2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance.

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.

The Relationship between COVID-19 and Hypothalamic-Pituitary-Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess-The CAPISCO International Expert Panel.

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic-pituitary-adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.

Experimental and Emerging Free Fatty Acid Receptor Agonists for the Treatment of Type 2 Diabetes.

The current management of Type 2 Diabetes Mellitus (T2DM) includes incretin-based treatments able to enhance insulin secretion and peripheral insulin sensitivity as well as improve body mass, inflammation, plasma lipids, blood pressure, and cardiovascular outcomes. Dietary Free Fatty Acids (FFA) regulate metabolic and anti-inflammatory processes through their action on incretins. Selective synthetic ligands for FFA1-4 receptors have been developed as potential treatments for T2DM. To comprehensively review the available evidence for the potential role of FFA receptor agonists in the treatment of T2DM, we performed an electronic database search assessing the association between FFAs, T2DM, inflammation, and incretins. Evidence indicates that FFA1-4 agonism increases insulin sensitivity, induces body mass loss, reduces inflammation, and has beneficial metabolic effects. There is a strong inter-relationship between FFAs and incretins. FFA receptor agonism represents a potential target for the treatment of T2DM and may provide an avenue for the management of cardiometabolic risk in susceptible individuals. Further research promises to shed more light on this emerging topic.

The role of statins in the differentiation and function of bone cells.

BACKGROUND: Statins are 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors blocking cholesterol biosynthesis in hepatic cells, thereby causing an increase in low-density lipoprotein (LDL) receptors resulting in enhanced uptake and clearance of atherogenic LDL-cholesterol (LDL-C) from the blood. Accordingly, statins decrease the risk of developing atherosclerosis and its acute complications, such as acute myocardial infarction and ischaemic stroke. Besides the LDL-C-lowering impact, statins also have other so-called pleiotropic effects. Among them, the ability to modulate differentiation and function of bone cells and exert direct effects on osteosynthesis factors. Specifically, earlier studies have shown that statins cause in vitro and in vivo osteogenic differentiation. DESIGN: The most relevant papers on the bone-related 'pleiotropic' effects of statins were selected following literature search in databases and were reveiwed. RESULTS: Statins increase the expression of many mediators involved in bone metabolism including bone morphogenetic protein-2 (BMP-2), glucocorticoids, transforming growth factor-beta (TGF-ß), alkaline phosphatase (ALP), type I collagen and collagenase-1. As a result, they enhance bone formation and improve bone mineral density by modulating osteoblast and osteoclast differentiation. CONCLUSION: This review summarizes the literature exploring bone-related 'pleiotropic' effects of statins and suggests an anabolic role in the bone tissue for this drug class. Accordingly, current knowledge encourages further clinical trials to assess the therapeutic potential of statins in the treatment of bone disorders, such as arthritis and osteoporosis.

The role of potassium in atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is a chronic progressive inflammatory condition with a leading prevalence worldwide. Endothelial dysfunction leads to low-density lipoprotein trafficking into subendothelial space and the subsequent form of oxidized LDL (ox-LDL) within intimal layer, perpetuating the vicious cycle of endothelial dysfunction. K+ exerts beneficial effects in vascular wall by reducing LDL oxidization, vascular smooth muscle cells (VSMCs) proliferation, and free radical generation. K+ also modulates vascular tone through a regulatory effect on cell membrane potential. MATERIALS AND METHODS: The most relevant papers on the association between 'potassium channels' and 'atherosclerosis' were selected among those deposited on PubMed from 1990 to 2020. RESULTS: Here, we provide a short narrative review that elaborates on the role of K+ in atherosclerosis. This review also update the current knowledge about potential pharmacological agents targeting K+ channels with a special focus on pleiotropic activities of agents such as statins, sulfonylureas and dihydropyridines. CONCLUSION: In this review, the mechanism of different K+ channels on vascular endothelium will be summarized, mainly focusing on their pathophysiological role in atherosclerosis and potential therapeutic application.

Nutraceuticals in the Management of Dyslipidemia: Which, When, and for Whom? Could Nutraceuticals Help Low-Risk Individuals with Non-optimal Lipid Levels?

PURPOSE OF REVIEW: The aim of this review is to summarize the available clinical efficacy and safety data related to the most studied and used lipid-lowering nutraceuticals. RECENT FINDINGS: A growing number of meta-analyses of randomized clinical trials supports the effectiveness and tolerability of some lipid-lowering nutraceuticals such as red yeast rice, plant sterols and stanols, soluble fibers, berberine, artichoke extracts, bergamot polyphenol fraction, garlic, green tea, and spiruline. No significant safety concern has been raised for the use of such products. Association of more lipid-lowering nutraceuticals and of some nutraceuticals with lipid-lowering drugs has been tested as well. Current evidence suggests that some clinically tested lipid-lowering nutraceuticals could be safely used to improve plasma lipid levels in subjects affected by mild-to-moderate dyslipidaemia with low cardiovascular risk.

Protective Effects of Curcumin on Endothelium: An Updated Review.

Endothelial dysfunction is the common early stage of most cardiovascular afflictions. The endothelium is considered the main mediator of vascular homeostasis via its vasodilator, anti-inflammatory and anticoagulant properties. Among the different endothelial-derived mediators, nitric oxide is produced by nitric oxide synthase and has a critical role in regulating endothelial function. Physiological and pathological processes such as aging and diabetes mellitus are associated with disturbances of endothelial function which, at least at the earliest stage, can be reversed by lifestyle and pharmacological intervention to reduce the risk of incident cardiovascular diseases. Among dietary strategies, curcumin is a cheap and safe nutraceutical polyphenol with proven antioxidant and anti-inflammatory properties. Given the important role of such processes in the development of endothelium dysfunction, a role for curcumin in the prevention or treatment of this condition has been hypothesized. This review summarizes the available literature on the beneficial role of curcumin on vascular endothelial function.

Novel Therapeutical Approaches to Managing Atherosclerotic Risk.

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem.

Anti-fibrotic effects of curcumin and some of its analogues in the heart.

Cardiac fibrosis stems from the changes in the expression of fibrotic genes in cardiac fibroblasts (CFs) in response to the tissue damage induced by various cardiovascular diseases (CVDs) leading to their transformation into active myofibroblasts, which produce high amounts of extracellular matrix (ECM) proteins leading, in turn, to excessive deposition of ECM in cardiac tissue. The excessive accumulation of ECM elements causes heart stiffness, tissue scarring, electrical conduction disruption and finally cardiac dysfunction and heart failure. Curcumin (Cur; also known as diferuloylmethane) is a polyphenol compound extracted from rhizomes of Curcuma longa with an influence on an extensive spectrum of biological phenomena including cell proliferation, differentiation, inflammation, pathogenesis, chemoprevention, apoptosis, angiogenesis and cardiac pathological changes. Cumulative evidence has suggested a beneficial role for Cur in improving disrupted cardiac function developed by cardiac fibrosis by establishing a balance between degradation and synthesis of ECM components. There are various molecular mechanisms contributing to the development of cardiac fibrosis. We presented a review of Cur effects on cardiac fibrosis and the discovered underlying mechanisms by them Cur interact to establish its cardio-protective effects.

Statins: Epidrugs with effects on endothelial health?

BACKGROUND: Epigenetic events involving the methylation of CpG cites in DNA, histone modifications and noncoding RNAs correlated with many essential processes in human cells and diseases, such as cancer and cardiovascular diseases. HMG-CoA reductase inhibitors (statins)-the LDL cholesterol-lowering drugs-are broadly used in cardio- and cerebro-vascular diseases. It is well established that statins exert pleiotropic functions, but how they exert effects on epigenetic modifications independently of HMG-CoA reductase inhibition is not yet clear. Thereby, understanding these mechanisms may pave the way for further clinical application of statin therapy. DESIGN: Following and electronic database search, studies reporting substantial effects of statins on epigenetic reprogramming in both cultured cells and in vivo models were retrieved and reviewed. RESULTS: Epigenetic mechanisms play an essential role in cellular development and function, and data collected in the past few years have revealed that many of the pleiotropic properties of statins are mediated by epigenetic mechanisms. Furthermore, those 'nonclassical' effects are not limited to CV field but they would extend to other conditions such as malignancies. CONCLUSION: This review suggests that the epigenetic effects of statins mediate, at least in part, the pleiotropic actions of these drugs but further validation of such effects in clinical studies is yet to be provided.

Healthcare resource utilization in patients on lipid-lowering therapies outside Western Europe and North America: findings of the cross-sectional observational International ChoLesterol management Practice Study (ICLPS).

BACKGROUND: Few recent large-scale studies have examined healthcare consumption associated with dyslipidemia in countries outside Western Europe and North America. METHODS: This analysis, from a cross-sectional observational study conducted in 18 countries in Eastern Europe, Asia, Africa, the Middle East and Latin America, evaluated avoidable healthcare consumption (defined as ≥1 hospitalization for cardiovascular reasons or ≥1 visit to the emergency room for any reason in the previous 12 months) in patients receiving stable lipid-lowering therapy (LLT). A total of 9049 patients (aged ≥18 years) receiving LLT for ≥3 months and who had had their low-density lipoprotein cholesterol (LDL-C) value measured on stable LLT in the previous 12 months were enrolled between August 2015 and August 2016. Patients who had received a proprotein convertase subtilisin/kexin type 9 inhibitor in the previous 6 months were excluded. Patients were stratified by cardiovascular risk level using the Systematic Coronary Risk Estimation chart for high-risk countries. RESULTS: The proportion of patients at their LDL-C goal was 32.1% for very-high risk patients compared with 55.7 and 51.9% for patients at moderate and high cardiovascular risk, respectively. Overall, 20.1% of patients had ≥1 reported hospitalization in the previous 12 months (7.9% for cardiovascular reasons), 35.2% had ≥1 intensive care unit stay and 13.8% visited the emergency room. Avoidable healthcare resource consumption was reported for 18.7% patients overall, and in 27.8, 7.7, 7.7 and 13.2% of patients at very-high, high, moderate and low risk, respectively. Across all risk groups 22.4% of patients not at LDL-C goal and 16.6% of patients at LDL-C goal had avoidable healthcare resource consumption. Being at very-high cardiovascular risk, having cardiovascular risk factors (including hypertension and smoking), and having factors indicating that the patient may be difficult to treat (including statin intolerance, comorbidities and chronic medication), were independent risk factors for avoidable healthcare resource consumption (all p <0.05). CONCLUSIONS: Healthcare resource consumption associated with adverse clinical outcomes was observed in patients on stable LLT in countries outside Western Europe and North America, particularly those at very-high cardiovascular risk and those who were difficult to treat.

Potential effects of curcumin in the treatment of COVID-19 infection.

Coronavirus disease 2019 (COVID-19) outbreak is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with considerable mortality worldwide. The main clinical manifestation of COVID-19 is the presence of respiratory symptoms, but some patients develop severe cardiovascular and renal complications. There is an urgency to understand the mechanism by which this virus causes complications so as to develop treatment options. Curcumin, a natural polyphenolic compound, could be a potential treatment option for patients with coronavirus disease. In this study, we review some of the potential effects of curcumin such as inhibiting the entry of virus to the cell, inhibiting encapsulation of the virus and viral protease, as well as modulating various cellular signaling pathways. This review provides a basis for further research and development of clinical applications of curcumin for the treatment of newly emerged SARS-CoV-2.

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

PCSK9 and infection: A potentially useful or dangerous association?

Elevated plasma low-density lipoprotein-cholesterol (LDL-C) concentration is the most important risk factor for atherosclerotic cardiovascular diseases (CVDs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a ubiquitously expressed serine proteinase which plays a key role in cholesterol metabolism, but has been found to be implicated in some other lipid-independent physiological processes. In this review, the role of PCSK9 was evaluated not only concerning lipid metabolism but also hepatitis C virus (HCV) infection, bacterial infections/sepsis, and septic shock. Collected data from clinical trials revealed that treatment with PCSK9 inhibitors has beneficial effects in lowering LDL-C via inhibition of LDL-receptors (LDL-R), an antiviral effect on HCV infection via down-regulating the surface expression of LDL-R and CD81 on hepatic cells, and a positive association with increased inflammatory responses, as well as with septic shock by down-regulation of hepatocyte LDL-R. On the other hand, PCSK9 inhibition by therapeutic fully humanized antibodies has positive effects in reducing elevated LDL-C. However, their safety and tolerability is an important issue which has to be taken into consideration.

Sex disparity in the management and outcomes of dyslipidemia of diabetic patients in the Arabian Gulf: findings from the CEPHEUS study.

BACKGROUND: Little is known about sex gap in the management and outcomes of dyslipidemia among diabetics in the Arabian Gulf. The aim if this study was to determine sex differences in the management and outcomes of dyslipidemia in diabetic patients in the Arabian Gulf. METHODS: This study was derived from the Centralized Pan-Middle-East Survey on the management of hypercholesterolemia. Patients recruited were aged ≥18 years on lipid lowering drugs for ≥3 months (stable medication for ≥6 weeks). Outcomes were based on the joint Consensus Statement of the American Diabetes Association and American College of Cardiology Foundation. Analyses were performed using univariate and multivariate logistic regression techniques. RESULTS: The mean age of the cohort (n = 3336) was 57 ± 11 years and 45% (n = 1486) were females. Females were less likely to be on rosuvastatin (7.6% vs 12%; P < 0.001), atorvastatin (41% vs 46%; P = 0.005) and combination hypolipidemic therapy (5.6% vs 2.8%; P < 0.001) but more likely to be on simvastatin (51% vs 39%; P < 0.001) than males. Females, especially those with very high atherosclerotic cardiovascular disease (ASCVD) risk status, were also less likely to achieve LDL-cholesterol [adjusted odds ratio (aOR), 0.58; 95% confidence interval (CI): 0.40-0.86; P = 0.006], non-HDL-cholesterol [aOR, 0.68; 95% CI: 0.46-0.99; P = 0.048] and apolipoprotein B [aOR, 0.64; 95% CI: 0.44-0.92; P = 0.016] lipid targets. CONCLUSIONS: Diabetic women were less likely to be on optimal hypolipemic therapy and consequently less likely to attain lipid goals compared to men. This shows a sex gap on dyslipidemia treatment in the region. Diabetic women with very high ASCVD risk status need to be aggressively treated to lower their risk of cardiovascular events.

ScreenPro FH - Screening Project for Familial Hypercholesterolemia in Central, Southern and Eastern Europe: Basic Epidemiology.

INTRODUCTION: Despite great recent progress, familial hypercholesterolemia (FH) is still underestimated, under-diagnosed and thus undertreated worldwide. We have very little information on exact prevalence of patients with FH in the Central, Eastern and Southern Europe (CESE) region. The aim of the study was to describe the epidemiological situation in the CESE region from data available. METHODS: All local leaders of the ScreenPro FH project were asked to provide local data on (a) expert guess of FH prevalence (b) the medical facilities focused on FH already in place (c) the diagnostic criteria used (d) the number of patients already evidenced in local database and (e) the availability of therapeutic options (especially plasma apheresis). RESULTS: With the guess prevalence of FH around 1 : 500, we estimate the overall population of 588 363 FH heterozygotes in the CESE region. Only 14 108 persons (2.4 %) were depicted in local databases; but the depiction rate varied between 0.1 % and 31.6 %. Only four out of 17 participating countries reported the the LDL apheresis availability. CONCLUSION: Our data point to the large population of heterozygous FH patients in the CESE region but low diagnostic rate. However structures through the ScreenPro FH project are being created and we can hope that the results will appear soon.Key words: diagnosis - epidemiology - familial hypercholesterolemia - screening.

Familial hypercholesterolaemia.

PURPOSE OF REVIEW: Familial hypercholesterolaemia is associated with lifelong elevated cholesterol levels and is an important cause of premature coronary heart disease (CHD). This condition is often underdiagnosed and undertreated. Awareness of this condition is poor among nonlipid specialists. Treatment of elevated cholesterol levels with statins reduces the risk for CHD. The review will increase the awareness of this condition among nonspecialists. RECENT FINDINGS: Recently, several guidelines have been produced by different countries, but a unified approach to this global problem is addressed through a recent guideline facilitated by the Familial Hypercholesterolaemia Foundation. Although the widespread use of statins has been successful in reducing the risk for CHD in familial hypercholesterolaemia, there have been difficulties in getting to targets, especially in those with established vascular disease. New therapies such as mipomersen, a second-generation antisense oligonucleotide, microsomal triglyceride transfer protein inhibitors that decrease the synthesis of apolipoprotein B-containing lipoproteins and proprotein convertase subtilisin/kexin type 9 inhibitors hold promise in reducing cholesterol levels in those patients in whom low density lipoprotein cholesterol (LDL-C) reduction is required beyond the use of statins, especially in those with severe heterozygous familial hypercholesterolaemia or homozygous familial hypercholesterolaemia. SUMMARY: Increased awareness and wider availability of guidance to treat familial hypercholesterolaemia will improve management of familial hypercholesterolaemia. New therapies, if they become available after appropriate outcome studies, will reduce LDL-C levels in both homozygous familial hypercholesterolaemia and severe heterozygous familial hypercholesterolaemia, thus reducing the risk for premature CHD.

Correlation of iron overload and glomerular filtration rate estimated by cystatin C in patients with ß-thalassemia major.

Historically, renal involvement has not been a commonly recognized complication in patients with ß-thalassemia major (ß-TM). Herein, we studied the impact of iron overload on glomerular filtration rate (GFR) estimated by cystatin C based GFR (Cyst C eGFR). We enrolled 149 patients with ß-TM in a cross sectional study in a single center in Oman. We investigated the correlation between measurement of serum ferritin and Cyst C eGFR. We used univariable linear regression to study the impact of serum ferritin on Cyst C eGFR and backwards stepwise regression to adjust for potential confounders. We included 78 males and 71 females with a mean age of 17.3 ± 9 years (range 2.5-38.5). Seventeen patients had diabetes mellitus. Patients were taking deferiprone (DFP) and deferoxamine (DFO) (26 patients), DFP (58 patients), deferasirox (DFX) (62 patients) and one patient was taking only DFO. There was a very weak negative linear relationship between serum ferritin and Cyst C eGFR (correlation coefficient -0.25). In the univariable analyses, serum ferritin (p = 0.004), diabetes status (p < 0.001) and chelation therapy (p < 0.001) were statistically significant. In the multivariable model, age (p = 0.033), chelation with DFX (p = 0.05) and diabetes status (p < 0.001) were statistically significant. We found a very weak inverse linear correlation between serum ferritin and Cyst C eGFR. However, when concomitant use of chelation therapy was considered, serum ferritin did not associate with glomerular function. Prospective and larger studies are needed to confirm these findings.

Lipidomic profiling in patients with familial hypercholesterolemia: Abnormalities in glycerolipids and oxysterols.

OBJECTIVES AND AIM: This study aimed to identify precise biomarkers and develop targeted therapeutic strategies for preventing premature atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH) by investigating the quantitative and qualitative abnormalities in the metabolic network of lipids in these patients using an advanced lipidomics platform. DESIGN & METHODS: The study population comprised 18 homozygous (HoFH), 18 heterozygous (HeFH) FH patients, and 20 healthy controls. Cholesterol oxidation products (oxysterol, COPs) and main lipid classes were determined using gas chromatography-mass spectrometry. Results were expressed as percentages of total fat matter for lipid classes and percentages of total COPs for oxysterols. The principal component analysis (PCA) was also carried out, to highlight the correlation between studied parameters and groups investigated. RESULTS: Patients (both HoFH and HeFH) showed lower content of free fatty acids (FFAs) and greater values of triacylglycerols (TAGs) in comparison to controls. HoFH showed lower monoacylglycerols (P<0.01) and higher free cholesterol (FC) (P<0.05) when compared to HeFH and controls. The total content of COPs ranged from 1.96 to 4.25 mg/dL, from 2.27 to 4.05 mg/dL, and from 0.79 to 4.12 mg/dL in healthy controls, HoFH and HeFH groups, respectively, with no significant differences between patients and controls. In general, the 7α-hydroxycholesterol (7α-HC) was greater than other COPs. However, no significant differences were found between the three studied groups. Moreover, an opposite trend was observed between 7α-HC and 7-ketocholesterol (7-KC). Additionally, when PCA was carried out, the first two PCs explained 92.13 % of the total variance, of which the PC1 describes 53.94 % of variance mainly correlated to TAGs, diacylglycerols (DAGs), and 7-KC. On the other hand, the PC2 was correlated primarily for FFAs, FC and esterified sterols (E-STE). CONCLUSIONS: In conclusion, abnormal levels of TAGs, DAGs and 7-KC were associated with HeFH while HoFH was associated with the abnormal amount of E-STE.

Identification of Critical Genes Differentiating Stable and Unstable Atherosclerotic Plaques: A Bioinformatic and Computational Analysis.

BACKGROUND: Identification of biomarkers to distinguish between stable and unstable plaque formation would be very useful to predict plaque vulnerability. METHODS: We downloaded microarray profiles of gene set enrichment (GSE) accession numbers including GSE71226 and GSE20680 (group A: containing healthy vs stable plaque samples) and GSE62646 and GSE34822 (group B: containing stable vs unstable plaque samples) from Gene expression omnibus (GEO) database. Differentially expressed genes were compared in both data sets of each group. RESULTS: Ten and 12 key genes were screened in groups A and B, respectively. Gene Ontology (GO) enrichment was applied by the plugin "BiNGO" (Biological networks gene ontology tool) of the Cytoscape. The key genes were mostly enriched in the biological process of positive regulation of the cellular process. The protein-protein interaction and co-expression network were analyzed by the STRING (search tool for the retrieval of interacting genes/proteins) and GeneMANIA (gene multiple association network integration algorithm) plugin of Cytoscape, respectively, which showed that Epidermal growth factor (EGF), Heparin-binding EGF like growth factor (HBEGF), and Matrix metalloproteinase 9 (MMP9) were at the core of the network. Further validation of key genes using two datasets showed that Phosphodiesterase 5A (PDE5A) and Protein S (PROS1) were decreased in unstable plaques, while Suppressor of cytokine signaling (SOCS3), HBEGF, and Leukocyte immunoglobulin-like receptor B4 (LILRB4) were increased. CONCLUSION: The present study used several datasets to identify key genes associated with stable and unstable atherosclerotic plaque.