High-Density Lipoproteins Annema, Wijtske; Eckardstein, Arnold von
Circulation Journal,
2013, Letnik:
77, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary artery disease (CAD). HDL particles exert many effects in vitro and in vivo that may ...protect arteries from chemical or biological harm or facilitate repair of injuries. Nevertheless, HDL has not yet been successfully exploited for therapy. One potential reason for this shortfall is the structural and functional complexity of HDL particles, which carry more than 80 different proteins and more than 200 lipid species as well as several microRNAs and other potentially bioactive molecules. This physiological heterogeneity is further increased in several inflammatory conditions that increase cardiovascular risk, including CAD itself but also diabetes mellitus, chronic kidney disease, and rheumatic diseases. The quantitative and qualitative modifications of the proteome and lipidome, as well as the resulting loss of functions or gain of dysfunctions, are not recovered by the biomarker HDL-cholesterol. As yet the relative importance of the many physiological and pathological activities of normal and dysfunctional HDL, respectively, for the pathogenesis of atherosclerosis is unknown. The answer to this question, as well as detailed knowledge of structure-function-relationships of HDL-associated molecules, is a prerequisite to exploit HDL for the development of anti-atherogenic drugs as well as of diagnostic biomarkers for the identification, personalized treatment stratification, and monitoring of patients at increased cardiovascular risk. (Circ J 2013; 77: 2432–2448)
Acute aortic dissection is a rare but life-threatening condition with a lethality rate of 1 to 2% per hour after onset of symptoms in untreated patients. Therefore, its prompt and proper diagnosis is ...vital to increase a patient's chance of survival and to prevent grievous complications. Typical symptoms of acute aortic dissection include severe chest pain, hypotension or syncope and, hence, mimic acute myocardial infarction or pulmonary embolism. Advanced age, male gender, long-term history of arterial hypertension and the presence of aortic aneurysm confer the greatest population attributable risk. However, patients with genetic connective tissue disorders such as Marfan, Loeys Dietz or Ehlers Danlos syndrome, and patients with bicuspid aortic valves are at the increased risk of aortic dissection at a much younger age. Imaging provides a robust foundation for diagnosing acute aortic dissection, as well as for monitoring of patients at increased risk of aortic disease. As yet, easily accessible blood tests play only a small role but have the potential to make diagnosis and monitoring of patients simpler and more cost-effective.
Low high-density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C ...is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect high-density lipoprotein (HDL) function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target. HDLs comprise distinct subpopulations of particles of varying size, charge, and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and antidiabetic properties. HDLs can be anti-inflammatory (which may protect against atherosclerosis and diabetes) and proinflammatory (which may help clear pathogens in sepsis). The molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and noncoding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A through I) have revealed nonlinear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus noncoronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers (namely, cholesterol efflux capacity) are associated with coronary disease, but they remain research tools. Therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None has proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.
This open access book is supported by the European Atherosclerosis Society Association (EAS). This follow-up edition of the well-received Handbook volume 'Atherosclerosis: Diet and Drugs' reflects ...the state-of-the-art and most recent developments in atherosclerosis research. Outstanding international experts give a comprehensive overview of the field covering topics, such as improving the treatment focusing on established targets, novel drug developments addressing pre-defined targets, hypothesis-based and hypothesis-free approaches to unravel novel targets.
To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting ...lipid profiles.
Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant +0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hypercholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterolemia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) >150 mg/dL (99th percentile).
We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive.
Endothelial injury and dysfunction (ED) represent a link between cardiovascular risk factors promoting hypertension and atherosclerosis, the leading cause of death in Western populations. ...High-density lipoprotein (HDL) is considered antiatherogenic and known to prevent ED. Using HDL from children and adults with chronic kidney dysfunction (HDLCKD), a population with high cardiovascular risk, we have demonstrated that HDLCKD in contrast to HDLHealthy promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDLCKD that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDLCKD reduced endothelial NO availability via toll-like receptor-2 (TLR-2), leading to impaired endothelial repair, increased proinflammatory activation, and ABP. These data demonstrate how SDMA can modify the HDL particle to mimic a damage-associated molecular pattern that activates TLR-2 via a TLR-1- or TLR-6-coreceptor-independent pathway, linking abnormal HDL to innate immunity, ED, and hypertension.
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► HDLCKD inhibits endothelial NO and increases oxidant stress and inflammation via TLR-2 ► TLR-2 deficiency prevents increased arterial blood pressure in response to HDLCKD ► HDL-SDMA mediates adverse endothelial effects of HDLCKD by TLR-2 activation ► HDLCKD activates TLR2 via a TLR-1- or TLR-6-coreceptor-independent pathway
We sought to identify circulating microRNAs as biomarkers of prevalent or incident diabetes. In a pilot study of 18 sex- and age-matched patients with metabolic syndrome, nine of whom developed ...diabetes during 6 years of follow-up, an array of 372 microRNAs discovered significantly elevated serum levels of microRNAs -122, -192, -194, and -215 in patients who developed diabetes mellitus type 2 (T2DM). In two cross-sectional validation studies, one encompassing sex- and age-matched groups of patients with T2DM, impaired fasting glucose (IFG) and euglycemic controls (n = 43 each) and the other 53 patients with type 1 diabetes and 54 age- and BMI-matched euglycemic controls, serum levels of miR-192, miR-194, and mi215 were significantly higher in diabetic subjects than in probands with euglycemia or IFG. In a longitudinal study of 213 initially diabetes-free patients of whom 35 developed diabetes during 6 years of follow-up, elevated serum levels of microRNAs 192 and 194 were associated with incident T2DM, independently of fasting glucose, HbA1c and other risk factors. Serum levels of miR-192 and miR-194 were also elevated in diabetic Akt2 knockout mice compared to wild type mice. In conclusion, circulating microRNAs -192 and -194 are potential biomarkers for risk of diabetes.
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