Development of a Passive Immunization Strategy Against Atherosclerosis

Atherosclerosis is a chronic inflammatory disease, characterized by the accumulation of lipids and fibrous tissue in the wall of medium and large-sized arteries. The characteristic culprit of the disease is the atheroma, or atherosclerotic plaque, a patchy thickening of the arterial wall which affects the lumen, inducing various degrees of stenosis. The rupture of the atherosclerotic plaques, followed by local thrombosis, is the underlying cause of myocardial infarction and stroke, which claim millions of lives every year worldwide. Oxidized LDL and the immune system play very important roles in atherosclerosis. Several studies have demonstrated the existence of both atherogenic and atheroprotective immune responses against oxidized LDL. We have identified several of the epitopes in the oxidized LDL particle which trigger immune responses. These epitopes are aldehyde-modified peptide sequences of apoB-100, the main protein in LDL structure. Immunization of atherosclerosis-prone mice with some of the apoB-100 peptides reduced plaque area by up to 60% in the immunized mice compared to controls. We tested the effects of recombinant human IgG1 antibodies against two of these peptide sequences on the development of atherosclerosis in mice. Passive immunization with the IEI-E3 and 2D03 antibodies, specific for MDA-p45 (aa 661-680), significantly inhibited atherosclerosis progression and induced plaque regression in the descending aorta. 2D03 prevented constrictive remodeling after injury in the carotid arteries and potently reduced lesion extent in the uninjured carotid arteries in mice. Additionally, antibody treatment decreased the local and systemic inflammatory responses. We have also found that plasma levels of human IgG1 autoantibodies which recognize the same aldehyde-modified apoB-100 peptide are inversely correlated with carotid stenosis in healthy individuals, which further supports the hypothesis of the potential atheroprotective role of these antibodies. The influence of the antibodies on human atherosclerosis and their potential side effects need to be carefully characterized. In the future, the oxidized LDL-specific recombinant human IgG1 antibodies could be developed into novel diagnostic and therapeutic tools for the management of atherosclerosis-related cardiovascular diseases

Plasma S100A8/A9 Correlates With Blood Neutrophil Counts, Traditional Risk Factors, and Cardiovascular Disease in Middle-Aged Healthy Individuals.

The S100 alarmins A8, A9, and A8/A9, secreted by activated neutrophils and monocytes/macrophages, are involved in the pathogenesis of various inflammatory diseases. S100A8/A9 has previously been linked to atherogenesis and cardiovascular (CV) disease. We investigated whether S100A8, A9, and A8/A9 correlate with carotid artery disease and CV risk in apparently healthy individuals

Influence of GSTM1, GSTT1 and GSTP1 gene polymorphisms on the appearance of microalbuminuria in type 2 diabetes mellitus patients

[Section: Letter to the Editor] This work was funded by an internal research grant from The University of Medicine and Pharmacy from of Târgu Mures, number 649/14.01.2016

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: A Meta-Analysis of Population-Based Studies Involving 17,180 Individuals.

RATIONALE: Pro-inflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. OBJECTIVE: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. METHODS AND RESULTS: We used previously unpublished data on 17,180 stroke-free individuals (mean age 56.7{plus minus}8.1 years; 48.8% males) from six population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke over a mean follow-up interval of 16.3 years (280,522 person-years at risk; 1,435 incident stroke events). We applied Cox proportional hazard models and pooled hazard ratios (HR) using random-effects meta-analyses. Following adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1 SD increment in ln-transformed MCP-1: 1.07, 95%CI: 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR: 1.11, [1.02-1.21]), but not hemorrhagic stroke (HR: 1.02, [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared to the 1st quartile (HRs: 2nd quartile: 1.19 [1.00-1.42]; 3rd quartile: 1.35, [1.14-1.59]; 4th quartile: 1.38, [1.07-1.77]). There was no indication for heterogeneity across studies and in a sub-sample of four studies (12,516 individuals) the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein. CONCLUSIONS: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1-signaling might represent a therapeutic target to lower stroke risk.M. Georgakis is funded by scholarships from the German Academic Exchange Service (DAAD) and Onassis Foundation. The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). The DHS study was funded by a grant from the Donald W. Reynolds Foundation. The EPIC-Norfolk study is funded by grants from the Medical Research Council UK (G9502233, G0401527) and Cancer Research UK (C864/A8257, C864/A2883). FHS is supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and No. HHSN268201500001I and 75N92019D00031), received funding by grants from the National Institute of Aging (R01s AG054076, AG049607, AG059421, U01-AG049505, AG058589 and AG052409) and the National Institute of Neurological Disorders and Stroke (R01 NS017950, UH2 NS100605), as well as grants for the MCP-1 measurements by NIH (1RO1 HL64753, R01 HL076784, 1 R01 AG028321). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The MDCS-CV study has been supported with funding from the Swedish Research Council, Swedish Heart and Lung Foundations, and the Swedish Foundation for Strategic Research. This project has received funding from the European Union’s Horizon 2020 research and innovation programme (No 666881), SVDs@target (to M. Dichgans) and No 667375, CoSTREAM (to M. Dichgans); the DFG as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and the CRC 1123 (B3) (to M. Dichgans); the Corona Foundation (to M. Dichgans); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)(to M. Dichgans); the e:Med program (e:AtheroSysMed) (to M. Dichgans) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456) (to M. Dichgans)

S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease.

Amplification of innate immune responses by endogenous danger-associated molecular patterns (DAMPs) promotes inflammation. The involvement of S100A8 and S100A9, DAMPs belonging to the S100 calgranulin family, in the pathogenesis of cardiovascular disease is attracting an increasing amount of interest. S100A8 and S100A9 (also termed MRP8 and MRP14) preferentially form the S100A8/A9 heterodimer (MRP8/14 or calprotectin) and are constitutively expressed in myeloid cells. The levels of circulating S100A8/A9 in humans strongly correlate to blood neutrophil counts and are increased by traditional cardiovascular risk factors such as smoking, obesity, hyperglycemia, and dyslipidemia. S100A8/A9 is an endogenous ligand of toll-like receptor 4 (TLR4) and of the receptor for advanced glycation end products (RAGE) and has been shown to promote atherogenesis in mice. In humans, S100A8/A9 correlates with the extent of coronary and carotid atherosclerosis and with a vulnerable plaque phenotype. S100A8/A9 is locally released following myocardial infarction and amplifies the inflammatory responses associated with myocardial ischemia/reperfusion injury. Elevated plasma levels of S100A8/A9 are associated with increased risk of future coronary events in healthy individuals and in myocardial infarction survivors. Thus, S100A8/A9 might represent a useful biomarker and therapeutic target in cardiovascular disease. Importantly, S100A8/A9 blockers have been developed and are approved for clinical testing

STUDY ON PRODUCTIVITY INDICATORS IN EDUCATION

This paper aims to outline synthetically a set of indicators for the study of productivity in education and to critically analyze their suitability as input, output or outcome. References were made to the indicators available in the databases of Romania, World Bank, Eurostat, OECD relevant for measuring productivity in education, which opposed to usual reporting between effect / result and inputs elements consumed in the production process,in the case of educational services should be considered the quantitative, but also qualitative aspects - and especially - mediated effects, on long-term and very long term. The research results presented, emphasize the importance of the educational reform efforts to focus more on qualitative aspects in measuring productivity, more precisely on the abilities, competencies that have pupils /students and adults, on motivating teachers, to achieve educational outcomes which could increase students performance, productivity growth on long-term and very long term effects, with an impact at the macroeconomic level

Innate Immune Mechanisms in Myocardial Infarction - An Update

Acute myocardial infarction (AMI) is a disease associated with high morbidity and mortality. Currently there are no available treatments specifically targeting the post-ischemic myocardial processes that lead to heart failure and recurrent coronary events. The innate immune system plays a central role in the two consecutive phases that follow an acute ischemic event: the inflammatory phase and the reparatory phase. The inflamatory phase involves a massive infiltration of neutrophils and inflammatory Ly6Chi monocytes into the injured myocardium. The reparatory phase is orchestrated by reparatory Ly6Clo macrophages that clear necrotic and apoptotic cells through efferocytosis, secrete anti-inflammatory mediators and stimulate fibrosis and repair. Important recent studies provided proof that Ly6Chi monocytes that enter the myocardium in the inflammatory phase upregulate the orphan nuclear receptor Nr4a1 and switch phenotype to Ly6CloNr4a1hi reparatory macrophages. Additionally, neutrophils have been shown to promote cardiac recovery by upregulating expression of the efferocytosis receptor MerTK on reparatory macrophages. A finely tuned balance between the inflammatory and the reparatory phases is thus essential for limiting myocardial damage and promoting efficient recovery. Treatment strategies targeting only the inflammatory phase have so far failed to improve prognosis in AMI patients. A detailed understanding of the interplay between the two phases of the innate immune response is paramount for designing efficient therapies able to improve post- AMI prognosis. In the current review, we summarize the state-of-the-art of the field and discuss previous therapeutic attempts and currently ongoing clinical trials targeting innate immune mechanisms in AMI patients

Association between attending exercisebased cardiac rehabilitation and cardiovascular risk factors at one-year post myocardial infarction

Background: Randomized trials confirm the benefits of exercise-based cardiac rehabilitation on cardiovascular risk factors. Whether exercise-based cardiac rehabilitation provides the same favourable effects in real-life cardiac rehabilitation settings, in the modern era of myocardial infarction treatment, is less well known. We examined the association between attending exercise-based cardiac rehabilitation and improvements in cardiovascular risk factors at one-year post myocardial infarction in patients included in the Swedish heart disease registry, SWEDEHEART. Methods: In this retrospective registry-based cohort study, we included 19 136 patients post myocardial infarction (75% men, 62.8±8.7 years) who were registered in SWEDEHEART between 2011 and 2013. The association between attending exercise-based cardiac rehabilitation (43% participation rate) and changes in cardiovascular risk profile between baseline and one-year follow-up was assessed using multivariable regression analysis adjusting for age, comorbidities and medication. Results: Attenders more often reported to have stopped smoking (men 64% vs 50%; women 64% vs 53%, p<0.001 for both, only smokers at baseline considered), be more physically active (men 3.9±2.5 vs 3.4±2.7 days/week; women 3.8±2.6 vs 3.0±2.8 days/week, p<0.001 for both) and achieved a slightly larger reduction in triglycerides (men -0.2±0.8 vs -0.1±0.9 mmol/L, p = 0.001; women -0.1±0.6 vs 0.0±0.8 mmol/L, p = 0.01) at one-year compared to non-attenders. Male attenders gained less weight (+0.0±5.7 vs +0.3±5.7 kg, p = 0.01) while female attenders achieved better lipid control (total cholesterol -1.2±1.4 vs -0.9±1.4 mmol/L, p<0.001; low-density lipoprotein -1.2±1.2 vs -0.9 ±1.2 mmol/L, p<0.001) compared to nonattenders. Conclusions: In an unselected registry cohort of patients post myocardial infarction, compared to nonattenders those attending exercise-based cardiac rehabilitation achieved significantly larger improvements in cardiovascular risk factors at one-year after the acute event

Elevated IL-27 in patients with acute coronary syndrome is associated with adverse ventricular remodeling and increased risk of recurrent myocardial infarction and cardiovascular death

Background and aims: IL-27 is an immunoregulatory cytokine belonging to the IL-6/IL-12 family that was found to be elevated in acute coronary syndrome (ACS) patients. We investigated whether IL-27 is related to post-ischemic cardiac remodeling and long-term prognosis in this patient group. Methods: We included 524 ACS patients, defined as acute myocardial infarction (AMI) or unstable angina (UA). A subgroup of 107 patients donated blood samples 6 weeks after the index event, and underwent a follow-up echocardiographical examination at 1 year. We measured plasma levels of IL-27, high sensitivity troponin T (hsTNT), C-reactive protein (hsCRP) and cystatin C at baseline and in the 6-week samples. The median follow-up period of the cohort was 2.2 years. Results: The incidence of the combined end-point of AMI and cardiovascular death was higher in patients with plasma IL-27 within the top two tertiles both at baseline and after 6 weeks. After correction for cardiovascular risk factors, medication, hsTNT, hsCRP, and eGFR, patients with baseline IL-27 levels within the highest tertile had a significantly elevated risk for the combined end-point compared with the lowest tertile (hazard ratio 2.70, 95% CI 1.06–6.90, p =.038). Additionally, higher baseline IL-27 levels were associated with deleterious left ventricular remodeling and deterioration of systolic and diastolic function during the first year of follow-up. Conclusions: Elevated IL-27 at the time of an ACS is independently related to impaired cardiac function and worse long-term prognosis. Our data warrants further mechanistic studies to elucidate the involvement of IL-27 in cardiac repair and remodeling after ACS

Innate immune mechanisms in myocardial infarction - An update

Acute myocardial infarction (AMI) is a disease associated with high morbidity and mortality. Currently there are no available treatments specifically targeting the post-ischemic myocardial processes that lead to heart failure and recurrent coronary events. The innate immune system plays a central role in the two consecutive phases that follow an acute ischemic event: the inflammatory phase and the reparatory phase. The inflamatory phase involves a massive infiltration of neutrophils and inflammatory Ly6Chi monocytes into the injured myocardium. The reparatory phase is orchestrated by reparatory Ly6Clo macrophages that clear necrotic and apoptotic cells through efferocytosis, secrete anti-inflammatory mediators and stimulate fibrosis and repair. Important recent studies provided proof that Ly6Chi monocytes that enter the myocardium in the inflammatory phase upregulate the orphan nuclear receptor Nr4a1 and switch phenotype to Ly6CloNr4a1hi reparatory macrophages. Additionally, neutrophils have been shown to promote cardiac recovery by upregulating expression of the efferocytosis receptor MerTK on reparatory macrophages. A finely tuned balance between the inflammatory and the reparatory phases is thus essential for limiting myocardial damage and promoting efficient recovery. Treatment strategies targeting only the inflammatory phase have so far failed to improve prognosis in AMI patients. A detailed understanding of the interplay between the two phases of the innate immune response is paramount for designing efficient therapies able to improve post- AMI prognosis. In the current review, we summarize the state-of-the-art of the field and discuss previous therapeutic attempts and currently ongoing clinical trials targeting innate immune mechanisms in AMI patients