Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia.

BACKGROUND: The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in dyslipidemia may go beyond its immediate effects on low-density lipoprotein receptor (LDL-R) activity. OBJECTIVE: This study aimed to assess PCSK9-derived alterations of high-density lipoprotein (HDL) physiology, which bear a potential to contribute to cardiovascular risk profile. METHODS: HDL was isolated from 33 patients with familial autosomal dominant hypercholesterolemia (FH), including those carrying PCSK9 gain-of-function (GOF) genetic variants (FH-PCSK9, n = 11), together with two groups of dyslipidemic patients employed as controls and carrying genetic variants in the LDL-R not treated (ntFH-LDLR, n = 11) and treated (tFH-LDLR, n = 11) with statins, and 11 normolipidemic controls. Biological evaluations paralleled by proteomic, lipidomic and glycomic analyses were applied to characterize functional and compositional properties of HDL. RESULTS: Multiple deficiencies in the HDL function were identified in the FH-PCSK9 group relative to dyslipidemic FH-LDLR patients and normolipidemic controls, which involved reduced antioxidative, antiapoptotic, anti-thrombotic and anti-inflammatory activities. By contrast, cellular cholesterol efflux capacity of HDL was unchanged. In addition, multiple alterations of the proteomic, lipidomic and glycomic composition of HDL were found in the FH-PCSK9 group. Remarkably, HDLs from FH-PCSK9 patients were systematically enriched in several lysophospholipids as well as in A2G2S2 (GP13) glycan and apolipoprotein A-IV. Based on network analysis of functional and compositional data, a novel mosaic structure-function model of HDL biology involving FH was developed. CONCLUSION: Several metrics of anti-atherogenic HDL functionality are altered in FH-PCSK9 patients paralleled by distinct compositional alterations. These data provide a first-ever overview of the impact of GOF PCSK9 genetic variants on structure-function relationships in HDL.

Diagnosis of chylous abdominal effusions: what is the triglyceride threshold value?

Introduction: Chylous abdominal effusions are serious complications that can be triggered by various aetiologies. The biochemical diagnosis of chyle leakage in ascites or in peritoneal fluid capsules relies on the detection of chylomicrons. Assaying the fluid's concentration of triglycerides is still the first-line tool. Given that only one comparative study has sought to quantify the value of the triglyceride assay for diagnosing chylous ascites in humans, our objective was to provide practical triglyceride thresholds. Materials and methods: We conducted a 9-year, retrospective, single-centre study of adult patients and compared a triglyceride assay with lipoprotein gel electrophoresis for the analysis of 90 non-recurring abdominal effusions (ascites and abdominal collections) of which 65 were chylous. Results: A triglyceride threshold of 0.4 mmol/L was associated with a sensitivity > 95%, and a threshold of 2.4 mmol/L was associated with a specificity > 95%. According to Youden index, the best threshold was 0.65 mmol/L with a sensitivity of 88 (77-95)%, a specificity of 72 (51-88)%, and, in our series, a positive predictive value of 89 (79-95)% and a negative predictive value of 69 (48-86)%. Conclusions: In our series, cut-off of 0.4 mmol/L could be used for ruling-out diagnosis of chylous effusions, while cut-off of 2.4 mmol/L could be used for reasonably confirming diagnosis.

Could the chylomicron marker apoB48 be of value in the diagnosis of chylous effusions?

BACKGROUND: Chylous effusions such as chylothorax, chylopericardium and chylous ascites are marked by the abnormal presence of chylomicrons in serous membranes. These relatively rare situations are associated with high morbidity and mortality rates. Given that a macroscopic assessment of the fluid is insufficient, the current gold standard method for chylous effusion is the electrophoretic separation of lipoproteins. Serous effusions are most frequently assayed for triglycerides, with a diagnostic threshold varying between studies. The present study is the first to assess the value of the apolipoprotein B48, specific of the chylomicron, in the diagnosis of chylous effusions. METHODS: A chemiluminescent sandwich enzyme immunoassay was used to measure levels of apoB48 in remnant samples of effusion fluid sent to our laboratory for chylomicron detection and lipid assays. The diagnostic values of apoB48 and triglyceride assays were compared with that of the gold standard method. RESULTS: The triglyceride and apoB48 levels and the triglyceride/cholesterol ratio in the effusion fluid were significantly higher in patients with chylous effusion. The threshold values for apoB48 were respectively 2.45, 0.25 and 19.00 µg/mL for a maximal Youden index, a sensitivity > 95 %, and a specificity > 95 %. The apoB48 assay's diagnostic value might be at least as high as that of a triglyceride assay (area under the receiver operating characteristic curve [95 % confidence interval]: 0.84 [0.72, 0.96]) and 0.80 [0.67, 0.94], respectively). CONCLUSION: ApoB48 appears to be a promising marker for the diagnosis of chylous effusions; the putative diagnostic improvement must be confirmed in larger studies.

Chylopericardium or contamination by injectable lipid emulsion? / « Mets la main sur mon cœur, Et vois comme il se trouble ¼ ­ un pseudo-chylopéricarde ?

Effusions can show some surprises. We document the case of a fourteen-month-old male patient with short-bowel syndrome, hospitalized in a cardiology unit, receiving a chronic parenteral nutrition by a Broviac® catheter. The patient presented several thrombosis following iterative catheter replacements. In parallel with superior vena cava plasty, a right intra-atrial Broviac® catheter was placed in the absence of other peripheral venous accesses. This device has a cutaneous exit site to allow for infusion of a hyperosmolar lipid emulsion. Seven days later, a milky liquid was secreted from pericardial/mediastinal redon. A gel lipoprotein electrophoresis of the fluid suggested a preliminary diagnosis of chylopericardium. However, biochemical testing of certain analytes evoked a parenteral nutrition-related pericardial effusion and a possible pseudochyloperitoneum caused by the shearing of a migrated Broviac® in pericardium. The patient, on a fat-free diet, was admitted to the ICU to drain the effusion and reposition the catheter, with success. In the light of new datas on the interference of parenteral lipid emulsions with the lipoproteins gel electrophoresis, we will try to determine whether the apparent presence of chylomicrons in the gel would be the sign of a lesion of the lymphatic system, or rather the result of a contamination by artificial chylomicron in the lipid emulsion, if not the sign of contaminated blood. In our article, we highlight several considerations in identifying and confirming cases of pericardial effusion, such as chylopericardium and parenteral nutrition-related one, as well as points concerning the use of lipid emulsions for pediatric patients with short-bowel syndrome.

Les liquides d'épanchements peuvent renfermer quelques surprises. Nous documentons le cas d'un patient de quatorze mois, hospitalisé en cardiologie, présentant un syndrome de grêle court et recevant une nutrition parentérale au long cours par cathéter Broviac®. Le patient présentait de multiples occlusions veineuses consécutives aux changements itératifs du dispositif. En parallèle d'une plastie de la veine cave supérieure, un Broviac® a été posé en intra-atrial droit devant l'absence d'autres abords veineux périphériques. Ce dispositif comporte un orifice de sortie sous-cutané pour apporter une solution de nutrition hyperosmolaire de type émulsion lipidique. Le liquide recueilli dans les drains péricardiques en post-opératoire est lactescent, particulièrement à partir du septième jour. Le lipidogramme du liquide d'épanchement péricardique semble conclure à la présence de chylomicrons - un chylopéricarde. Cependant, le dosage de certains analytes penche en faveur d'un perfusopéricarde, probablement pseudochyleux, lié au cisaillement du Broviac® dont l'extrémité a migré de l'oreillette droite au péricarde. Le patient, sous régime sans graisses, sans nutrition parentérale, sera réopéré pour drainer l'épanchement et repositionner le cathéter, avec succès. À la lumière de données originales quant à l'interférence des émulsions lipidiques sur le lipidogramme, nous tâcherons de déterminer si l'apparente présence de chylomicrons sur le gel serait le témoin d'une réelle lésion du lymphatique, ou plutôt le fruit d'une contamination par l'émulsion, si ce n'est par le sang. Des considérations au sujet des épanchements péricardiques, dont les chylopéricarde et nutripéricarde, ainsi que sur les émulsions lipidiques pédiatriques dans le contexte du grêle court émailleront ce travail.

Extracellular Vesicle-Mediated Metastasis Suppressors NME1 and NME2 Modify Lipid Metabolism in Fibroblasts.

Nowadays, extracellular vesicles (EVs) raise a great interest as they are implicated in intercellular communication between cancer and stromal cells. Our aim was to understand how vesicular NME1 and NME2 released by breast cancer cells influence the tumour microenvironment. As a model, we used human invasive breast carcinoma cells overexpressing NME1 or NME2, and first analysed in detail the presence of both isoforms in EV subtypes by capillary Western immunoassay (WES) and immunoelectron microscopy. Data obtained by both methods showed that NME1 was present in medium-sized EVs or microvesicles, whereas NME2 was abundant in both microvesicles and small-sized EVs or exosomes. Next, human skin-derived fibroblasts were treated with NME1 or NME2 containing EVs, and subsequently mRNA expression changes in fibroblasts were examined. RNAseq results showed that the expression of fatty acid and cholesterol metabolism-related genes was decreased significantly in response to NME1 or NME2 containing EV treatment. We found that FASN (fatty acid synthase) and ACSS2 (acyl-coenzyme A synthetase short-chain family member 2), related to fatty acid synthesis and oxidation, were underexpressed in NME1/2-EV-treated fibroblasts. Our data show an emerging link between NME-containing EVs and regulation of tumour metabolism.

Clinico-biological markers for the prognosis of status epilepticus in adults.

Prediction of mortality, functional outcome and recovery after status epilepticus (SE) is a challenge. Biological and clinical markers have been proposed to reflect the brain injury or to monitor critical ill patients' severity. The aim of this study was to characterize short-term and long-term prognostic factors for SE patients hospitalized in intensive care unit. Patient's outcome was assessed using the modified Rankin Scale at discharge and after 6-12 months. We first assessed the univariate prognosis significance of 51 clinical, demographic or biochemical markers. Next, we built multivariate clinico-biological models by combining most important factors. Statistical models' performances were compared to those of two previous published scales STESS and mSTESS. Eighty-one patients were enrolled. Thirty-five patients showed a steady state while 46 patients clinically worsened at discharge: 14 died, 14 had persistent disability at 6-12 months and 18 recovered. Logistic regression analysis revealed that clinical markers (SE refractoriness, SE duration, de novo SE) were significant independent predictors of worsening while lipids markers and progranulin better predicted mortality. The association of clinico-biological variables allowed to accurately predict worsening at discharge (AUC > 0.72), mortality at discharge (AUC 0.83) and recovery at long-term (AUC 0.89). Previous scales provided lower prediction for worsening (AUC 0.63, STESS; 0.53, mSTESS) and mortality (AUC 0.56, STESS; 0.62, mSTESS) (p < 0.001). We proposed new clinico-biological models with a strong discrimination power for prediction of short- and long-term outcome of hospitalized status epilepticus patients. Their implementation in electronic devices may enhance their clinical liability.

Myocardial fibrosis assessed by magnetic resonance imaging in asymptomatic heterozygous familial hypercholesterolemia: the cholcoeur study.

BACKGROUND: Familial Hypercholesterolemia (FH) is an underdiagnosed condition with an increased cardiovascular risk. It is unknown whether lipid accumulation plays a role in structural myocardial changes. Cardiovascular Magnetic Resonance (CMR) is the reference technique for the morpho-functional evaluation of heart chambers through cine sequences and for myocardial tissue characterization through late gadolinium enhancement (LGE) and T1 mapping images. We aimed to assess the prevalence of myocardial fibrosis in FH patients. METHODS: Seventy-two asymptomatic subjects with genetically confirmed FH (mean age 49·24, range 40 to 60 years) were prospectively recruited along with 31 controls without dyslipidaemia matched for age, sex, BMI, and other cardiovascular risk factors. All underwent CMR including cine, LGE, pre- and post-contrast T1 mapping. Extracellular volume (ECV) and enhancement rate of the myocardium (ERM = difference between pre- and post-contrast myocardial T1, normalized by pre-contrast myocardial T1) were calculated. FINDINGS: Five FH patients and none of the controls had intramyocardial LGE (p= 0·188). While no changes in Native T1 and ECV were found, post-contrast T1 was significantly lower (430·6 ± 55ms vs. 476·1 ± 43ms, p<0·001) and ERM was higher (57·44± 5·99 % vs 53·04±4·88, p=0·005) in HeFH patients compared to controls. Moreover, low post-contrast T1 was independently associated with the presence of xanthoma (HR 5·221 [1·04-26·28], p= 0·045). A composite score combining the presence of LGE, high native T1 and high ERM (defined as ≥ mean ± 1·5 SD) was found in 20·8% of the HeFH patients vs. 0% in controls (p<0·000, after adjustment for main confounders). INTERPRETATION: CMR revealed early changes in myocardial tissue characteristics in HeFH patients, that should foster further work to better understand and prevent the underlying pathophysiological processes.

Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients' cohorts, one treated with lomitapide in Italy (n = 30) and the other with LA in France (n = 29). RESULTS: The two cohorts differed significantly for genotype (p = 0.004), baseline lipid profile (p < 0.001), age of treatment initiation (p < 0.001), occurrence of cardiovascular disease (p = 0.003) as well as follow-up duration (p < 0.001). The adjunct of lomitapide to conventional lipid-lowering therapies determined an additional 58.0% reduction of last visit LDL-C levels, compared to 37.1% when LA was added (padj = 0.004). Yearly on-treatment LDL-C < 70 mg/dl and < 55 mg/dl goals were only achieved in 45.5% and 13.5% of HoFH patients treated with lomitapide. The long-term exposure to LDL-C burden was found to be higher in LA than in Lomitapide cohort (13,236.1 ± 5492.1 vs. 11,656.6 ± 4730.9 mg/dL-year respectively, padj = 0.002). A trend towards fewer total cardiovascular events was observed in the Lomitapide than in the LA cohort. CONCLUSIONS: In comparison with LA, lomitapide appears to provide a better control of LDL-C in HoFH. Further studies are needed to confirm this data and establish whether this translates into a reduction of cardiovascular risk.

Disturbances of brain cholesterol metabolism: A new excitotoxic process associated with status epilepticus.

The understanding of the excitotoxic processes associated with a severe status epilepticus (SE) is of major importance. Changes of brain cholesterol homeostasis is an emerging candidate for excitotoxicity. We conducted an overall analysis of the cholesterol homeostasis both (i) in fluids and tissues from patients with SE: blood (n = 63, n = 87 controls), CSF (n = 32, n = 60 controls), and post-mortem brain tissues (n = 8, n = 8 controls) and (ii) in a mouse model of SE induced by an intrahippocampal injection of kainic acid. 24-hydroxycholesterol levels were decreased in kainic acid mouse hippocampus and in human plasma and post-mortem brain tissues of patients with SE when compared with controls. The decrease of 24-hydroxycholesterol levels was followed by increased cholesterol levels and by an increase of the cholesterol synthesis. Desmosterol levels were higher in human CSF and in mice and human hippocampus after SE. Lanosterol and dihydrolanosterol levels were higher in plasma from SE patients. Our results suggest that a CYP46A1 inhibition could occur after SE and is followed by a brain cholesterol accumulation. The excess of cholesterol is known to be excitotoxic for neuronal cells and may participate to neurological sequelae observed after SE. This study highlights a new pathophysiological pathway involved in SE excitotoxicity.

LDL apheresis as an alternate method for plasma LPS purification in healthy volunteers and dyslipidemic and septic patients.

Lipopolysaccharide (LPS) is a key player for innate immunity activation. It is therefore a prime target for sepsis treatment, as antibiotics are not sufficient to improve outcome during septic shock. An extracorporeal removal method by polymyxin (PMX) B direct hemoperfusion (PMX-DHP) is used in Japan, but recent trials failed to show a significant lowering of circulating LPS levels after PMX-DHP therapy. PMX-DHP has a direct effect on LPS molecules. However, LPS is not present in a free form in the circulation, as it is mainly carried by lipoproteins, including LDLs. Lipoproteins are critical for physiological LPS clearance, as LPSs are carried by LDLs to the liver for elimination. We hypothesized that LDL apheresis could be an alternate method for LPS removal. First, we demonstrated in vitro that LDL apheresis microbeads are almost as efficient as PMX beads to reduce LPS concentration in LPS-spiked human plasma, whereas it is not active in PBS. We found that PMX was also adsorbing lipoproteins, although less specifically. Then, we found that endogenous LPS of patients treated by LDL apheresis for familial hypercholesterolemia is also removed during their LDL apheresis sessions, with both electrostatic-based devices and filtration devices. Finally, LPS circulating in the plasma of septic shock and severe sepsis patients with gram-negative bacteremia was also removed in vitro by LDL adsorption. Overall, these results underline the importance of lipoproteins for LPS clearance, making them a prime target to study and treat endotoxemia-related conditions.

[Electrophoresis of serum lipoproteins (lipoproteinogram) with the Hydragel Lipo + Lp(a)® (Sebia) kit: evaluation of Fat Red 7B staining]. / Électrophorèse des lipoprotéines sériques (lipoprotéinogramme) par le kit Hydragel Lipo + Lp(a)® (Sebia) : évaluation de la coloration au Fat Red 7B.

The lipoproteinogram (or lipidogram) consists in an electrophoretic separation of the main classes of serum lipoproteins. Separation was done in agarose gel using the Sebia Hydragel Lipo + Lp(a)® kit. A repeatability study (n=6) was conducted on 3 sera (1 normolipidemic, 1 hypertriglyceridemic and 1 with a high Lp(a) concentration). The reproducibility was studied on these 3 sera and on an ascites liquid containing chylomicrons, upon 6 days (n=6). A quantitative approach was made by studying areas under the curve and percentages of fractions. In both cases (repeatability and reproducibility), the revelation of the lipoproteins in the gel after electrophoretic migration was made either by staining with Sudan Black (procedure recommended by Sebia), or with Fat Red 7B. Regardless of staining, both repeatability and reproducibility studies show that all lipoprotein fractions were correctly detected at their respective positions, leading to satisfactory interpretations of lipoproteinograms. Our reproducibility study also confirmed a good stability of the fractions over 6 days (storage at +5 ± 3̊C). In addition, the Fat Red 7B staining leads to a shorter technical time (about 40 min) for the gel drying and staining/destaining phases, which allows us to respond more quickly to certain urgent requests such as chylothorax diagnosis.

Evaluation of a semi-automatic isoelectric focusing method for apolipoprotein E phenotyping.

A qualitative, semi-automatized method for apolipoprotein E (apoE) phenotyping by isoelectric focusing method has been evaluated on 40 serum samples from patients previously genotyped for apoE, especially as regards concordance with genotyping, but also repeatability and reproducibility of the method, and sample storage. Total concordance with genotyping and good precision criteria, together with its practicability and requirement of a little sample volume, lead to conclude to the usefulness of this method to help clinicians in the diagnosis of dyslipidemic and neurodegenerative diseases.

Antiatherogenic properties of high-density lipoproteins from arterial plasma are attenuated as compared to their counterparts of venous origin.

BACKGROUND AND AIMS: High-density lipoprotein (HDL) particles play atheroprotective roles by their ability to efflux cholesterol from foam cells and to protect low-density lipoproteins (LDLs) from oxidative damage in the arterial intima. We hypothesized that antioxidative properties of HDLs can be attenuated in the oxygen-rich prooxidative arterial environment, contributing to the development of atherosclerosis. To evaluate this hypothesis, we compared antioxidative activity of HDLs from arterial and venous plasmas. METHODS AND RESULTS: Arterial and venous blood samples were simultaneously obtained from 16 patients (age 68 ± 10 years; 75% males) presenting with ischemic or valvular heart disease. Major HDL subfractions and total HDLs were isolated by density gradient ultracentrifugation and their chemical composition and the capacity to protect LDLs from in vitro oxidation were evaluated. HDL-cholesterol, triglycerides and apolipoprotein (apo) B-100 levels were slightly but significantly reduced by -4 to -8% (p < 0.01) in the arterial vs. venous samples. Total mass of HDL subpopulations was similar and HDL subpopulations did not reveal marked compositional differences between the arterial and venous circulation. Potent antioxidative activity of the small, dense HDL3c subpopulation was significantly reduced in the particles of arterial origin vs. their counterparts from venous plasma (increase of +21% in the propagation rate of LDL oxidation, p < 0.05). Interestingly, antioxidative properties of venous HDLs were enhanced in statin-treated patients relative to untreated subjects. CONCLUSION: Antioxidative properties of small, dense HDLs from arterial plasma are attenuated as compared to the particles of venous origin, consistent with the development of atherosclerosis in the arterial wall.

Polyvascular subclinical atherosclerosis in familial hypercholesterolemia: The role of cholesterol burden and gender.

BACKGROUND AND AIM: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disease characterized by a heterogeneous phenotype. The assessment of cardiovascular (CV) risk is challenging for HeFH. Cholesterol burden (CB) allows to estimate the lifelong exposure to high levels of cholesterol. The aim of this study was to analyze the distribution of subclinical atherosclerosis and the relationship between atherosclerosis and the CB in a sample of HeFH patients, focusing on sex-related differences. METHODS AND RESULTS: 154 asymptomatic HeFH subjects underwent coronary-artery-calcium score (CACs) and Doppler ultrasound of carotid and femoral arteries. Yearly lipid profiles and HeHF history were obtained from patients' files in order to calculate total CB. Atherosclerotic burden was defined by the presence of CACs > 0 or by the presence of carotid or femoral plaque. Study population was stratified according to gender. The prevalence of CAC, carotid and femoral atherosclerosis was of 62%, 55% and 56%, respectively. Coronary district was the least involved in women, who had a higher prevalence in carotid atherosclerosis. When two vascular districts were affected, women had an increased prevalence of femoral and carotid atherosclerosis whereas men had a higher prevalence of coronary and femoral atherosclerosis. CB correlated to the presence of atherosclerosis in any of the three vascular districts with a significant increasing trend depending on the number of affected areas. CONCLUSIONS: A polyvascular atherosclerotic burden is found in asymptomatic HeFH patients. Gender differences in the territory distribution were observed. The early and lasting exposure to high cholesterol, as expressed by CB, is a major determinant of atherosclerotic burden.

Early central blood pressure elevation in adult patients with 21-hydroxylase deficiency.

CONTEXT: Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH). OBJECTIVE: To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals. DESIGN: Case-control study. SETTING: Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France. PATIENTS OR OTHER PARTICIPANTS: Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included. INTERVENTION: Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation. MAIN OUTCOME MEASURE: The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls. RESULTS: Although PWV and cIMT were identical in patients and controls, higher rAI (64.6 ±â€Š1.7 vs. 59.9 ±â€Š1.6%, P = 0.02) and higher central SBP (101.8 ±â€Š1.5 vs. 95.1 ±â€Š1.5 mmHg, P < 0.001) were observed in CAH patients. Regarding microcirculatory indices, there was a higher functional resting capacity and a lower anatomical capillary density in CAH patients. In multivariate analysis, we found an independant association between CAH and central SBP elevation. CONCLUSION: We found an early rise in central SBP in CAH patients whereas sublinical arterial damages markers were normal. Our study suggest that vascular damages and increased cardiovascular risk could be mainly BP-driven.

Lipoprotein-apheresis in familial hypercholesterolemia: Long-term patient compliance in a French cohort.

BACKGROUND AND AIMS: Lipoprotein apheresis (LA) is a complex therapeutic option and poor compliance can adversely affect treatment outcome. The aim of this study was to describe long-term compliance to treatment in patients undergoing regular LA therapy and to investigate factors related to low compliance. METHODS: We analysed 11,391 prescribed procedures of LA performed between 1990 and 2007 in 51 patients with familial hypercholesterolemia. Regular LA treatment was initiated in patients presenting with either homozygous familial hypercholesterolemia (n = 21), or severe heterozygous familial hypercholesterolemia (n = 30) with elevated LDL-cholesterol levels and who did not respond adequately to diet and drug therapy; the majority of these patients (n = 30) had cardiovascular disease at initiation of therapy. RESULTS: The overall observed compliance rate based on the number of achieved/programmed procedures was 87.5%. Neither cardiovascular history nor subtypes of hypercholesterolemia was associated with compliance. In addition, there was no impact of patient demography on compliance. Treatment frequency alone significantly impacted non-compliance (i.e. patient with weekly procedures were less compliant). Interestingly, a non-significant decrease in compliance was observed among patients aged <20 years. CONCLUSIONS: Despite the complexity of the LA procedure and its impact on the organisation of patients' daily lives, overall compliance was very high. The choice of an appropriate and adequate frequency of treatment significantly impacted patient compliance.

Early coronary calcifications are related to cholesterol burden in heterozygous familial hypercholesterolemia.

BACKGROUND: The identification of high-risk patients with heterozygous familial hypercholesterolemia (HeFH) that may benefit from early treatment is challenging. Coronary Artery Calcification (CAC) score accounts for coronary atherosclerotic burden. It has proven its accuracy in cardiovascular risk assessment in the general population but data in HeFH are lacking. OBJECTIVE: The aim of our study was to assess CAC prevalence and its relationship with lifelong cholesterol exposure, calculated by total cholesterol burden (TCB) in patients with HeFH. METHODS: A total of 112 HeFH patients (50% males, median age 45 years) regularly followed-up since diagnosis were prospectively recruited at Pitié-Salpêtrière Hospital, Paris, France. CAC score was assessed using noncontrast multi-detector computed tomography. TCB was calculated as total cholesterol (TC) × age at diagnosis plus annually assessed TC. RESULTS: The prevalence of CAC was 58%. Patients without CAC showed lower TCB than patients with CAC (298 ± 110 vs 417.9 ± 89 mmol-years/L, P < .001). Among patients aged <45 years (n = 56), 39% exhibited CAC and a higher TCB compared with patients without CAC (352 ± 71 vs 255 ± 88 mmol-years/L, P < .001) due to higher TC levels at diagnosis (10.2 ± 2 vs 8.7 ± 2 mmol/L, P = .01). Multivariate analysis indicated that TCB was independently associated to CAC. CONCLUSIONS: Asymptomatic HeFH subjects exhibit early coronary atherosclerosis directly associated with TCB burden. CAC score may be useful to identify higher risk HeFH patients who can benefit from earlier and more aggressive treatment.