Current opinion in lipidology最新文献

Purpose of review: Inflammation is gaining attention as a target for prevention of atherosclerotic cardiovascular disease (ASCVD). The purpose of this review is to compare the evidence for inflammation with the evidence for low-density lipoprotein (LDL) cholesterol in ASCVD.

Recent findings: Evidence from human genetic studies and randomized controlled trials implicate the inflammatory pathway from the inflammasome through interleukin (IL)-1 to IL-6 as a cause of ASCVD. Higher levels of IL-6 may lead to proportionally increased risk of ASCVD, and randomized controlled trials of IL-6 inhibitors are underway. The causal evidence for LDL cholesterol in ASCVD is overwhelming and recent important findings instead revolve around development of improved LDL cholesterol lowering therapy through RNA and DNA based therapeutics. Even though some lipid-lowering therapies lower IL-6, the IL-6 inflammatory pathway and LDL cholesterol are two separate causes of ASCVD.

Summary: IL-6 mediated inflammation most likely causes ASCVD, in parallel with LDL cholesterol. However, fewer individuals in the general population are exposed to high IL-6 than high LDL cholesterol. For inflammation, future research should focus on improving efficacy and safety of anti-inflammatory therapy, and for LDL cholesterol, future research should focus on wider and more effective implementation of LDL cholesterol lowering therapy.

Purpose of review: Exosomes are lipid-bound particles that carry lipids, protein, and nucleic acid and affect cellular function. This review highlights the current knowledge on the crosstalk between exosomes and lipid metabolism and their impact on cardiometabolic disease.

Recent findings: Recent studies revealed that lipids and lipid metabolizing enzymes are important for exosome biogenesis and internalization and conversely how exosomes affect lipid metabolism, secretion, and degradation. The interplay between exosomes and lipid metabolism affects disease pathophysiology. More importantly, exosomes and lipids might function as biomarkers for diagnosis and prognosis or possibly therapies.

Summary: Recent advances in our understanding of exosomes and lipid metabolism have implications for our understanding of normal cellular and physiological functions as well as disease pathogenesis. Exosome and lipid metabolism have implications in novel diagnostic tests and treatments of cardiometabolic disease.

Purpose of review: Genetic lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare, inherited, recessive disease, which manifests as two different syndromes: Familial LCAT deficiency (FLD) and Fish-eye disease (FED), characterized by low HDL-C and corneal opacity. FLD patients also develop anaemia and renal disease. There is currently no therapy for FLD, but novel therapeutics are at different stages of development. Here, we summarize the most recent advances and the opportunities for and barriers to the further development of such therapies.

Recent findings: Recent publications highlight the heterogeneous phenotype of FLD and the uncertainty over the natural history of disease and the factors contributing to disease progression. Therapies that restore LCAT function (protein and gene replacement therapies and LCAT activators) showed promising effects on markers of LCAT activity. Although they do not restore LCAT function, HDL mimetics may slow renal disease progression.

Summary: The further development of novel therapeutics requires the identification of efficacy endpoints, which include quantitative biomarkers of disease progression. Because of the heterogeneity of renal disease progression among FLD individuals, future treatments for FLD will have to be tailored based on the specific clinical characteristics of the patient. Extensive studies of the natural history and biomarkers of the disease will be required to achieve this goal.

Purpose of review: Familial hypercholesterolemia (FH) is a monogenic disorder of elevated low-density lipoprotein cholesterol (LDL-C) from birth leading to increased risk for atherosclerotic cardiovascular disease. However, not all carriers of FH variants display an FH phenotype. Despite this fact, FH variants confer increased risk for atherosclerotic disease in population cohorts. An important question to consider is whether measurements of LDL-C can fully account for this risk.

Recent findings: The atherosclerotic risk associated with FH variants is independent of observed adult LDL-C levels. Modeling adult longitudinal LDL-C accounts for more of this risk compared to using a single measurement. Still, even when adjusting for observed longitudinal LDL-C in adult cohorts, FH variant carriers are at increased risk for coronary artery disease. Genetic analyses, observational studies, and clinical trials all suggest that cumulative LDL-C is a critical driver of cardiovascular risk that may not be fully appreciated by routine LDL-C measurements in adulthood. As such, FH variants confer risk independent of adult LDL-C because these variants increase cumulative LDL-C exposure starting from birth.

Summary: Both research and clinical practice focus on LDL-C measurements in adults, but measurements during adulthood do not reflect lifelong cumulative exposure to LDL-C. Genetic assessments may compliment clinical assessments by better identifying patients who have experienced greater longitudinal LDL-C exposure.

Purpose of review: Combined hyperlipidemia is the most common lipid disorder and is strongly polygenic. Given its prevalence and associated risk for atherosclerotic cardiovascular disease, this review describes the potential for utilizing polygenic risk scores for risk prediction and management of combined hyperlipidemia.

Recent findings: Different diagnostic criteria have led to inconsistent prevalence estimates and missed diagnoses. Given that individuals with combined hyperlipidemia have risk estimates for incident coronary artery disease similar to individuals with familial hypercholesterolemia, early identification and therapeutic management of those affected is crucial. With diagnostic criteria including traits such apolipoprotein B, low-density lipoprotein cholesterol, and triglyceride, polygenic risk scores for these traits strongly associate with combined hyperlipidemia and could be used in combination for clinical risk prediction models and developing specific treatment plans for patients.

Summary: Polygenic risk scores are effective tools in risk prediction of combined hyperlipidemia, can provide insight into disease pathophysiology, and may be useful in managing and guiding treatment plans for patients. However, efforts to ensure equitable polygenic risk score performance across different genetic ancestry groups is necessary before clinical implementation in order to prevent the exacerbation of racial disparities in the clinic.

Purpose of review: Sepsis is the extreme response to infection associated with high mortality, yet reliable biomarkers for its identification and stratification are lacking.

Recent findings: Our scoping review of studies published from January 2017 to September 2022 that investigated circulating protein and lipid markers to inform non-COVID-19 sepsis diagnosis and prognosis identified interleukin (IL)-6, IL-8, heparin-binding protein (HBP), and angiopoietin-2 as having the most evidence. Biomarkers can be grouped according to sepsis pathobiology to inform biological data interpretation and four such physiologic processes include: immune regulation, endothelial injury and coagulopathy, cellular injury, and organ injury. Relative to proteins, the pleiotropic effects of lipid species' render their categorization more difficult. Circulating lipids are relatively less well studied in sepsis, however, low high-density lipoprotein (HDL) is associated with poor outcome.

Summary: There is a lack of robust, large, and multicenter studies to support the routine use of circulating proteins and lipids for sepsis diagnosis or prognosis. Future studies will benefit from standardizing cohort design as well as analytical and reporting strategies. Incorporating biomarker dynamic changes and clinical data in statistical modeling may improve specificity for sepsis diagnosis and prognosis. To guide future clinical decisions at the bedside, point-of-care circulating biomarker quantification is needed.

Purpose of review: Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to pancreatitis.

Recent findings: Genetic determinants of pancreatitis include: rare Mendelian disorders caused by highly penetrant pathogenic variants in genes involved in trypsinogen activation; uncommon susceptibility variants in genes involved in trypsinogen activation, protein misfolding as well as calcium metabolism and cystic fibrosis, that have variable penetrance and show a range of odds ratios for pancreatitis; and common polymorphisms in many of the same genes that have only a small effect on risk. The role of these genetic variants in modulating pancreatitis risk in hypertriglyceridemia is unclear. However, among genetic determinants of plasma triglycerides, those predisposing to more severe hypertriglyceridemia associated with chylomicronemia appear to have higher pancreatitis risk.

Summary: Currently, among patients with severe hypertriglyceridemia, the most consistent predictor of pancreatitis risk is the triglyceride level. Furthermore, pancreatitis risk appears to be modulated by a higher genetic burden of factors associated with greater magnitude of triglyceride elevation. The role of common and rare genetic determinants of pancreatitis itself in this metabolic context is unclear.

Purpose of review: The aim is to provide an update on omega-3 polyunsaturated fatty acids (n-3 PUFA) in preventing cognitive decline and dementia.

Recent findings: Prospective studies and three new meta-analyses suggest that fish or n-3 PUFA intake are associated with a reduction in development of mild cognitive decline and Alzheimer's disease. Supplementation with docosahexaenoic acid (DHA) in randomized controlled trials (RCTs) in those with mild cognitive impairment showed benefit on cognitive decline, whereas there was no benefit in Alzheimer's disease. In cognitively healthy individuals with clinical coronary artery disease (CAD), 3.36 g EPA and DHA daily slowed cognitive ageing by 2.5 years. Of 15 RCTs in cognitively healthy individuals age more than 55 years, seven reported benefit, whereas eight did not. Potential mechanisms for differences in outcomes include dose, trial duration, apolipoproteinE genotype, sex, stage and rate of cognitive decline, cognitive testing employed and individual characteristics. The downstream product of DHA, neuroprotectin D1, may be involved in beneficial effects.

Summary: Patients with early memory complaints or a family history of dementia and those with CAD should be counselled on the potential benefits of fish intake and supplementation with n-3 PUFA. ApolipoproteinE4 carriers may especially benefit from DHA supplementation prior to development of cognitive decline.