Decreased Serum Stromal Cell-Derived Factor-1 in Patients with Familial Hypercholesterolemia and Its Strong Correlation with Lipoprotein Subfractions.

Stromal cell-derived factor-1 (SDF-1) is a chemokine that exerts multifaceted roles in atherosclerosis. However, its association with hyperlipidemia is contradictory. To date, serum SDF-1 and its correlations with lipid fractions and subfractions in heterozygous familial hypercholesterolemia (HeFH) have not been investigated. Eighty-one untreated patients with HeFH and 32 healthy control subjects were enrolled in the study. Serum SDF-1, oxidized LDL (oxLDL) and myeloperoxidase (MPO) were determined by ELISA. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly lower serum SDF-1 was found in HeFH patients compared to healthy controls. Significant negative correlations were detected between serum total cholesterol, triglycerides, LDL-cholesterol (LDL-C), apolipoprotein B100 (ApoB100) and SDF-1. Furthermore, serum SDF-1 negatively correlated with VLDL and IDL, as well as large LDL and large and intermediate HDL subfractions, while there was a positive correlation between mean LDL-size, small HDL and SDF-1. SDF-1 negatively correlated with oxLDL and MPO. A backward stepwise multiple regression analysis showed that the best predictors of serum SDF-1 were VLDL and oxLDL. The strong correlation of SDF-1 with lipid fractions and subfractions highlights the potential common pathways of SDF-1 and lipoprotein metabolism, which supports the role of SDF-1 in atherogenesis.

Sphingosine 1-Phosphate and Apolipoprotein M Levels and Their Correlations with Inflammatory Biomarkers in Patients with Untreated Familial Hypercholesterolemia.

High-density lipoprotein (HDL)-bound apolipoprotein M/sphingosine 1-phosphate (ApoM/S1P) complex in cardiovascular diseases serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. To date, S1P and ApoM in patients with untreated heterozygous familial hypercholesterolemia (HeFH) have not been extensively studied. Eighty-one untreated patients with HeFH and 32 healthy control subjects were included in this study. Serum S1P, ApoM, sCD40L, sICAM-1, sVCAM-1, oxLDL, and TNFα concentrations were determined by ELISA. PON1 activities were measured spectrophotometrically. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly higher serum S1P and ApoM levels were found in HeFH patients compared to controls. S1P negatively correlated with large HDL and positively with small HDL subfractions in HeFH patients and the whole study population. S1P showed significant positive correlations with sCD40L and MMP-9 levels and PON1 arylesterase activity, while we found significant negative correlation between sVCAM-1 and S1P in HeFH patients. A backward stepwise multiple regression analysis showed that the best predictors of serum S1P were large HDL subfraction and arylesterase activity. Higher S1P and ApoM levels and their correlations with HDL subfractions and inflammatory markers in HeFH patients implied their possible role in endothelial protection.

Identifying Patients with Familial Chylomicronemia Syndrome Using FCS Score-Based Data Mining Methods.

BACKGROUND: There are no exact data about the prevalence of familial chylomicronemia syndrome (FCS) in Central Europe. We aimed to identify FCS patients using either the FCS score proposed by Moulin et al. or with data mining, and assessed the diagnostic applicability of the FCS score. METHODS: Analyzing medical records of 1,342,124 patients, the FCS score of each patient was calculated. Based on the data of previously diagnosed FCS patients, we trained machine learning models to identify other features that may improve FCS score calculation. RESULTS: We identified 26 patients with an FCS score of ≥10. From the trained models, boosting tree models and support vector machines performed the best for patient recognition with overall AUC above 0.95, while artificial neural networks accomplished above 0.8, indicating less efficacy. We identified laboratory features that can be considered as additions to the FCS score calculation. CONCLUSIONS: The estimated prevalence of FCS was 19.4 per million in our region, which exceeds the prevalence data of other European countries. Analysis of larger regional and country-wide data might increase the number of FCS cases. Although FCS score is an excellent tool in identifying potential FCS patients, consideration of some other features may improve its accuracy.

Determination of Serum Progranulin in Patients with Untreated Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated LDL-C concentrations and is associated with an increased risk of premature atherosclerosis. Progranulin (PGRN) is a multifunctional protein that is known to have various anti-atherogenic effects. To date, the use of serum PGRN in patients with FH has not been studied. METHODS: In total, 81 untreated patients with heterozygous FH (HeFH) and 32 healthy control subjects were included in this study. Serum PGRN, sICAM-1, sVCAM-1, oxLDL and TNFα concentrations were determined by ELISA. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. RESULTS: We could not find a significant difference between the PGRN concentrations of the HeFH patients and controls (37.66 ± 9.75 vs. 38.43 ± 7.74 ng/mL, ns.). We found significant positive correlations between triglyceride, TNFα, sVCAM-1, the ratio of small HDL subfraction and PGRN, while significant negative correlations were found between the ratio of large HDL subfraction and PGRN both in the whole study population and in FH patients. PGRN was predicted by sVCAM-1, logTNFα and the ratio of small HDL subfraction. CONCLUSIONS: The strong correlations between HDL subfractions, inflammatory markers and PGRN suggest that PGRN may exert its anti-atherogenic effect in HeFH through the alteration of HDL composition and the amelioration of inflammation rather than through decreasing oxidative stress.

Assessment of Associations Between Serum Lipoprotein (a) Levels and Atherosclerotic Vascular Diseases in Hungarian Patients With Familial Hypercholesterolemia Using Data Mining and Machine Learning.

Background and aims: Premature mortality due to atherosclerotic vascular disease is very high in Hungary in comparison with international prevalence rates, though the estimated prevalence of familial hypercholesterolemia (FH) is in line with the data of other European countries. Previous studies have shown that high lipoprotein(a)- Lp(a) levels are associated with an increased risk of atherosclerotic vascular diseases in patients with FH. We aimed to assess the associations of serum Lp(a) levels and such vascular diseases in FH using data mining methods and machine learning techniques in the Northern Great Plain region of Hungary. Methods: Medical records of 590,500 patients were included in our study. Based on the data from previously diagnosed FH patients using the Dutch Lipid Clinic Network scores (≥7 was evaluated as probable or definite FH), we trained machine learning models to identify FH patients. Results: We identified 459 patients with FH and 221 of them had data available on Lp(a). Patients with FH had significantly higher Lp(a) levels compared to non-FH subjects [236 (92.5; 698.5) vs. 167 (80.2; 431.5) mg/L, p < .01]. Also 35.3% of FH patients had Lp(a) levels >500 mg/L. Atherosclerotic complications were significantly more frequent in FH patients compared to patients without FH (46.6 vs. 13.9%). However, contrary to several other previous studies, we could not find significant associations between serum Lp(a) levels and atherosclerotic vascular diseases in the studied Hungarian FH patient group. Conclusion: The extremely high burden of vascular disease is mainly explained by the unhealthy lifestyle of our patients (i.e., high prevalence of smoking, unhealthy diet and physical inactivity resulting in obesity and hypertension). The lack of associations between serum Lp(a) levels and atherosclerotic vascular diseases in Hungarian FH patients may be due to the high prevalence of these risk factors, that mask the deleterious effect of Lp(a).

Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common autosomal, dominantly inherited diseases affecting cholesterol metabolism, which, in the absence of treatment, leads to the development of cardiovascular complications. The disease is still underdiagnosed, even though an early diagnosis would be of great importance for the patient to receive proper treatment and to prevent further complications. No studies are available describing the genetic background of Hungarian FH patients. In this work, we present the clinical and molecular data of 44 unrelated individuals with suspected FH. Sequencing of five FH-causing genes (LDLR, APOB, PCSK9, LDLRAP1 and STAP1) has been performed by next-generation sequencing (NGS). In cases where a copy number variation (CNV) has been detected by NGS, confirmation by multiplex ligation-dependent probe amplification (MLPA) has also been performed. We identified 47 causal or potentially causal (including variants of uncertain significance) LDLR and APOB variants in 44 index patients. The most common variant in the APOB gene was the c.10580G>A p.(Arg3527Gln) missense alteration, this being in accordance with literature data. Several missense variants in the LDLR gene were detected in more than one index patient. LDLR variants in the Hungarian population largely overlap with variants detected in neighboring countries.

Connection between small vessel disease related stroke and the MTHFR C677T polymorphism in a Hungarian population.

INTRODUCTION: There are conflicting results in the literature regarding the connection between thrombophilias and ischaemic stroke. However, most of the clinical studies have not differentiated between various ischaemic stroke subtypes. Our aim was to investigate whether there is an association between the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism and ischaemic stroke due to small vessel disease (SVD) in patients ≤50 years of age. PATIENTS AND METHODS: We performed a retrospective search in the database used at our Health Centre. Our study population consisted of 100 ischaemic stroke patients. 65 patients had MTHFR C677T variants: 21 were homozygous (TT allele), 45 were heterozygous (CT). 35 stroke patients did not carry MTHFR C677T polymorphism (wild genotype, CC). Stroke subtypes were determined according to the TOAST classification. Pearson's chi-squared test of independence was used to evaluate differences between subgroups and multivariate logistic regression was also performed. RESULTS: More than half of our study population (52.00%) had lacunar strokes. The ratio of SVD in patients ≤50 years of age with TT homozygous variant was significantly higher compared to heterozygous and wild type subjects (p = 0.032 and p = 0.03 respectively). Multivariate logistic regression also showed, that apart from hypertension, only TT homozygosity was a predictive factor for SVD related stroke (p = 0.014, OR 1.619, 95% CI 1.390-18.338). CONCLUSION: Our results demonstrate that in a Hungarian population of ischaemic stroke patients ≤50 years of age, SVD is the most common stroke subtype. In addition, we found association of SVD stroke with hypertension and MTHFR 677TT homozygous polymorphism.

Co-Hydrothermal gasification of Chlorella vulgaris and hydrochar: The effects of waste-to-solid biofuel production and blending concentration on biogas generation.

This study investigates enhanced biogas production via co-Hydrothermal gasification (co-HTG) of wet Chlorella vulgaris biomass and hydrochar (HC). Hydrothermal carbonization was applied to valorize struvite containing waste microalgae stream into solid bio-fuel with improved combustion properties. The effects of HC quality and mixing ratio are investigated on biogas yield, composition and carbon conversion ratio. The results show that the application of blending components promotes H2, CH4 formation and selectivity in hydrothermal gasification. The total co-HTG gas yield is increased from 19.13 to 46.95 mol kg-1 at 650 °C and 300 bar by applying 5 wt% HC blending concentration and reduced level of volatile matter content (24.61 wt%). The obtained high hydrogen, methane yields and carbon conversion ratio (19.49, 2.98 mol kg-1, 82.31%, respectively) indicate effective hydrothermal upgrading potentials in case of wet and waste biomass feedstocks.

A Rare Double Heterozygous Mutation in Low-Density Lipoprotein Receptor and Apolipoprotein B-100 Genes in a Severely Affected Familial Hypercholesterolaemia Patient.

Familial hypercholesterolaemia (FH) is characterized by high plasma low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease risk. Mutations in the genes that encode proteins involved in LDL uptake and catabolism, including LDL-receptor (LDLR) and apolipoprotein-B (APOB), are known to cause FH. We present the case of a severely affected FH proband with two mutations in two different causing genes and characterize her first-degree blood relatives. The proband was a 54-year-old woman with a severe FH phenotype with treated LDL-C of 8.3 mmol/L, total cholesterol (TC) level of 11.6 mmol/L, peripheral artery disease, early myocardial infarction, aortic stenosis, and carotid artery disease. Exons of the LDLR and APOB genes were amplified by polymerase chain reactions (PCR). PCR products were examined by pyrosequencing and proven by bidirectional DNA sequencing. The proband was heterozygous for both the LDLR c.420G>C (p.Glu140Asp) mutation known to be pathogenic and a rare APOB c.10708C>T (p.His3570Tyr) mutation with unproven pathogenicity. Cascade testing has been performed in her 15 first-degree blood relatives. Her daughter carries only the LDLR c.420 G>C mutation with a TC of 8.4 mmol/L. Her two sisters carry only the APOB c.10708C>T with a TC of 5.7 and 6.2 mmol/L. This case provides evidence that the rare APOB c.10708C>T mutation alone is not pathogenic, but has a synergic effect on LDLR mutation. The finding is important for understanding the genotype-phenotype correlation and highlights the need to consider the presence of additional mutations in FH families where relatives have varying phenotypes.

Changes in serum afamin and vitamin E levels after selective LDL apheresis.

BACKGROUND: Afamin is a plasma vitamin E-binding glycoprotein partially associated with ApoA1-containing high-density lipoprotein (HDL) subfractions. In a previous study, the serum vitamin E decreased after low-density lipoprotein (LDL) apheresis, while vitamin E/cholesterol ratio increased. We aimed to study the effect of LDL apheresis on serum afamin level. METHODS: The serum level of afamin and oxidized LDL were measured by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments and in seven healthy controls. We also investigated the changes in total cholesterol, LDL-C, HDL-C, ApoB, ApoA1, HDL subfractions, and α- and γ-tocopherol levels during the treatment. HDL subfractions were detected by an electrophoretic method on polyacrylamide gel (Lipoprint). Serum α- and γ-tocopherol levels were detected by gas chromatography-mass spectrometry. RESULTS: The first treatment sessions decreased serum afamin levels by an average of 9.4%. Total cholesterol, LDL-C, HDL-C and ApoA1 levels decreased by 52.6; 61.8; 10.5; and 14.1%, respectively. We found that α- and γ-tocopherol levels markedly decreased (by 34.1 and 32.9%, respectively), while α- tocopherol/cholesterol and γ-tocopherol/cholesterol ratios significantly increased (by 41.4 and 40.3%, respectively). Oxidized LDL levels significantly decreased. There was a shift toward the larger HDL subfractions. CONCLUSION: LDL apheresis moderately decreases the circulating levels of afamin parallel to lowering HDL-C and ApoA1 levels. Tocopherol levels decreases markedly compared to afamin levels, however, beneficial changes in vitamin E/cholesterol ratios, oxidized LDL levels and HDL subfraction distribution were detected. These additional effects of LDL apheresis may result in further cardiovascular risk reduction in FH patients.

[The role of apolipoprotein M and sphingosine 1-phosphate axis in the prevention of atherosclerosis]. / Az apolipoprotein M és a szfingozin-1-foszfát tengely jelentosége az érelmeszesedés kialakulásának gátlásában.

Previous studies showed that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to risk of cardiovascular diseases. However, in the last few decades it became obvious that beyond its plasma level, HDL structure and function have a critical role in its anti-atherogenic efficacy. Apolipoprotein M (ApoM) is an HDL-associated plasma protein affecting HDL metabolism and exhibits various anti-atherosclerotic functions, such as protection against oxidation and regulation of cholesterol efflux. Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that regulates numerous cellular responses including cell differentiation and migration, apoptosis and vascular inflammation. The majority of S1P is associated to ApoM containing HDL particles. Therefore, ApoM and S1P content of HDL have an impact on the atherosclerotic process. Moreover, HDL-ApoM and S1P content can be altered in several pathologic conditions such as coronary artery disease. This review covers the currently available data on the contribution of ApoM and S1P to HDL function in health and cardiovascular diseases. Orv Hetil. 2018; 159(5): 168-175.

[Statin-induced adverse effects -- facts and genes]. / Statin okozta mellékhatások -- tények és gének.

Statin therapy is considered to be safe and rarely associated with serious adverse events. However, a significant proportion of patients on statin therapy show some degree of intolerance which can lead to decreased adherence to statin therapy. The authors summarize the symptoms, signs and frequencies of the most common statin-induced adverse effects and their most important risk factors including some single nucleotide polymorphisms and gene mutations. Also, they review the available approaches to detect and manage the statin-intolerant patients.