Hypercholesterolemic Patients Research Articles

Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling.

BackgroundHypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking.MethodsHuman bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics‐related proteins were detected by RT‐qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)‐6 and IL‐8 were detected by RT‐qPCR.ResultsWe found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia‐driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism‐associated genes in CSE‐induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3‐MFN2 pathway, cholesterol re‐distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down‐regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation.ConclusionsOur data provide new insights for understanding molecular mechanisms of cholesterol‐altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes.

Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel.

The most common form of inherited lipid disorders is familial hypercholesterolemia (FH). It is characterized primarily by high concentrations of the clinical triad of low-density lipoprotein cholesterol, tendon xanthomas and premature CVD. The well-known genetic background are mutations in LDLR, APOB and PCSK9 gene. Causative mutations can be found in 60–80% of definite FH patients and 20–30% of those with possible FH. Their occurrence could be attributed to the activity of minor candidate genes, whose causal mechanism has not been fully discovered. The aim of the conducted study was to identify disease-causing mutations in FH-related and candidate genes in pediatric patients from Poland using next generation sequencing (NGS). An NGS custom panel was designed to cover 21 causative and candidate genes linked to primary dyslipidemia. Recruitment was performed using Simon Broome diagnostic criteria. Targeted next generation sequencing was performed on a MiniSeq sequencer (Illumina, San Diego, CA, USA) using a 2 × 150 bp paired-end read module. Sequencing data analysis revealed pathogenic and possibly pathogenic variants in 33 out of 57 studied children. The affected genes were LDLR, APOB, ABCG5 and LPL. A novel pathogenic 7bp frameshift deletion c.373_379delCAGTTCG in the exon 4 of the LDLR gene was found. Our findings are the first to identify the c.373_379delCAGTTCG mutation in the LDLR gene. Furthermore, the double heterozygous carrier of frameshift insertion c.2416dupG in the LDLR gene and missense variant c.10708C>T in the APOB gene was identified. The c.2416dupG variant was defined as pathogenic, as confirmed by its cosegregation with hypercholesterolemia in the proband’s family. Although the APOB c.10708C>T variant was previously detected in hypercholesterolemic patients, our data seem to demonstrate no clinical impact. Two missense variants in the LPL gene associated with elevated triglyceride plasma level (c.106G>A and c.953A>G) were also identified. The custom NGS panel proved to be an effective research tool for identifying new causative aberrations in a genetically heterogeneous disease as familial hypercholesterolemia (FH). Our findings expand the spectrum of variants associated with the FH loci and will be of value in genetic counseling among patients with the disease.

The role of cholesterol in the regulation of adenosine A2A receptor: A basic and clinical approach

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide and hypercholesterolemia is one of the main CVD risk factors. During inflammation, adenosine blood concentration increases and activates A2A adenosine receptors (expressed by endothelial cells and lymphocytes), thus producing a protective effect via its vasodilatory and immunosuppressive functions. Conversely, alterations of A2A receptor expression and properties have been found in CVD patients. Cholesterol seems to directly regulate the functional characteristics of this receptor and studies suggest that A2A receptor alterations are also associated with dyslipidemia. In order to study the role of cholesterol in A2A receptor regulation, two approaches are used: 1) basic, via the analysis in cellular models of the effect of cholesterol modulation on A2AR localization and signaling, and 2) clinical, by characterizing A2AR expression and functions in patients with familial hypercholesterolemia (FH) and by studying a possible correlation between A2AR, blood cholesterol levels and patient's clinical status. T cells (CEM) and endothelial cells (HMEC-1) are depleted (Methyl-β-Cyclodextrin) or supplemented with cholesterol (Water Soluble Cholesterol) and stimulated with a selective A2A receptor agonist, Adonis. Ligand interaction and A2A receptor activation are analyzed by western blot, flow cytometry and ELISA, A2AR localization by immunofluorescence and microscopy. 2) FH patients and healthy subjects are selected by age, gender and clinical status. After isolation of peripheral blood mononuclear cells (PBMCs), A2AR expression is analyzed by western blot. 1) Cholesterol depletion in CEM does not affect receptor affinity (KD) for its agonist, but increases its binding capacity (Bmax). 2) Our pilot study on a small cohort of patients shows a decrease in A2A receptor expression compared with healthy subjects and an inverse correlation between A2AR expression and total and LDL cholesterol blood levels. Our results demonstrate that cholesterol modulates A2A receptor and that alterations of A2A properties are associated with hypercholesterolemia, which might help to better understand the high cardiovascular risk in hypercholesterolemia patients.

ANALISA NILAI GIZI DAN UJI ORGANOLEPTIK BOLU PEPAYA SEBAGAI ALTERNATIF MAKANAN SELINGAN PADA HIPERKOLESTEROLEMIA

According to the World Health Organization (WHO) in 2018, it was recorded that people with high cholesterol in Indonesia increased every year by 28%, this number is likely to increase to 29.25 in 2025. Papaya fruit is rich in nutrition, contains high fiber and antioxidants. Papaya fruit will be processed into sponge, which is a very popular food as a snack for hypercholesterolemia. The purpose of the study was to know the average value of the color, aroma, texture, taste of the sponge and to know the value of the fiber content of the best sponge. The method used in this study is an experiment using a Completely Randomized Design method consisting of four treatments and two replications. Treatment A (25 grams of papaya), treatment B (50 grams of papaya), treatment C (75 grams of papaya) and treatment D (100 grams of papaya). This research was conducted in July 2021. Sampling was carried out at the researcher's house, while organoleptic tests were carried out at the Perintis Indonesia University campus and the fiber content inspection site at Baristand (Industrial Research and Standardization Center Padang). Based on the results of the organoleptic test, it showed that the panelists' assessment of the papaya sponge product had a very significant effect on the color, aroma, texture, and taste of the papaya sponge. Based on the panelists' assessment, treatment A (pawpaw 25 grams) was the best product, namely color 4.3; fragrance 4.56; texture 4.42 and taste 4.72 with the highest average value of 18. Treatment A contained fiber content of 5.53 with a weight of 50 grams of papaya sponge. In this study it can be concluded that the best papaya sponge is treatment A, the best papaya cake contains fiber content which is very beneficial for hypercholesterolemic patients so that it can meet fiber levels per person in a day.

Effects of treatment with monacolin K, berberine and coenzyme Q10 on lipid metabolism in patients with moderate cardiovascular risk

ObjectiveThe use of nutritional supplements to treat hypercholesterolemia is gradually increasing, however further studies on their efficacy and safety are required. Patients and methodsThe present clinical trial included patients with moderate hypercholesterolemia and cardiovascular risk who were treated either with a nutraceutical preparation containing 3.75mg of monacolin K, 515mg of berberine and 50mg of coenzyme Q10 per tablet (Lipok®) or with a placebo. The clinical and laboratory variables were analyzed at baseline and at three and six months. None of the patients was diabetic, and none was being treated with lipid-lowering drugs or with any other nutritional supplements affecting lipid metabolism. ResultsIn patients of the intervention group and of the placebo group, baseline LDL-C was 134.7mg/dL (14.4) and 138.7mg/dL (15.2), respectively. At three months after treatment start, LDL-C had decreased by 26.1mg/dL (−32.4 to 19.7) and increased by 4.5mg/dL (−1.5 to 10.5) in the respective groups. In the intervention group, a similar decrease in non-HDL-C and total cholesterol was observed, while no significant changes were observed in either group for HDL-C, triglycerides and lipoprotein(a). A good tolerance and safety profile was observed. ConclusionIn conclusion, this study demonstrates that the combination of monacolin K, berberine and coenzyme Q10 is effective and safe for treating hypercholesterolemia in patients with a moderate degree of excess LDL-C and cardiovascular risk.

A PCSK9 inhibitor induces a transient decrease in the neutrophil-lymphocyte ratio and monocyte-lymphocyte ratio in homozygous familial hypercholesterolemia patients

Background and aimsExtremely elevated levels of low-density lipoprotein-cholesterol (LDL-C) contribute to long-term chronic systemic inflammation in homozygous familial hypercholesterolemia (HoFH) patients. The aims of this study is to describe the inflammatory profile of HoFH patients and explore the effect of a PCSK9 inhibitor (PCSK9i) on a series of inflammatory biomarkers, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-HDL ratio (MHR), monocyte-lymphocyte ratio (MLR) and mean platelet volume-lymphocyte ratio (MPVLR). MethodsIn this prospective cohort study, 25 definitive HoFH patients on high-intensity statins plus ezetimibe were administered subcutaneous injections of 420 mg PCSK9i every 4 weeks (Q4W). The biochemical parameters and inflammatory profile were analyzed on the day before PCSK9i therapy and 3 months and 6 months after PCSK9i therapy. ResultsHoFH on the maximum tolerated statin dose plus ezetimibe displayed elevated lipid and disturbed blood biomarker profiles. After 3 months of add-on PCSK9i therapy, a significant reduction in LDL-C was observed. Moreover, the percentage and count of neutrophils, monocyte counts, MPV, and two inflammatory biomarkers, the NLR and MLR, were reduced. However, at 6 months of PCSK9i treatment, the NLR and MLR returned to pre-PCSK9i treatment levels. ConclusionsPCSK9i induces a transient decrease in the NLR and MLR in HoFH patients in a lipid-lowering independent manner.

Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia.

The inducible degrader of low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase involved in the post-transcriptional regulation of LDL receptor (LDLR). Statins lower plasma LDL by activating transcription of hepatic LDLR expression, and we have determined whether statins modulate IDOL expression and influence LDLR protein abundance. IDOL expression in monocytes and serum IDOL level was determined in statin-treated familial hypercholesterolemia (FH) patients and compared with control subjects. Serum IDOL level was also evaluated in a group of untreated FH patients before and after the initiation of statin. The mechanism underlying the inhibitory effect of statin on IDOL expression was investigated in vitro. In statin-treated FH patients, serum IDOL level and its expression in monocytes was reduced compared with control (P < 0.05). In contrast, untreated FH patients had higher serum levels of IDOL and proprotein convertase subtilisin/kexintype 9 (PCSK9) than control (P < 0.05), and serum IDOL level decreased after statin therapy (P < 0.05) whereas an increase was observed in PCSK9 level (P < 0.01). In vitro, atorvastatin significantly decreased IDOL abundance in a dose-dependent manner in cultured macrophages and hepatocytes with a concomitant increase in LDLR expression. The transcription of IDOL was restored by adding either an LXR agonist T0901317 or oxysterol 22(R)-hydroxycholesterol, indicating that statin inhibited IDOL expression by reducing LXR activation. The LXR-IDOL-LDLR axis can be modulated by statins in vitro and in vivo. Statins inhibit IDOL expression by reducing LXR activation and upregulate LDLR, and statins exert the opposite effect on IDOL and PCSK9.

Effectiveness of Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy on Lipid Levels in Type 2 Diabetes: a Meta-analysis

IntroductionObesity and its co-morbidities, including type 2 diabetes (T2DM) and dyslipidemia, are accompanied by excess cardiovascular morbi-mortality. Aside from excess low density lipoprotein-cholesterol (LDL-C), atherogenic dyslipidemia (AD), mainly characterized by elevated triglycerides and decreased high density lipoprotein-cholesterol (HDL-C) levels, is often present in T2DM obese patients. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), has become a reference treatment in that population. However, the respective effects of RYGB vs SG on lipid metabolism in T2DM patients have been rarely studied. MethodsA meta-analysis of randomized controlled trials, comparing the effects of RGYBG vs SG on lipid metabolism 12 months after surgery in T2DM patients, was performed. ResultsFour studies including a total of 298 patients (151 patients in the RYGB and 147 patients in the SG group) were examined. Despite a greater decrease in body mass index and greater improvement in glycemic control in RYGB compared to SG. RYGB vs SG was more effective in reducing total cholesterol, LDL-C, and non-HDL-C levels (mean difference [MD] −26.10 mg/dL, 95 % CI −38.88 to −13.50, p<0.00001; [MD] −20.10 mg/dL, 95 % CI −27.90 to −12.20, p<0.00001 and MD 31.90 mg/dl, 95 % CI −46.90 to −16.80, p<0.00001, respectively). ConclusionsThe superiority of RYGB vs SG in reducing LDL-C, with an effect comparable to a moderate-intensity statin, suggests RYBG should be favored in hypercholesterolemic T2DM patients in order to further reduce cardiovascular risk.

MO244: PCSK9 Inhibitors are Efficient in Treatment of Resistant Hypercholesterolemia in Nephrotic Syndrome

Abstract BACKGROUND AND AIMS Hypercholesterolemia in nephrotic syndrome is commonly resistant to statin therapy and represents an important clinical challenge both for cardiovascular risk prevention and to eliminate lipotoxic effect on podocytes. Serum PCSK9 level is elevated in nephrotic syndrome and has a key pathophysiologic role in development and persistance of hyperlipidemia. Thus, we aimed to investigate the role of PCSK9 inhibitors in control of hypercholesterolemia in patients with neprotic syndrome. METHOD Consecutive patients with nephrotic syndrome and elevated atherogenic Lp (a) (n = 4) and patients with resistant secondary glomerulonephritis with nephrotic proteinuria (n = 2) were included. In all patients, in addition to full dose statin therapy, evolocumab 420 mg s.c. monthly was introduced. Lipid levels were measured after a median of 4 (range 2–9) months after starting evolocumab. RESULTS Nephrotic syndrome was caused by focal segmental glomerulosclerosis in four patients (66.7%) and membranous nepropathy was the cause in two patients (33.3%). Median age of included patients was 49.5 (range 24–70) years. Four patients with primary cause of glomerulonephritis received specific imunosupressive treatment. During follow-up, we observed descrease in glomerular filtration rate (eGFR median 58.5 interquartile range (IQR) [46.7–98.7] mL/min/1.73 m2 versus median 47 IQR [38.25–89.25] mL/min/1.73 m2; P = .046) and persistence of proteinuria [median 11 970 IQR (3862–13 765) mg/dU versus median 10 847 (5407–14 340) mg/dU; P = .753]. However, despite persistent proteinuria and decrease in eGFR, significant decrease in total cholesterol [median 9.10 IQR (6.92–10.87) mmol/L versus median 6.81 (5.4–8.45) mmol/L; P = .028] and LDL cholesterol [median 5.40 IQR (4.12–7.25) versus median 4.04 IQR (2.70–4.60); P = .046] was observed. There was no significant difference in Lp (a) and triglyceride levels. CONCLUSION PCSK9 inhibitors are a promising new therapeutic option for hyperlipidemia in patients with nephrotic syndrome. Further research, including a larger number of patients, is needed to correctly position PCSK9 inhibitors in treatment of hyperlipidemia in patients with nephrotic syndrome.

MicroRNA-20a-5p Downregulation by Atorvastatin: A Potential Mechanism Involved in Lipid-Lowering Therapy

The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.

Efficacy and Safety of Lomitapide in Homozygous Familial Hypercholesterolaemia: A Systematic Review.

Homozygous familial hypercholesterolaemia (HoFH) patients have little or no low-density lipoprotein receptor (LDLR) function. HMG-CoA (3-hydroxy-3-methyl glutaryl coenzyme A) reductase inhibitors (statins) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have limited lipid-lowering effects, therefore, there is an urgent need to develop new HoFH treatments. In 2012, the US Food and Drug Administration (FDA) approved the administration of lomitapide for lowering low-density lipoprotein cholesterol (LDL-C) levels. However, lomitapide is associated with various gastrointestinal disorders, elevated hepatic alanine aminotransferase (ALT) levels and other adverse reactions, thus, its long-term efficacy and safety in pediatrics and adults should be evaluated. A systematic review conducted in 2017 reported the efficacy and safety of lomitapide in Family hypercholesterolaemia (FH) patients. In this systematic review, we elucidate on the efficacy and safety of lomitapide in HoFH patients. A search was conducted in PubMed, Embase, Web of Science and Cochrane library databases to identify valid studies involving lomitapide-treated HoFH patients published before 11th August 2021. A total of 18 clinical studies involving 120 lomitapide-treated HoFH patients were identified. Lomitapide significantly suppressed LDL-C levels in HoFH patients. Clinical manifestations for lomitapide in children were comparable to those in adults. The most common adverse events were gastrointestinal disturbances and elevated ALT levels. However, most patients tolerated the treatment-associated adverse reactions. Low-fat diets and drug dose adjustments were appropriate measures for controlling the treatment-associated adverse reactions. In pediatric and adult HoFH patients, lomitapide significantly suppresses LDL-C levels, therefore, it is an important option for HoFH treatment. The most common adverse events of lomitapide treatment include gastrointestinal disorders and elevated hepatic ALT levels. Despite the limitations, lomitapide is feasible for long-term treatment of HoFH patients, with dietary and safety monitoring. CRD42021284425.

Efficacy and Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors as Adjuvant Treatments for Patients with Hypercholesterolemia Treated with Statin: A Systematic Review and Network Meta-analysis.

Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent LDL-C lowering agents. However, few head-to-head studies evaluated the efficacy on the lowering in other atherogenic apolipoproteins and safety of PCSK9 inhibitors at different dosages as an add-on statins therapy in hypercholesterolemia patients. Methods: This study is a systematic review and network meta-analysis of randomized control trials to compare the efficacy of lipid reduction and adverse events of PCSK9 inhibitors in statin-treated hypercholesterolemia patients. PubMed, EMBASE, and Cochrane Library databases were searched till April 20, 2021, for randomized controlled trials. Random-effect network meta-analyses were undertaken to compare the differences in the percent reduction in low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) [Lp(a)] levels and the risk of AEs among different PCSK9 inhibitors. Results: A total of 22 articles with 42,786 patients were included. The lipid reductions in LDL-C, ApoB, and Lp(a) with add-on PCSK9 inhibitors vs. placebo in statin-treated patients across all trials were 50–63%, 43–52%, and 23–31%, respectively. Evolocumab 140 mg Q2W was ranked the best among all treatment strategies for lowering LDL-C, ApoB, and Lp(a) levels, and the treatment difference was 68.05% (95% confidence interval (CI), 62.43% to 73.67) in LDL-C reduction, 54.95% (95% CI, 49.55% to 60.35%) in ApoB reduction, and 34.25% (95% CI, 27.59% to 40.91%) in Lp(a) reduction compared with the placebo. No significant risk difference of adverse events between PCSK9 inhibitors and placebo was found. Conclusion: PCSK9 inhibitors showed a significant effect on the reduction in LDL-C, ApoB, and Lp(a) levels in statin-treated patients. Evolocumab 140 mg Q2W showed significantly larger degrees of LDL-C, ApoB, and Lp(a) reduction.

Homozygous familial hypercholesterolemia in China: Genetic and clinical characteristics from a real-world, multi-center, cohort study

BackgroundThere is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia. ObjectiveTo define the characteristics of phenotypic and genetic HoFH probands from mainland China. MethodsWe collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test. ResultsA total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH. ConclusionsThis report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH.

Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients

Background and aimsFamilial hypercholesterolemia (FH) is the most relevant genetic cause of early cardiovascular disease (CVD). FH is suspected when low density lipoprotein cholesterol (LDL-C) levels exceed the 95th percentile of the population distribution. Different diagnostic scoring systems have been developed, as the Dutch Lipid Clinic Network (DLCN) score, used worldwide. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic, and evaluate the DLCN score performance applied retrospectively to the case study. Methods836 hypercholesterolemic patients with LDL-C > 4.88 mmol/L were genotyped for FH causative gene variants in the LDLR, PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening. ResultsGene variant carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) non-carriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects showed that variant carriers had an odds ratio of 3.66 (1.43–10.24) for atherosclerotic plaques in comparison with non-carriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C. = 0.737) resulted to be more performing than the DLCN score (A.U.C. = 0.662), even including carotid US data (A.U.C. = 0.641) in a modified DLCN score version. Conclusionsthe DLCN score failed to demonstrate a clear superiority in predicting FH gene variants in comparison with the measure of LDL-C levels in a retrospective case study.

Quality of life and coping in Dutch homozygous familial hypercholesterolemia patients: A qualitative study

Background and aimsHomozygous familial hypercholesterolemia (HoFH) is characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels leading to extremely premature atherosclerotic cardiovascular disease. Therefore, healthcare professionals consider HoFH to have major impact on patients’ life. Remarkably, little is known on how patients deal with their condition. The aim of this study is to investigate how Dutch patients experience and cope with HoFH in daily life. MethodsAdult patients with genetically confirmed HoFH, treated at the 3 specialized HoFH-centers in the Netherlands, were interviewed in-depth. Interview transcripts were analyzed according to grounded theory. Health-related quality of life (QoL) and coping were measured with the EuroQol (EQ)-5D-5L questionnaire and the Threatening Medical Situations Inventory (TMSI), respectively. Results20 Dutch HoFH patients were interviewed: 50% women, median age 38 years, 60% with cardiovascular disease, 10% on apheresis. Coding of the transcripts resulted in a conceptual model, with disease perception as the central theme. Individual TMSI-results corresponded to the interviews, with most patients showing both monitoring (information-seeking behavior) and blunting (distractive strategies) coping styles. The median EQ-5D-5L health utility score (0.839) was only 5% below the Dutch population (0.887). Transient anxiety was reported when confronted with the consequences of HoFH in daily life. Patients reported high confidence in treatment by a dedicated HoFH center, which helped them cope with their disease. ConclusionsDutch HoFH patients use a variety of effective coping mechanisms in such a way that their subjective QoL is only slightly affected. Healthcare professionals can use this knowledge to tailor their care to the specific needs of these patients.

Protocolo del observatorio de las dislipemias: Tratamiento de la hipercolesterolemia en España, contexto e identificación de medidas de mejora en práctica clínica habitual

Introduction and objectivesThe treatment of dyslipidemia exhibits wide variability in clinical practice and important limitations that make lipid-lowering goals more difficult to attain. Getting to know the management of these patients in clinical practice is key to understand the existing barriers and to define actions that contribute to achieving the therapeutic goals from the most recent Clinical Practice Guidelines. MethodsObservatory where the information gathered is based on routine clinical practice and the experience from the healthcare professionals involved in the treatment of dyslipidemia in Spain. The information is collected by health area through: (i) face-to-face meeting with three different medical specialties and (ii) quantitative information related to hypercholesterolemia patients’ management (ad-hoc questionnaire). Information includes patients’ profiles, assistance burden, guidelines and protocols used, goal attainment, limitations and opportunities in clinical practice. Results145 health areas are planned to be included, with the participation of up to 435 healthcare professionals from the 17 Autonomous Regions of Spain. Information collection will result in aggregated data from over four thousand patients. ConclusionsThis observatory aims to understand how hypercholesterolemia is being treated in routine clinical practice in Spain. Even though the preliminary results show important improvement areas in the treatment of dyslipidemias, mechanisms to drive a change towards health outcomes optimization are also identified.

Identification and functional characterization of two rare LDLR stop gain variants (p.C231* and p.R744*) in Saudi familial hypercholesterolemia patients.

Familial hypercholesterolemia (FH) is a globally underdiagnosed inherited metabolic disorder. Owing to limited published data from Arab world, this study was conducted with the aim of identifying the genetic and molecular basis of FH in highly consanguineous Saudi population. We performed clinical screening, biochemical profiling, whole exome sequencing and variant segregation analysis of two Saudi FH families. Additionally, 500 normolipic individuals were screened to ensure the absence of FH variant in general Saudi population. Functional characterization of FH variants on secondary structure characteristics of RNA and protein molecules was performed using different bioinformatics modelling approaches. WES analysis identified two independent rare LDLR gene stop gain variants (p.C231* and p.R744*) consistent to the clinical presentation of FH patients from two different families. RNAfold analysis has shown that both variants were predicted to disturb the free energy dynamics of LDLR mRNA molecule and destabilize its folding pattern and function. PSIPRED based structural modelling analysis has suggested that both variants bring drastic changes disturbing the secondary structural elements of LDLR molecule. The p.C231* and p.R744* variants are responsible for partial or no protein product, thus they are class 1 variants causing loss of function (LoF) LDLR variants. This study highlights the effectiveness of the WES, sanger sequencing, and computational analysis in expanding FH variant spectrum in culturally distinct populations like Saudi Arabia. Genetic testing of FH patients is very essential in better clinical diagnosis, screening, treatment, and management and prevention of cardiovascular disease burden in the society.

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Monocyte and Macrophage Lipid Accumulation Results in Down-Regulated Type-I Interferon Responses.

Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The down regulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signaling pathways and suggest that this phenotype is mediated via down regulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.

Targeting ApoC3 Paradoxically Aggravates Atherosclerosis in Hamsters With Severe Refractory Hypercholesterolemia.

RationaleApoC3 plays a central role in the hydrolysis process of triglyceride (TG)-rich lipoproteins mediated by lipoprotein lipase (LPL), which levels are positively associated with the incidence of cardiovascular disease (CVD). Although targeting ApoC3 by antisense oligonucleotide (ASO), Volanesorsen markedly reduces plasma TG level and increase high-density lipoprotein cholesterol (HDL-C) in patients with hypertriglyceridemia (HTG), the cholesterol-lowering effect of ApoC3 inhibition and then the consequential outcome of atherosclerotic cardiovascular disease (ASCVD) have not been reported in patients of familial hypercholesterolemia (FH) with severe refractory hypercholesterolemia yet.ObjectiveTo investigate the precise effects of depleting ApoC3 on refractory hypercholesterolemia and atherosclerosis, we crossed ApoC3-deficient hamsters with a background of LDLR deficiency to generate a double knockout (DKO) hamster model (LDLR−/−, XApoC3−/−, DKO).Approach and ResultsOn the standard laboratory diet, DKO hamsters had reduced levels of plasma TG and total cholesterol (TC) relative to LDLR−/− hamsters. However, upon high-cholesterol/high-fat (HCHF) diet feeding for 12 weeks, ApoC3 deficiency reduced TG level only in female animals without affecting refractory cholesterol in the circulation, whereas apolipoprotein A1 (ApoA1) levels were significantly increased in DKO hamsters with both genders. Unexpectedly, loss of ApoC3 paradoxically accelerated diet-induced atherosclerotic development in female and male LDLR−/− hamsters but ameliorated fatty liver in female animals. Further analysis of blood biological parameters revealed that lacking ApoC3 resulted in abnormal platelet (PLT) indices, which could potentially contribute to atherosclerosis in LDLR−/− hamsters.ConclusionsIn this study, our novel findings provide new insight into the application of ApoC3 inhibition for severe refractory hypercholesterolemia and ASCVD.