The vicious circle of chronic kidney disease and hypertriglyceridemia: What is first, the hen or the egg?

Chronic kidney disease (CKD) is documented to cause alterations in lipid metabolism, and this was considered a potent driver of increased cardiovascular risk. Among the diverse alteration of lipid traits in CKD, research endeavours have predominantly concentrated on low-density lipoproteins (LDL) in view of the potent pro-atherogenic role of these lipoprotein particles and the demonstration of protective cardiovascular effect of reducing LDL. However, few studies have focused on the metabolism of triglyceride-rich lipoproteins and even fewer on their role in causing kidney damage.

Cortical areas associated to higher cognition drove primate brain evolution.

Although intense research effort is seeking to address which brain areas fire and connect to each other to produce complex behaviors in a few living primates, little is known about their evolution, and which brain areas or facets of cognition were favored by natural selection. By developing statistical tools to study the evolution of the brain cortex at the fine scale, we found that rapid cortical expansion in the prefrontal region took place early on during the evolution of primates. In anthropoids, fast-expanding cortical areas extended to the posterior parietal cortex.

Protocol for oil red O staining of low-density lipoproteins for in vivo cell treatment.

Low-density lipoproteins (LDLs) are the most abundant circulating lipoproteins and the most critical factor in the development of atherosclerosis. This protocol allows the staining of LDLs with oil red O to monitor particle uptake in bright-field microscopy. Here, we describe how to stain isolated LDLs using oil red O and how to use them to monitor LDL uptake in time-lapse experiments or fixed cells.

Genetic heterogeneity of familial hypercholesterolaemia in two populations from two different countries.

Background: Familial hypercholesterolemia (FH) is a genetically determined monogenic disorder of predominantly autosomal dominant inheritance. A number of studies on differences in the genetic profile of patients with FH have demonstrated the importance of a more substantive evaluation of genetic features. The aim of this study was to evaluate the genetic profile of patients with clinical FH among Italian and Russian patients.

ANGPTL3 Deficiency and Risk of Hepatic Steatosis.

Background: ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3.

The heterogeneous cellular landscape of atherosclerosis: Implications for future research and therapies. A collaborative review from the EAS young fellows.

Single cell technologies, lineage tracing mouse models and advanced imaging techniques unequivocally improved the resolution of the cellular landscape of atherosclerosis. Although the discovery of the heterogeneous nature of the cellular plaque architecture has undoubtedly improved our understanding of the specific cellular states in atherosclerosis progression, it also adds more complexity to current and future research and will change how we approach future drug development. In this review, we will discuss how the revolution of new single cell technologies allowed us to map the cellular networks in the plaque, but we will also address current (technological) limitations that confine us to identify the cellular drivers of the disease and to pinpoint a specific cell state, cell subset or cell surface antigen as new candidate drug target for atherosclerosis.

Effectiveness of clinical scores in predicting coronary artery disease in familial hypercholesterolemia: a coronary computed tomography angiography study.

Purpose: One of the major challenges in the management of familial hypercholesterolemia (FH) is the stratification of cardiovascular risk in asymptomatic subjects. Our purpose is to investigate the performance of clinical scoring systems, Montreal-FH-score (MFHS), SAFEHEART risk (SAFEHEART-RE) and FH risk score (FHRS) equations and Dutch Lipid Clinic Network (DLCN) diagnostic score, in predicting extent and severity of CAD at coronary computed tomography angiography (CCTA) in asymptomatic FH.

Material And Methods: One-hundred and thirty-nine asymptomatic FH subjects were prospectively enrolled to perform CCTA.

How ANGPTL3 Inhibition Will Help Our Clinical Practice?

Purpose Of Review: This review aims to summarize the most recently published literature highlighting the potential of pharmacological inhibition of ANGPTL3 in treating patients suffering from dyslipidemias. The rational for this strategy will be discussed considering evidence describing the role of ANGPTL3 in lipid metabolism and the consequences of its deficiency in humans.

Recent Findings: Recent trials have demonstrated the efficacy and safety of ANGPTL3 inhibition in treating homozygous familial hypercholesterolemia even in those patients carrying biallelic null/null variants, thus supporting the notion that the LDL-lowering effect of ANGPLT3 inhibition is LDLR-independent.

Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study.

Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH.

The Fibrinogen-like Domain of ANGPTL3 Facilitates Lipolysis in 3T3-L1 Cells by Activating the Intracellular Erk Pathway.

Background: ANGPTL3 stimulates lipolysis in adipocytes, but the underlying molecular mechanism is yet unknown. The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) activates the AKT pathway in endothelial cells. Hence, we evaluated whether ANGPTL3-Fld stimulates lipolysis in adipocytes through the MAPK kinase pathway.

Metabolic Syndrome but Not Fatty Liver-Associated Genetic Variants Correlates with Glomerular Renal Function Decline in Patients with Non-Alcoholic Fatty Liver Disease.

The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in non-metabolic adults and children, but the genetic impact on NAFLD-CKD association is still a matter of debate. The aim of the study was to investigate the impact of PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and glucokinase regulatory protein (GCKR) gene variants rather than metabolic syndrome features on renal function in a large population of NAFLD patients.

Deep Resequencing of 9 Candidate Genes Identifies a Role for ARAP1 and IGF2BP2 in Modulating Insulin Secretion Adjusted for Insulin Resistance in Obese Southern Europeans.

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1-5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.

Efficacy and safety of lomitapide in homozygous familial hypercholesterolaemia: the pan-European retrospective observational study.

Aims: Lomitapide is a lipid-lowering agent indicated as an adjunct therapy for adult homozygous familial hypercholesterolaemia (HoFH). This study evaluated the medium-term effectiveness and safety of lomitapide in a large cohort of HoFH patients in Europe.

Methods And Results: In a multicentre retrospective, observational study including 75 HoFH patients treated with lomitapide in a real-world clinical setting from 9 European countries, low-density lipoprotein cholesterol (LDL-C) changes, adverse events (AEs), and major adverse cardiovascular events (MACE) were assessed.

Refinement of pathogenicity classification of variants associated with familial hypercholesterolemia: Implications for clinical diagnosis.

Background: The lack of functional evidence for most variants detected during the molecular screening of patients with clinical familial hypercholesterolemia (FH) makes the definitive diagnosis difficult.

Methods: A total of 552 variants in LDLR, APOB, PCSK9 and LDLRAP1 genes found in 449 mutation-positive FH (FH/M+) patients were considered. Pathogenicity update was performed following the American College of Medical Genetics and Genomics (ACMG) guidelines with additional specifications on copy number variants, functional studies, in silico prediction and co-segregation criteria for LDLR, APOB and PCSK9 genes.

Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long-Term Response to Treatment, Coronary Atherosclerosis Burden, and Cardiovascular Events.

Background Familial hypercholesterolemia (FH) may arise from deleterious monogenic variants in FH-causing genes as well as from a polygenic cause. We evaluated the relationships between monogenic FH and polygenic hypercholesterolemia in influencing the long-term response to therapy and the risk of atherosclerosis. Methods and Results A cohort of 370 patients with clinically diagnosed FH were screened for monogenic mutations and a low-density lipoprotein-rising genetic risk score >0.

Elevated Serum Concentrations of Remnant Cholesterol Associate with Increased Carotid Intima-Media Thickness in Children and Adolescents.

Objective: To evaluate the relationship between remnant cholesterol and carotid intima-media thickness (cIMT), a surrogate marker for atherosclerosis, in children and adolescents.

Study Design: Anthropometric, laboratory, liver, and carotid ultrasonographic data were obtained from 767 youths (594, overweight/obese; 173, normal weight). Fasting remnant cholesterol was calculated from the standard lipid profile.