (ICD-10 code: E78.0) and 9 (9%) had a personal history of CV event. 93 patients (95%) had a LDL-C measurement prior to DLCN assessment (definite FH, 36/38 [95%]; probable FH, 57/60 [95%]). Among screened FH patients, 61.2% had LDL-C between 190 to 250 mg/dL and 16.3% had LDL-C higher than 250 mg/dL. At the time of DLCN assessment, one third (30/98 [31%]) of patients were not receiving any LLT, one third ([35%] 34/98) were receiving statins alone, 19% (19/98) receiving LLT combination with statin, and 15% (15) other LLTs. Moderate statin intensity was prescribed in 20% (20/98) of patients; high intensity statin, 17%, (17/98); low intensity, 10% (10/98). No improvement on LLT use (including use of high statin intensity) was observed over the 12-month follow-up. Conclusion This is the first study in France that use EMR to screen possible FH patients and support GPs in identifying patients that need to be treated. Our data highlight the need to screen, diagnosis and treat potential FH patients in ambulatory care settings. Longer follow-up is needed to evaluate the impact of FH assessment on referral to specialists, LLT and clinical outcomes. Acknowledgement/Funding Amgen

P5321The association of Lp(a) levels and cardiovascular disease in adult patients with familial hypercholesterolemia: analysis from the HELLAS-FH registry

Abstract Introduction Familial hypercholesterolemia (FH) as well as elevated Lp(a) levels are both associated with increased cardiovascular disease (CVD) risk. There are limited data on the association of Lp(a) levels with CVD in FH Patients. Purpose To evaluate the association between Lp(a) levels and CVD in adult FH patients included in the HELLAS-FH registry in Greece. Methods Adult patients with FH and measured Lp(a) levels were included in this analysis. Demographics, CVD prevalence and lipid profile were evaluated. Results A total of 337 patients were evaluated (46% male, 48.3±15.4 years old). The median [IQR] of Lp(a) at baseline was 22.6 (9.7–56.2) mg/dL. Patients were categorized into 4 different groups according to the Lp(a) levels quartiles. There was no gender or age difference between the 4 groups. Moreover, all groups had similar smoking status, hypertension, body mass index and type 2 diabetes prevalence. There was no significant difference between groups regarding baseline and on treatment lipid profile. We observed a significant positive association between Lp(a) quartile and coronary artery disease (CAD) prevalence (p=0.004). Patients in the highest vs lowest quartile had greater CAD prevalence (21.7% vs 7%, p=0.006). No association was observed between Lp(a) quartile and the prevalence of cerebrovascular disease or peripheral artery disease. Conclusions Elevated Lp(a) levels have a positive correlation with CAD in patients with FH.

P5334A 15-year follow-up of 315 patients with familial hypercholesterolemia from the North-West region of Russia

Abstract Familial hypercholesterolemia (FH) is one of the most common inherited diseases that lead to premature atherosclerosis and coronary heart disease (CHD). Aim of the study to ascertain genetic and environmental factors influencing the time course of FH during a 15-year follow-up in a large FH cohort from the North-West region of Russia. We screened more than 1ehz746.0302 high risk patients in order to reveal FH in Saint-Petersburg and Petrozavodsk using DLCN criteria. In most patients DNA analysis was also performed. Definite FH (≥8 according to DLCN) was found in 315 patients (221 - in Saint-Petersburg, 94 - in Petrozavodsk). These patients were followed-up for 15 years and more. CHD was more frequent in male patients, patients older than 60 years of age and was associated with higher levels of total cholesterol, LDL cholesterol, lower levels of HDL cholesterol, arterial hypertension, smoking and higher DLCN scoring. Patients without CHD had lowest LDL/HDL ratio (5.2±0.45) whereas patients with stable and progressive CHD had LDL/HDL ratio - 7.7±0.89 and 10.4±0.78, respectively (p≤0.05). Genetic study revealed only 1 homozygous patient and 1 patient with apoB-100 (FDP) gene mutation. Only 1 case of FH-North Karelia mutation that is typical for Finland was found in Petrozavodsk. Most of revealed mutations in LDL-receptor gene were unique i.e. found only in 1 family. This suggest the absence of a strong founder effect associated with FH in the North-West Region of Russia. Due to high heterogeneity of FH-causing mutations we failed to establish interrelations between type of LDL-receptor gene mutations and severity of atherosclerosis and CHD time course. 14% of FH patients didn't take any hypolipidemic medications at the onset of the follow-up, whereas 61% took statins and 25% statin + ezetimibe. Homozygous patient was treated both with statin, ezetimibe, evolocumab and LDL-apheresis. Nevertheless, 26% of the treated group didn't achieve the target LDL-C levels. It is interesting that 40% of patients who didn't reach LDL-goals were current smokers (compared with 5% of patients who reached LDL-goals). 33 patients (10.5%) died during the follow-up mostly due to cardiovascular complications. Death rates in FH patients were strongly associated with age, male sex, LDL/HDL ratio, smoking and effectiveness of hypolipidemic treatment. FH is strongly associated with high CHD risk; the time course of FH is much more favourable in females, in patients with low LDL/HDL ratio and free of other modifiable risk factors. Type of LDL-receptor gene mutation doesn't influence lipid levels or clinical manifestations of FH.

The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9

Background and aimsFamilial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9, p.(Arg499His), located in the C-terminal domain, in two unrelated FH patients from Spain and Italy. MethodsWe studied familial segregation and determined variant activity in vitro. ResultsWe determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification. ConclusionsWe demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability.

Evolocumab Is Mainly Prescribed In Fh Patients With/Without Atherosclerotic Cardiovascular Disease (Ascvd) In Lipid/Internal Medicine Units In Spain: A Retrospective, Observational Study (Retoss-Imu)

Evolocumab Is Mainly Prescribed In Fh Patients With/Without Atherosclerotic Cardiovascular Disease (Ascvd) In Lipid/Internal Medicine Units In Spain: A Retrospective, Observational Study (Retoss-Imu)

The prevalence and related factors of familial hypercholesterolemia in rural population of China using Chinese modified Dutch Lipid Clinic Network definition

BackgroundFamilial hypercholesterolemia (FH) is a common monogenic disease, while studies about the epidemiology for the general population in China was scarce. Aim of the study was to estimate the prevalence of FH and explore related factors by the Chinese modified Dutch Lipid Clinic Network (DLCN) definition.MethodsA total of 39,205 participants (15,463 males and 23,742 females) aged 18–79 years old were enrolled from the Henan Rural Cohort Study. FH was defined by the Chinese modified DLCN definition, and score > 5 was classified as FH. Logistic regression analysis was used to calculate the odds ratio and 95% confidence interval.ResultsCrude prevalence of probable/definite FH was 0.35% (0.29–0.41%), estimated by the Chinese modified DLCN definition. Prevalence in female was 0.38%, and in male, it was 0.32%. Age-standardized prevalence in female increased significantly around the age of 50 years. Moreover, there were no FH patients getting low-density lipoprotein cholesterol controlled to the recommended level. Multivariate logistic regression identified that older, overweight/obesity were positively associated with FH.ConclusionsThe current study indicated that FH was not rare in rural area of China (1 in 286). Effective early detection and timely control of FH must be strengthened to reduce disease burden.

Can erectile dysfunction severity predict left main and/or three-vessel disease in acute coronary syndrome patients?

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis).Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers.We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations.A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism.Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.

Relation between Blood pressure variability and Coronary Artery Remodeling Index in Normotensive Patients with Coronary artery disease: An Intravascular ultrasound Study

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis).Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers.We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations.A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism.Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.

Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis).Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers.We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations.A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism.Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.

Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio.

Background Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in genes involved in low-density lipoprotein (LDL) uptake (LDLR, APOB and PCSK9). Genetic diagnosis is particularly useful in asymptomatic children allowing for the detection of definite FH patients. Furthermore, defining their genetic status may be of considerable importance as the compound heterozygous status is much more severe than the heterozygous one. Our study aims at depicting the genetic background of an Italian pediatric population with FH focusing on the correlation between lipid profile and genetic status. Methods Out of 196 patients with clinically suspected FH (LDL-cholesterol [LDL-C] levels above 3.37 mmol/L, cholesterol level above 6.46 mmol/L in a first-degree relative or the presence of premature cardiovascular acute disease in a first/second-degree relative), we screened 164 index cases for mutations in the LDLR, APOB and PCSK9 genes. Results Patients with mutations (129/164) showed increased levels of LDL-C, 95th percentile-adjusted LDL-C and LDL/high-density lipoprotein (HDL) ratio and decreased levels of HDL-C, adjusted HDL-C. The association of the LDL/HDL ratio with the presence of mutations was assessed independently of age, (body mass index) BMI, parental hypercholesterolemia, premature coronary artery disease (CAD), triglycerides by multivariate logistic regression (odds ratio [OR]=1.701 [1.103-2.621], p=0.016). The LDL/HDL ratio gradually increased from patients without mutations to patients with missense mutations, null mutations and compound heterozygotes. Conclusions In conclusion, the LDL/HDL ratio proved to be a better parameter than LDL-C for discriminating patients with from patients without mutations across different genetic statuses.

A Japanese case of familial hypercholesterolemia with a novel mutation in the LDLR gene.

Familial hypercholesterolemia (FH, OMIM number #143890) is an autosomal dominant disorder, resulting in low-density lipoprotein (LDL) receptor dysfunction. The prevalence of FH is estimated to be approximately, 1 in 200 and 1 in 170,000 among heterozygotes and homozygotes, respectively (1). Since FH patients develop severe coronary-artery disease (CAD) due to hypercholesterolemia in early adult life, lipid-lowering treatments must be started at childhood (2). Although pediatric FH is clinically diagnosed based on the serum LDL cholesterol (LDL-C) levels and a family history of hypercholesterolemia, genetic analysis is useful for a definitive diagnosis, as it can predict the risk stratification of CAD (3, 4) and assist in early diagnosis and intervention, leading to improved prognosis. Here, we present a novel mutation in the LDLR gene, in a patient with heterozygous FH (HeFH).

Familial hypercholesterolemia and young patients’ thoughts on own condition and treatment

ObjectivesFamilial hypercholesterolemia (FH) is a hereditary and usually asymptomatic condition characterized by elevated blood cholesterol and increased risk of premature cardiovascular disease. It is treated with dietary modifications and lipid lowering drugs. The objective was to learn about young FH patients’ perceptions and choices regarding treatment. MethodsData were collected through in-depth interviews with 24 patients (ages 16–35), and analysed according to Grounded Theory. ResultsThe findings are presented as theoretical concepts describing the participants’ way of handling their condition. The core category was identified as “Thoughts of consequences vs. Postponing thoughts of consequences”, which could be described through the following subcategories: 1. Normalising the condition, 2. Belittling of treatment vs. Committed to treatment and 3. Trust in advice vs. Avoid unnecessary interference. The participants’ position regarding these categories was described to affect motivation and challenges with treatment. ConclusionsParticipants who postpone the thoughts of consequences, belittle the treatment and avoid unnecessary interference represent a challenge to health care practitioners. Practical implicationsPractitioners should explore aspects such as thoughts of consequences, view of treatment and the feeling of interference to be able to better understand illness behaviour, adjust their communication and hopefully improve adherence.

Evaluation of the performance of Dutch Lipid Clinic Network score in an Italian FH population: The LIPIGEN study

Background and aimsFamilial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification. MethodsThis study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH. ResultsThe DLCN score was applied on a sample of 1377 adults (mean age 42.9 ± 14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3–5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score. ConclusionsAlthough the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects.

What have we learned from Turkish familial hypercholesterolemia registries (A-HIT1 and A-HIT2)?

Background and aimsFamilial hypercholesterolemia (FH) is a common genetic disease of high-level cholesterol leading to premature atherosclerosis. One of the key aspects to overcome FH burden is the generation of large-scale reliable data in terms of registries. This manuscript underlines the important results of nation-wide Turkish FH registries (A-HIT1 and A-HIT2). MethodsA-HIT1 is a survey of homozygous FH patients undergoing low density lipoprotein (LDL) apheresis (LA). A-HIT2 is a registry of adult FH patients (homozygous and heterozygous) admitted to outpatient clinics. Both registries used clinical diagnosis of FH. ResultsA-HIT1 evaluated 88 patients (27 ± 11 years, 41 women) in 19 centers. All patients were receiving regular LA. There was a 7.37 ± 7.1-year delay between diagnosis and initiation of LA. LDL-cholesterol levels reached the target only in 5 cases. Mean frequency of apheresis sessions was 19 ± 13 days. None of the centers had a standardized approach for LA. Mean frequency of apheresis sessions was every 19 ± 13 (7–90) days. Only 2 centers were aware of the target LDL levels.A–HIT2 enrolled 1071 FH patients (53 ± 8 years, 606 women) from 31 outpatients clinics specialized in cardiology (27), internal medicine (1), and endocrinology (3); 96.4% were heterozygous. 459 patients were on statin treatment. LDL targets were attained in 23 patients (2.1% of the whole population, 5% receiving statin) on treatment. However, 66% of statin-receiving patients were on intense doses of statins. Awareness of FH was 9.5% in the whole patient population. ConclusionsThe first nationwide FH registries revealed that FH is still undertreated even in specialized centers in Turkey. Additional effective treatment regiments are urgently needed.