Dysfunctional High-density Lipoprotein Research Articles

High-Density Lipoprotein Modifications: Causes and Functional Consequences in Type 2 Diabetes Mellitus.

High-density lipoprotein (HDL) is a group of small, dense, and protein-rich lipoproteins that play a role in cholesterol metabolism and various cellular processes. Decreased levels of HDL and HDL dysfunction are commonly observed in individuals with type 2 diabetes mellitus (T2DM), which is also associated with an increased risk for cardiovascular disease (CVD). Due to hyperglycemia, oxidative stress, and inflammation that develop in T2DM, HDL undergoes several post-translational modifications such as glycation, oxidation, and carbamylation, as well as other alterations in its lipid and protein composition. It is increasingly recognized that the generation of HDL modifications in T2DM seems to be the main cause of HDL dysfunction and may in turn influence the development and progression of T2DM and its related cardiovascular complications. This review provides a general introduction to HDL structure and function and summarizes the main modifications of HDL that occur in T2DM. Furthermore, the potential impact of HDL modifications on the pathogenesis of T2DM and CVD, based on the altered interactions between modified HDL and various cell types that are involved in glucose homeostasis and atherosclerotic plaque generation, will be discussed. In addition, some perspectives for future research regarding the T2DM-related HDL modifications are addressed.

Lipoprotein dysfunction in patients with chronic kidney disease (CKD). Pathogenesis and treatment of CKD dyslipidemia (literature review)

Dyslipidemia develops in the initial stages of chronic kidney disease (CKD) and worsens as nephropathy progresses. The main manifestation of dyslipidemia is hypercholesterolemia, especially in nephrotic syndrome. However, with CKD of stages 4-5, it is replaced by hypertriglyceridemia in combination with an increase in blood levels of lipoproteins low and very low density. Such changes are closely related to the development of cardiovascular pathology with high mortality. The content of high-density lipoproteins (HDL) in the blood is gradually decreasing, as well as the reversible transport of cholesterol. Thus, their anti-atherogenic, antioxidant and anti-inflammatory functions are lost. The main components of HDL – apolipoproteins ApoA-I and ApoA-II, which provide functionality, are replaced by acute-phase proteins, and HDL lose their cardioprotective potential and acquire a proinflammatory and proatherogenic phenotype. According to modern concepts, HDL dysfunction, along with metabolic shifts, is largely due to epigenetic disorders affecting gene expression and partially eliminated by prescribing drugs containing microRNAs (mRNAs) or antisense nucleotides. Drugs with interfering RNAs created in recent years have been successfully used not only for the treatment of dyslipidemia in nephrological patients, but also in patients with neoplastic processes, inflammatory arthritis, degenerative diseases of the central nervous system, porphyria, hemophilia and many other diseases. The proposed review is devoted to the mechanisms of disorders of the structure and functions of HDL in patients with CKD and the correction of these disorders.

Relationship between pattern reversal visual evoked potential P100 wave latency and dysfunctional HDL in patients with multiple sclerosis subjected to an optic neuritis attack: A case-control study.

Optic neuritis frequently occurs during the clinical course of multiple sclerosis (MS). In this condition, demyelination of the optic nerve occurs, which electrophysiologically causes a delay in P100 wave latency. Sensitive cholesterol homeostasis is critical for the formation of the myelin sheath and for myelin to become functionally mature. High-density lipoprotein (HDL) becomes dysfunctional under oxidative stress and plays an important role in the pathogenesis of MS. In this study, HDL levels of MS patients suffering from optic neuritis were compared with those of healthy individuals, and the relationship between pattern reversal visual evoked potential (PRVEP) P100 wave latency and HDL levels in patients with optic neuritis attacks was analyzed. PRVEP studies were performed in patients with MS who had an episode of optic neuritis, and P100 wave latencies were measured. Peripheral blood samples were collected from healthy participants and patients. Lipid levels and myeloperoxidase (MPO) and paraoxonase (PON) activities were measured, and the MPO/PON ratio was then calculated. The lipid profiles and dysfunctional HDL levels in the healthy and patient groups were compared. Finally, the relationship between these parameters and the PRVEP-P100 wave latency was examined. Total cholesterol and low-density lipoprotein (LDL) levels were significantly higher in the patient group (P = .044; P = .038, respectively). There was no statistically significant difference in HDL levels between groups (P = .659). The distribution of MPO values was similar between groups (P = .452). PON values were significantly lower, whereas the MPO/PON ratios were significantly higher in the patient group than in the control group (P = .025; P = .028, respectively). A statistically significant positive correlation was found between the elevated MPO/PON ratio, representing dysfunctional HDL, and both the mean and maximum PRVEP-P100 wave latencies (P < .001, R = 0.690; P < .001, R = 0.815, respectively). A dysfunctional form of HDL may lead to poor deactivation of remyelination-limiting factors and may ultimately be associated with poor outcomes in optic neuritis.

Type 2 Diabetes and HDL Dysfunction: A Key Contributor to Glycemic Control.

High-density lipoproteins (HDL) have been shown to exert multiple cardioprotective and antidiabetic functions, such as their ability to promote cellular cholesterol efflux and their antioxidant, anti-inflammatory, and antiapoptotic properties. Type 2 diabetes (T2D) is usually associated with low high-density lipoprotein cholesterol (HDL-C) levels as well as with significant alterations in the HDL composition, thereby impairing its main functions. HDL dysfunction also negatively impacts both pancreatic β-cell function and skeletal muscle insulin sensitivity, perpetuating this adverse self-feeding cycle. The impairment of these pathways is partly dependent on cellular ATP-binding cassette transporter (ABC) A1-mediated efflux to lipid-poor apolipoprotein (apo) A-I in the extracellular space. In line with these findings, experimental interventions aimed at improving HDL functions, such as infusions of synthetic HDL or lipid-poor apoA-I, significantly improved glycemic control in T2D patients and experimental models of the disease. Cholesteryl ester transfer protein (CETP) inhibitors are specific drugs designed to increase HDLC and HDL functions. Posthoc analyses of large clinical trials with CETP inhibitors have demonstrated their potential anti-diabetic properties. Research on HDL functionality and HDL-based therapies could be a crucial step toward improved glycemic control in T2D subjects.

Oxidized high-density lipoprotein associates with atrial fibrillation

BackgroundAtrial fibrillation (AF) is the most common heart arrhythmia and considered to be a progressive chronic disease associated with increased morbidity and mortality. Recent data suggest a link between inflammation, oxidative stress, and AF, although the underlying mechanisms are not fully understood. Because oxidized lipoproteins cause structural damage and electrophysiologic changes in cardiomyocytes, it is feasible that the transformation of atheroprotective high-density lipoprotein (HDL) into dysfunctional HDL contributes to the development of AF. ObjectiveThe purpose of this study was to determine whether a reduced antioxidant function of HDL is associated with the presence of AF. MethodsIn this multicenter cross-sectional cohort study, we assessed HDL function in sera of 1206 participants. Patients were divided into groups according to the presence of AF (n = 233) or no AF (n = 973). A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function as assessed by increased normalized HDL lipid peroxide content (nHDLox). ResultsParticipants with AF had a 9% higher mean relative nHDLox compared to persons without AF (P = .025). nHDLox was strongly associated with AF in all models of logistic regression, including the analysis adjusted for age, sex, and risk factors for AF (all P ≤.01). ConclusionReduced antioxidant HDL function is associated with the presence of AF, which supports growing evidence that impaired lipoprotein function is linked to electrophysiological changes in cardiomyocytes. nHDLox is one of several contributors to the initiation and perpetuation of AF.

S1P content as a characteristic of the cardioprotective properties of HDL in coronary heart disease and diabetes mellitus

Abstract Background Many basic science studies have demonstrated the cardioprotective effect of high-density lipoprotein (HDL). At the same time, several clinical studies in which plasma levels of HDL were pharmacologically increased showed no benefit in cardiovascular risk patients. Accordingly, HDL quantity seems to be less important than HDL quality. Many beneficial effects of HDL are attributed to the bioactive sphingolipid S1P in HDL (HDL-S1P). Purpose In this study, we are now investigating a) the cardioprotective properties of HDL of different patient groups and b) the possibility of loading S1P to restore cardioprotection that may be lacking. Methods HDL was extracted from plasma of diabetic (dmHDL), as well as CHD patients (CHD-HDL) and healthy subjects (healthy HDL) of the same age by ultracentrifugation and injected i.v. into the mouse five minutes before 30 minutes of ischemia (43 mg/KG). This was followed by 24 hours of reperfusion. Systolic cardiac function was determined by ultrasound, infarct size by TTC (2,3,5-triphenyltetrazolium chloride) staining, and S1P levels by mass spectrometry. The level of apolipoprotein M in HDL was determined by ELISA. Results Mice treated with healthy HDL showed smaller infarct size and improved ejection fraction (EF) after I/R than control mice (IS: control 42.95±7.40% [n=26] vs. healthy HDL 33.15±4.68% [n=16], p=0.0001; EF: control 33.68±4.49% vs. healthy HDL 40.00±5.74%, p=0.0016). Treatment with CHD-HDL or dmHDL showed no cardioprotective effects compared to control mice (IS: CHD-HDL 42.22±6.53% [n=16], p=0.9863; dmHDL 43.67±7.81% [n=12], p=0.9899). In both cases, the lack of cardioprotection is associated with lowered HDL-S1P levels (total HDL 210.6±32.6 pmol/mg; CHD-HDL 157.6±49.0 pmol/mg, p=0.0073; dmHDL 171.1±64.7 pmol/mg, p=0.0176). Loading the "sick" HDL with S1P restores cardioprotection only in CHD-HDL (IS: CHD-HDL 42.22±6.53% [n=16] vs. CHD-HDL loaded 32.03±6.45% [n=10], p=0.0023), but not in dmHDL (IS: dmHDL 43.67±7.81% [n=12] vs. dmHDL loaded 38.44±5.98% [n=7], p=0.5110). The very low level of apolipoprotein M (ApoM), responsible for S1P binding, could be a reason for this (total HDL 23.45±6.23 µg/mg [n=15] vs. dmHDL 13.79±4.72 µg/mg [n=14], p=0.0007). Conclusion We highlighted worsened cardioprotection as another characteristic of HDL dysfunction in CHD and in diabetes. This characteristic was based on a lower HDL-S1P content and could be therapeutically corrected by loading S1P in the case of CHD-HDL. A low content of ApoM in dmHDL may prevent successful restoration of cardioprotection by S1P loading.

High-density lipoprotein dysfunction in carotid artery stenosis.

Background: High density lipoprotein (HDL) is well established to have an athero-protective role under normal conditions; however, pro-inflammatory alteration of HDL proteins may transform the HDL particle into a dysfunctional molecule. Our aim was to investigate HDL dysfunction by measuring enzyme-based markers in carotid artery stenosis (CAS). Patients and methods: All participants underwent duplex ultrasound and 52 subjects diagnosed with CAS and 51 subjects who had no significant stenosis (as controls) were enrolled in this study. Serum lipid profiles and serum parameters associated with dysfunctional HDL including myeloperoxidase (MPO), paraoxonase 1 (PON1), arylesterase (ARE) activity, and lipid hydroperoxide (LOOH) levels were measured. Results: It was found that the patients with CAS had increased levels of MPO and LOOH while PON1 activity was decreased. There was no significant difference between the CAS and non-CAS groups in terms of HDL levels. MPO/PON1, MPO/ARE, and LOOH/PON1 ratios were significantly increased in the CAS group. MPO/PON1 and MPO/ARE ratios both demonstrated significant correlations with degree of stenosis (%). Conclusions: The MPO/PON1 and MPO/ARE ratios may be potential serum markers that can enable the monitoring of HDL functionality and the assessment of atherosclerotic disease risks. Additionally, monitoring the oxidative balance of lipids on HDL molecules by LOOH/PON1 ratio may have value in the early detection of pro-atherosclerotic transformation of the HDL particle.

The persistent inflammation, immunosuppression, and catabolism syndrome 10 years later.

With the implementation of new intensive care unit (ICU) therapies in the 1970s, multiple organ failure (MOF) emerged as a fulminant inflammatory phenotype leading to early ICU death. Over the ensuing decades, with fundamental advances in care, this syndrome has evolved into a lingering phenotype of chronic critical illness (CCI) leading to indolent late post-hospital discharge death. In 2012, the University of Florida (UF) Sepsis Critical Illness Research Center (SCIRC) coined the term Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) to provide a mechanistic framework to study CCI in surgical patients. This was followed by a decade of research into PICS-CCI in surgical ICU patients in order to define the epidemiology, dysregulated immunity, and long-term outcomes after sepsis. Other focused studies were performed in trauma ICU patients and emergency department sepsis patients. Early deaths were surprisingly low (4%); 63% experienced rapid recovery. Unfortunately, 33% progressed to CCI, of which 79% had a poor post-discharge disposition and 41% were dead within one year. These patients had biomarker evidence of PICS, and these biomarkers enhanced clinical prediction models for dismal one-year outcomes. Emergency myelopoiesis appears to play a central role in the observed persistent immune dysregulation that characterizes PICS-CCI. Older patients were especially vulnerable. Disturbingly, over half of the older CCI patients were dead within one year and older CCI survivors remained severely disabled. Although CCI is less frequent (20%) after major trauma, PICS appears to be a valid concept. This review will specifically detail the epidemiology of CCI, PICS biomarkers, effect of site of infection, acute kidney injury, effect on older patients, dysfunctional high-density lipoproteins, sarcopenia/cachexia, emergency myelopoiesis, dysregulated erythropoiesis, and potential therapeutic interventions.

High-Density Lipoprotein Lipidomics and Mortality in CKD

Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles that lack cardioprotective properties; altered lipid composition may be associated with these changes. To investigate HDL lipids as potential cardiovascular risk factors in CKD, we tested the associations of HDL ceramides, sphingomyelins, and phosphatidylcholines with mortality. We leveraged data from a longitudinal prospective cohort of participants with CKD. We included participants aged greater than 21 years with CKD, excluding those on maintenance dialysis or with prior kidney transplant. HDL particles were isolated using density gradient ultracentrifugation. We quantified the relative abundance of HDL ceramides, sphingomyelins, and phosphatidylcholines via liquid chromatography tandem mass spectrometry (LC-MS/MS). Our primary outcome was all-cause mortality. We tested associations using Cox regressions adjusted for demographics, comorbid conditions, laboratory values, medication use, and highly correlated lipids with opposed effects, controlling for multiple comparisons with false discovery rates (FDR). There were 168 deaths over a median follow-up of 6.12 years (interquartile range, 3.71-9.32). After adjustment, relative abundance of HDL ceramides (HR, 1.22 per standard deviation; 95% CI, 1.06-1.39), sphingomyelins with long fatty acids (HR, 1.44; 95% CI, 1.05-1.98), and saturated and monounsaturated phosphatidylcholines (HR, 1.22; 95% CI, 1.06-1.41) were significantly associated with increased risk of all-cause mortality (FDR<5%). We were unable to test associations with cardiovascular disease given limited power. HDL lipidomics may not reflect plasma lipidomics. LC-MS/MS is unable to differentiate between glucosylceramides and galactosylceramides. The cohort was comprised of research volunteers in the Seattle area with CKD. Greater relative HDL abundance of 3 classes of lipids was associated with higher risk of all-cause mortality in CKD; sphingomyelins with very long fatty acids were associated with a lower risk. Altered lipid composition of HDL particles may be a novel cardiovascular risk factor in CKD. Patients with chronic kidney disease have abnormal high-density lipoprotein (HDL) particles that lack the beneficial properties associated with these particles in patients with normal kidney function. To investigate if small lipid molecules found on the surface of HDL might be associated with these changes, we tested the associations of lipid molecules found on HDL with death among patients with chronic kidney disease. We found that several lipid molecules found on the surface of HDL were associated with increased risk of death among these patients. These findings suggest that lipid molecules may be risk factors for death among patients with chronic kidney disease.

High-Density Lipoprotein in Metabolic Disorders and Beyond: An Exciting New World Full of Challenges and Opportunities.

High-density lipoprotein (HDL) is an enigmatic member of the plasma lipid and lipoprotein transport system, best known for its ability to promote the reverse cholesterol efflux and the unloading of excess cholesterol from peripheral tissues. More recently, data in experimental mice and humans suggest that HDL may play important novel roles in other physiological processes associated with various metabolic disorders. Important parameters in the HDL functions are its apolipoprotein and lipid content, further reinforcing the principle that HDL structure defines its functionality. Thus, based on current evidence, low levels of HDL-cholesterol (HDL-C) or dysfunctional HDL particles contribute to the development of metabolic diseases such as morbid obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Interestingly, low levels of HDL-C and dysfunctional HDL particles are observed in patients with multiple myeloma and other types of cancer. Therefore, adjusting HDL-C levels within the optimal range and improving HDL particle functionality is expected to benefit such pathological conditions. The failure of previous clinical trials testing various HDL-C-raising pharmaceuticals does not preclude a significant role for HDL in the treatment of atherosclerosis and related metabolic disorders. Those trials were designed on the principle of "the more the better", ignoring the U-shape relationship between HDL-C levels and morbidity and mortality. Thus, many of these pharmaceuticals should be retested in appropriately designed clinical trials. Novel gene-editing-based pharmaceuticals aiming at altering the apolipoprotein composition of HDL are expected to revolutionize the treatment strategies, improving the functionality of dysfunctional HDL.

SARS-CoV-2 induced HDL dysfunction may affect the host's response to and recovery from COVID-19.

Covid-19 is linked with the development of cardio-metabolic disorders, including dyslipidemia, dysregulation of high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Furthermore, SARS-Co-2 infection is associated with noteworthy changes in lipid profile, which is suggested as a possible biomarker to support the diagnosis and management of Covid-19. This paper adopts the literature review method to obtain information about how Covid-19 affects high-risk group patients and may cause severe and critical effects due to the development of acute lung injury and acute respiratory distress syndrome. A narrative and comprehensive review is presented. Reducing HDL in Covid-19 is connected to the disease severity and poor clinical outcomes, suggesting that high HDL serum levels could benefit Covid-19. SARS-CoV-2 binds HDL, and this complex is attached to the co-localized receptors, facilitating viral entry. Therefore, SARS-CoV-2 infection may induce the development of dysfunctional HDL through different mechanisms, including induction of inflammatory and oxidative stress with activation of inflammatory signaling pathways. In turn, the induction of dysfunctional HDL induces the activation of inflammatory signaling pathways and oxidative stress, increasing Covid-19 severity. Covid-19 is linked with the development of cardio-metabolic disorders, including dyslipidemia in general and dysregulation of high-density lipoprotein and low-density lipoprotein. Therefore, the present study aimed to overview the causal relationship between dysfunctional high-density lipoprotein and Covid-19.

CIGB-258 Exerts Potent Anti-Inflammatory Activity against Carboxymethyllysine-Induced Acute Inflammation in Hyperlipidemic Zebrafish via the Protection of Apolipoprotein A-I.

Inflammation and atherosclerosis are intimately associated via the production of dysfunctional high-density lipoproteins (HDL) and modification of apolipoprotein (apo) A-I. A putative interaction between CIGB-258 and apoA-I was investigated to provide mechanistic insight into the protection of HDL. The protective activity of CIGB-258 was tested in the CML-mediated glycation of apoA-I. The in vivo anti-inflammatory efficacy was compared in paralyzed hyperlipidemic zebrafish and its embryo in the presence of CML. Treatment of CML induced greater glycation extent of HDL/apoA-I and proteolytic degradation of apoA-I. In the presence of CML, however, co-treatment of CIGB-258 inhibited the glycation of apoA-I and protected the degradation of apoA-I, exerting enhanced ferric ion reduction ability. Microinjection of CML (500 ng) into zebrafish embryos resulted in acute death with the lowest survivability with severe developmental defects with interleukin (IL)-6 production. Conversely, a co-injection of CIGB-258 or Tocilizumab produced the highest survivability with a normal development speed and morphology. In hyperlipidemic zebrafish, intraperitoneal injection of CML (500 μg) caused the complete loss of swimming ability and severe acute death with only 13% survivability 3 h post-injection. A co-injection of the CIGB-258 resulted in a 2.2-fold faster recovery of swimming ability than CML alone, with higher survivability of approximately 57%. These results suggest that CIGB-258 protected hyperlipidemic zebrafish from the acute neurotoxicity of CML. Histological analysis showed that the CIGB-258 group had 37% lower infiltration of neutrophils in hepatic tissue and 70% lower fatty liver changes than those of the CML-alone group. The CIGB-258 group exhibited the smallest IL-6 expression in the liver and the lowest blood triglyceride level. CIGB-258 displayed potent anti-inflammatory activity in hyperlipidemic zebrafish by inhibiting apoA-I glycation, promoting rapid recovery from the paralysis of CML toxicity and suppression of IL-6, and lowering fatty liver changes.

Evaluation of Dysfunctional HDL by Myeloperoxidase/Paraoxonase Ratio in Unexplained Infertility Patients Undergoing IVF/ICSI

Patients with UEI (study group, n = 40) and male factor infertility (control group, n = 36) were included in this prospective study. Demographics and laboratory assessments were analyzed. Total dosages of gonadotropin were higher in UEI when compared to the control group (p = 0.033). Number of Grade 1 embryos and the quality of blastocysts were lower in UEI than in the control group (p = 0.024, p = 0.020, respectively), whereas serum MPO/PON ratio was higher in UEI (p = 0.042). Stepwise linear regression analysis revealed that serum MPO/PON ratio levels could significantly predict the duration of infertility (p = 0.012). Serum MPO/PON ratio increased in patients with UEI, whereas the number of Grade 1 embryos and the quality of blastocysts decreased. Similar clinical pregnacy rates were found in both groups but the ET on day five is associated with higher clinical pregnancy rate in the male factor infertility.

High-Density Lipoprotein Subfractions Remodeling: A Critical Process for the Treatment of Atherosclerotic Cardiovascular Diseases.

Numerous studies have shown that a low level of high-density lipoprotein cholesterol (HDL-C) is an independent biomarker of cardiovascular disease. High-density lipoprotein (HDL) is considered to be a protective factor for atherosclerosis (AS). Therefore, raising HDL-C has been widely recognized as a promising strategy to treat atherosclerotic cardiovascular diseases (ASCVD). However, several studies have found that increasing HDL-C levels does not necessarily reduce the risk of ASCVD. HDL particles are highly heterogeneous in structure, composition, and biological function. Moreover, HDL particles from atherosclerotic patients exhibit impaired anti-atherogenic functions and these dysfunctional HDL particles might even promote ASCVD. This makes it uncertain that HDL-raising therapy will prevent and treat ASCVD. It is necessary to comprehensively analyze the structure and function of HDL subfractions. We review current advances related to HDL subfractions remodeling and highlight how current lipid-modifying drugs such as niacin, statins, fibrates, and cholesteryl ester transfer protein inhibitors regulate cholesterol concentration of HDL and specific HDL subfractions.

High-Density Lipoprotein Lipidomics in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles as compared with the general population. Understanding the lipid composition of HDL may provide mechanistic insight. We tested associations of estimated glomerular filtration rate (eGFR) and albuminuria with relative HDL abundance of ceramides, sphingomyelins, and phosphatidylcholines in participants with CKD. We studied 490 participants with CKD from the Seattle Kidney Study. HDL was isolated from plasma; targeted lipidomics was used to quantify the relative abundance of ceramides, sphingomyelins, and phosphatidylcholines per 10 µg of total HDL protein. We evaluated the associations of eGFR and albuminuria with levels of individual lipids and lipid classes (including 7 ceramides, 6 sphingomyelins, and 24 phosphatidylcholines) using multivariable linear regression, controlling for multiple comparisons via the false discovery rate. The mean (SD) eGFR was 45 (24) mL/min/1.73 m2; the median (IQR[interquartile range]) albuminuria was 108 (16, 686) mg/g (12.2 [1.8, 77.6] mg/mmol) urine creatinine. After adjusting for demographics, past medical history, laboratory values, and medication use, eGFR was not associated with higher relative abundance of any class of lipids or individual lipids. Greater albuminuria was significantly associated with a higher relative abundance of total ceramides and moderate-long R-chain sphingomyelins, ceramides 22:0 and 24:1, hexosylceramide 16:0, sphingomyelin 16:0, and phosphatidylcholines 29:0, 30:1, and 38:2; the strongest association was for hexosylceramide 16:0 (increase per doubling of urine albumin to creatinine ratio 0.022 (95% CI, 0.012-0.032). Greater albuminuria was significantly associated with specific alterations in the lipid composition of HDL in participants with CKD.

Dysfunctional high-density lipoprotein in chronic inflammatory rheumatic diseases.

The mechanism explaining low cholesterol concentrations in chronic inflammatory rheumatic disease (CIRD) is incompletely understood. We hypothesized that chronic inflammation impairs the functionality of high-density lipoprotein (HDL), for example, by oxidative processes. Assessment of oxidized HDL (HDLox), a marker of dysfunctional HDL, in newly diagnosed patients with CIRD before and after initiation of immunosuppressive therapy and comparison of HDLox values of patients with CIRD to non-CIRD controls. Prospective observational trial. The study was conducted on 44 newly diagnosed CIRD patients, who were initiated on immunosuppressive therapy (baseline). A total of 136 patients without CIRD served as control. Lipid profiles including HDLox levels and C-reactive protein (CRP) were measured in both groups at baseline. In CIRD patients, measurements were repeated 12 weeks after baseline. Validated outcome tools for disease activity and function were assessed at baseline and 12 weeks. A total of 33 (75%) patients with rheumatoid arthritis, 7(16%) with axial spondyloarthritis, and 4 (9%) with systemic lupus erythematosus were included. Groups were comparable for age and BMI. CIRD patients had higher HDLox concentrations (1.57 versus 0.78, p = 0.02) and tended to have lower low-density lipoprotein cholesterol, HDL cholesterol, and cholesterol concentrations compared to controls. HDLox (1.57 versus 1.4, p = 0.26) and CRP levels (2.1 versus 0.7 mg/dl, p < 0.01) decreased in CIRD patients from baseline to follow-up. CIRD is associated with an impairment of the anti-inflammatory properties of HDL as reflected by an increase in HDLox concentrations. This effect may contribute to the increased cardiovascular risk in chronic inflammatory diseases.

Air Pollution: Another Threat to HDL Function.

Epidemiological studies have consistently demonstrated a positive association between exposure to air pollutants and the incidence of cardiovascular disease, with the strongest evidence for particles with a diameter < 2.5 μm (PM2.5). Therefore, air pollution has been included among the modifiable risk factor for cardiovascular outcomes as cardiovascular mortality, acute coronary syndrome, stroke, heart failure, and arrhythmias. Interestingly, the adverse effects of air pollution are more pronounced at higher levels of exposure but were also shown in countries with low levels of air pollution, indicating no apparent safe threshold. It is generally believed that exposure to air pollution in the long-term can accelerate atherosclerosis progression by promoting dyslipidemia, hypertension, and other metabolic disorders due to systemic inflammation and oxidative stress. Regarding high density lipoproteins (HDL), the impact of air pollution on plasma HDL-cholesterol levels is still debated, but there is accumulating evidence that HDL function can be impaired. In particular, the exposure to air pollution has been variably associated with a reduction in their cholesterol efflux capacity, antioxidant and anti-inflammatory potential, and ability to promote the release of nitric oxide. Further studies are needed to fully address the impact of various air pollutants on HDL functions and to elucidate the mechanisms responsible for HDL dysfunction.

A green-inspired method to prepare non-split high-density lipoprotein (HDL) carrier with anti-dysfunctional activities superior to reconstituted HDL

Numerous studies have demonstrated that dysfunctional high-density lipoprotein (HDL), especially oxidized HDL (OxHDL), could generate multifaceted in vivo proatherogenic effects that run counter to the antiatherogenic activities of HDL. It thereby reminded us that the in vitro reconstituted HDL (rHDL) might encountered with oxidation-induced dysfunction. Accordingly, a green-inspired method was employed to recycle non-split HDL from human plasma fraction IV. Then it was compared with rHDL formulated by an ethanol-injection method in terms of physicochemical properties and anti-dysfunctional activities. Results exhibited that rHDL oxidation extent exceeded that of non-split HDL evidenced by higher malondialdehy content, weaker inhibition on low-density lipoprotein (LDL) oxidation and more superoxide anion. The reserved paraoxonase-1 activity on non-split HDL could partially explain for above experimental results. In the targeted transport mechanism experiment, upon SR-BI receptor inhibition and/or CD36 receptor blockage, the almost unchanged non-split HDL uptake in lipid-laden macrophage indicated its negligible oxidation modification profile with regard to rHDL again. Furthermore, compared to rHDL, better macrophage biofunctions were observed for non-split HDL as illustrated by accelerated cholesterol efflux, inhibited oxidized LDL uptake and lessened cellular lipid accumulation. Along with decreased ROS secretion, obviously weakened oxidative stress damage was also detected under treatment with non-split HDL. More importantly, foam cells with non-split HDL-intervention inspired an enhanced inflammation repression and apoptosis inhibition effect. Collectively, the anti-dysfunctional activities of non-split HDL make it suitable as a potential nanocarrier platform for cardiovascular drug payload and delivery.

1026 MYOCARDIAL INFARCTION AND STROKE IN A YOUNG PATIENT AFFECTED BY LES: KEY ROLE OF AN INTEGRATED IMAGING APPROACH

Abstract A male patient, 33 years old, smoker, with a 20-year history of SLE, consulted the ER for right hand fatigue. He didn't assume his medications constantly. Computed Tomography showed a fronto-parieto-occipital cerebral infarction, and the angio-CT showed a plaque in left internal carotid artery. The patient was admitted to the Stroke Unit for minor ischemic stroke. The ECG showed pathological Q waves in the anterior leads from V1 to V4 revealing a likely previous silent myocardial infarction. The echocardiogram demonstrated moderate left ventricular dysfunction with 40% EF and segmental wall motion abnormalities, namely ipoakinesia of anterior wall and apex. This findings were confirmed by cardiac MRI highliting subendocardial LGE in these areas suggesting an ischemic genesis. Due to the hemorrhagic risk related to recent cerebral ischemic event, coronary angiography was postponed a month later. The coronary angiography revealed a significant stenosis of the proximal left anterior descending artery (iFR &amp;lt; 0.65). Qualitative assessment of the lesion with IVUS showed a “mixed” plaque. The lesion was treated with PCI and the implant of two overlapped DES and the patient underwent dual antiplatelet therapy. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with heterogeneous presentation, characterised by alternating periods of flares and remission, and irreversible organ damage. The skin, joints, heart, kidneys, central nervous system and haematologic system are some of the most affected organs. Although recent data suggest that mortality decreased in patients with SLE over the last 30 years, mortality due to cardiovascular disease (CVD), usually defined as a combination of coronary, cerebrovascular and/or peripheral arterial disease, has remained high. Stroke and myocardial infarction (MI) are major CVD events that are potentially life-threatening. Lupus specific cardiovascular risk factors are believed to contribute to the high risk for MI, such as renal involvement, that has been associated with increased subclinical atherosclerosis and ischaemic heart disease, and antiphospholipid syndrome (APS), defined by venous, arterial or small vessel thrombosis and/or obstetric complications together with persistent positivity for antiphospholipid antibodies (aPL). Though several risk factors have been suggested, the exact mechanisms behind the high MI incidence in SLE remain essentially unknown. MIs in SLE are in most cases associated with coronary atherosclerosis. Subclinical atherosclerosis has been reported in many case–control studies, but a direct causal relationship between coronary artery disease (CAD) and MI in SLE has not yet been well documented. The pathogenesis of cardiovascular diseases in SLE is not fully understood. The inflammatory nature of SLE is believed to be an important factor in accelerating atherosclerosis. Systemic inflammation may lead to an abnormal lipid profile with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol and dysfunctional high-density lipoprotein cholesterol. Additionally, promotes endothelial dysfunction and vascular injury. Our case showed the key role of an integrated imaging approach with echocardiography and cardiac MRI to confirm diagnosis of past myocardial infarction in a very young man affected by LES. IVUS played a great role to characterize the nature of the lesion, confirming the association between coronary atherosclerosis and MIs in SLE.

Associations between myeloperoxidase and paraoxonase-1 and type 2 diabetes in patients with ischemic heart disease

BackgroundThe phrase “dysfunctional high-density lipoprotein” has been developed in the literature to describe the particle which loses its basic role- anti-oxidative and anti-inflammatory activity. In this porcess, the significance of enzymes- pro-oxidant myeloperoxidase (MPO) and antioxidant paraoxonase-1 (PON-1) from the perspective of HDL-C function has been noted.AimsThe objective of this study was to analyze the associations between two enzymes –MPO and PON-1 and type 2 diabetes (T2DM) in patients with ischemic heart disease (IHD).MethodsAn observational cross-sectional study including 70 patients with IHD of whom 35 had also T2DM, and 35 had no T2DM. Laboratory tests (MPO, PON-1, fasting glucose, glycated hemoglobin, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and high-sensitivity C-reactive protein) were performed.ResultsThe study revealed a significant difference in the serum concentration of the enzymes between patients with IHD with and without T2DM. Our results showed increased MPO concentration levels in diabetic patients. The analysis also revealed that T2DM is independently associated with an increase in MPO levels. Simultaneously, a decrease in PON-1 levels was observed in patients with T2DM. The study also revealed that T2DM is independently associated with a decrease in PON-1 levels.ConclusionsIn patients with type 2 diabetes the profile of enzymes involved in high-density lipoprotein metabolism in patients with IHD is worse than in patients without T2DM. The increase in the levels of MPO, an enzyme with oxidative and atherogenic properties and on a decrease in PON-1 levels, an enzyme with antioxidant and atheroprotective properties is observed.