R educed plasma levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of coronary artery disease (CAD).1 Moreover, in patients with CAD that are treated with statin and have low levels of low-density lipoprotein (LDL) cholesterol, reduced HDL cholesterol levels were predictive of major cardiovascular events.2 Besides promoting reverse cholesterol transport, 3,4 HDL has been demonstrated to exert antiatherosclerotic effects, including antiinflammatory properties and stimulation of endothelial nitric oxide (NO) production. [5][6][7][8][9] However, these effects of HDL have been observed to be highly heterogenous in patients with CAD or diabetes mellitus. 10-12 Editorial see p 868 Clinical Perspective on p 904Endothelial dysfunction and injury are thought to contribute importantly to the progression of CAD. [13][14][15] Experimental studies have indicated that atherosclerotic lesion-prone vascular regions are characterized by a high endothelial cell turnover, 16 which has been attributed to an increased rate of endothelial cell apoptosis. Moreover, superficial atherosclerotic plaque erosion with the loss of an intact endothelial cell monolayer is observed quite frequently in patients with an acute coronary syndrome (ACS) based on pathological studies, 17,18 and on Background-Endothelial dysfunction and injury are thought to play an important role in the progression of coronary artery disease (CAD). High-density lipoprotein from healthy subjects (HDL Healthy ) has been proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDL CAD and HDL Healthy on the activation of endothelial anti-and proapoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes. Methods and Results-HDL was isolated from patients with stable CAD (HDL sCAD ), an acute coronary syndrome (HDL ACS ), and healthy subjects. HDL Healthy induced expression of the endothelial antiapoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apolipoprotein E-deficient mice in vivo. In contrast, HDL sCAD and HDL ACS did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL, and stimulated endothelial proapoptotic pathways, in particular, p38-mitogen-activated protein kinase-mediated activation of the proapoptotic Bcl-2 protein tBid. Endothelial antiapoptotic effects of HDL Healthy were observed after inhibition of endothelial nitric oxide synthase and after delipidation, but not completely mimicked by apolipoprotein A-I or reconstituted HDL, suggesting an important role of the HDL proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin and increased apolipoprotein C-III content of HDL sCAD and HDL ACS as mechanisms leading to altered effects on endothelial apoptosis. Conclusions-The present study demonstrates for the first time that HDL CAD d...
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 (HDL(CKD)), a population with high cardiovascular risk, we have demonstrated that HDL(CKD) in contrast to HDL(Healthy) promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDL(CKD) that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDL(CKD) 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.
A remarkable excess mortality has coincided with the COVID-19 pandemic in Europe. We present preliminary pooled estimates of all-cause mortality for 24 European countries/federal states participating in the European monitoring of excess mortality for public health action (EuroMOMO) network, for the period March–April 2020. Excess mortality particularly affected ≥ 65 year olds (91% of all excess deaths), but also 45–64 (8%) and 15–44 year olds (1%). No excess mortality was observed in 0–14 year olds.
Background The inverse care law states that disadvantaged populations need more health care than advantaged populations but receive less. Gaps in COVID-19-related health care and infection control are not well understood. We aimed to examine inequalities in health in the care cascade from testing for SARS-CoV-2 to COVID-19-related hospitalisation, intensive care unit (ICU) admission, and death in Switzerland, a wealthy country strongly affected by the pandemic. MethodsWe analysed surveillance data reported to the Swiss Federal Office of Public Health from March 1, 2020, to April 16, 2021, and 2018 population data. We geocoded residential addresses of notifications to identify the Swiss neighbourhood index of socioeconomic position (Swiss-SEP). The index describes 1•27 million small neighbourhoods of approximately 50 households each on the basis of rent per m², education and occupation of household heads, and crowding. We used negative binomial regression models to calculate incidence rate ratios (IRRs) with 95% credible intervals (CrIs) of the association between ten groups of the Swiss-SEP index defined by deciles (1=lowest, 10=highest) and outcomes. Models were adjusted for sex, age, canton, and wave of the epidemic (before or after June 8, 2020). We used three different denominators: the general population, the number of tests, and the number of positive tests. Findings Analyses were based on 4 129 636 tests, 609 782 positive tests, 26 143 hospitalisations, 2432 ICU admissions, 9383 deaths, and 8 221 406 residents. Comparing the highest with the lowest Swiss-SEP group and using the general population as the denominator, more tests were done among people living in neighbourhoods of highest SEP compared with lowest SEP (adjusted IRR 1•18 [95% CrI 1•02-1•36]). Among tested people, test positivity was lower (0•75 [0•69-0•81]) in neighbourhoods of highest SEP than of lowest SEP. Among people testing positive, the adjusted IRR was 0•68 (0•62-0•74) for hospitalisation, was 0•54 (0•43-0•70) for ICU admission, and 0•86 (0•76-0•99) for death. The associations between neighbourhood SEP and outcomes were stronger in younger age groups and we found heterogeneity between areas. Interpretation The inverse care law and socioeconomic inequalities were evident in Switzerland during the COVID-19 epidemic. People living in neighbourhoods of low SEP were less likely to be tested but more likely to test positive, be admitted to hospital, or die, compared with those in areas of high SEP. It is essential to continue to monitor testing for SARS-CoV-2, access and uptake of COVID-19 vaccination and outcomes of COVID-19. Governments and healthcare systems should address this pandemic of inequality by taking measures to reduce health inequalities in response to the SARS-CoV-2 pandemic.
The identification of VEGF as a regulatory factor of transendothelial transport of HDL but not LDL supports the concept that the endothelium is a specific and, hence, druggable barrier for the entry of lipoproteins into the vascular wall.
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