Abstract Atherosclerosis is a multifactorial disease with numerous genes and environmental factors affecting its intiation and progression. During the past years many candidate genes for atherosclerosis have been suggested, and it has also become evident that the immune system plays a part in atherogenesis. Early atherosclerotic changes can be effectively detected by measuring carotid artery intima-media thickness (IMT). In the present study the associations between IMT and polymorphisms of three candidate genes for atherosclerosis were studied: endothelial nitric oxide synthase (eNOS), apolipoprotein E (apoE) and paraoxonase-1 (PON1). To assess the role of immunological factors determining carotid atherosclerosis, CRP and circulating autoantibodies to oxidised LDL were studied in relation to IMT. The study population consisted of 519 hypertensive and 526 control subjects from a middle-aged population in Oulu, Finland. The results showed that the investigated polymorphisms of eNOS and PON1 genes were not associated with IMT, suggesting that these polymorphisms are not major risk factors for atherosclerosis in the general Caucasian population. A significant interaction between the apoE polymorphism and smoking in relation to IMT was observed among men, indicating that carriers of the ε4 allele may be particularly prone to the atherogenic effects of smoking. This interaction was especially clear in hypertensive subjects. CRP was strongly associated with IMT before adjusting for confounding factors. After the adjustment, this association diasppeared. The finding suggests that instead of early atherosclerosis CRP may be related to the later phases of the disease. This may partly explain the strong correlation between CRP and future cardiovascular events. IgM type of autoantibodies binding to oxidised LDL were inversely associated with IMT, and this finding remained after adjusting for previously known risk factors for atherosclerosis, implying a possible protective role for these antibodies in atherogenesis.

Abstract The identification of risk factors for major adverse events after coronary artery bypass surgery is of main importance as it allows outcome prediction, facilitates preoperative patient selection and improves the quality of care. In the present clinical studies we have evaluated the impact of preoperative angiographic severity of a coronary artery disease and preoperative C-reactive protein (CRP) on the immediate outcome after coronary artery bypass surgery. We have reviewed the results of off-pump (OPCAB) versus conventional on-pump coronary artery bypass surgery (CCAB) in high risk patients. We have evaluated the impact of postoperative pulmonary artery blood temperature on the immediate outcome as well. In addition, we have investigated the incidence, timing and outcome of an atrial fibrillation (AF) related stroke after surgery. The multivariate analysis showed that among 2233 patients, the overall coronary angiographic score was predictive of postoperative death (p = 0.03; OR 1.027, 95% CI: 1.003–1.052) and of a low cardiac output syndrome (p = 0.04; OR 1.172, 95% CI: 1.010–1.218). The poor status of the proximal segment of the left circumflex coronary artery, the diagonal branches and the left obtuse marginal artery were most closely associated with adverse postoperative outcome. Patients (114/764) with a preoperative serum concentration of CRP ≥ 1.0 mg/dL had a higher risk of overall postoperative death (5.3% vs. 1.1%, p = 0.001), cardiac death (4.4% vs. 0.8%, p = 0.002), a low cardiac output syndrome (8.8% vs. 3.7%, p = 0.01). Among 179 high risk patients with an additive EuroSCORE6, the 30-day postoperative death and stroke rates were 7.5% and 6.0% in the OPCAB group, and 5.4% (p = 0.75) and 8.0% (p = 0.77) in the CCAB group, respectively. No significant differences were observed in other major outcome end-points between these non-randomised groups either. High pulmonary artery blood temperature on admission to the ICU among 1639 patients was significantly associated with an increased risk of overall postoperative death (p = 0.002), cardiac death (p = 0.03), and a low cardiac output syndrome (p < 0.0001), and was significantly correlated with prolonged length of the ICU stay (r = 0.095; p < 0.0001), and postoperative bleeding (ρ = –0.091; p = 0.001). Among 2,630 patients who underwent coronary artery bypass grafting (CABG), 52 (2.0%) experienced a postoperative stroke. Twelve out of these 52 patients (23.1%) died postoperatively. The ischemic cerebral event occurred after a mean of 3.7 days (0–33). In 19 patients (36.5%), atrial fibrillation preceded the occurrence of neurological complication. The angiographic severity of the coronary artery disease and the preoperative serum concentration of CRP predict postoperative outcome after a CABG operation. OPCAB can be performed safely in high-risk patients with results as satisfactory as those achieved with CCAB. CABG patients with a high pulmonary artery blood temperature on admission to the ICU seem to have a higher risk of postoperative adverse events. Atrial fibrillation occurring after coronary artery bypass grafting is a major determinant of a postoperative stroke.

La schizophrénie est une pathologie caractérisée par des symptômes positifs (idées délirantes et hallucinations), des symptômes négatifs (émoussement affectif, alogie, apragmatisme, retrait social) et des symptômes de désorganisation (cognitifs et affectifs). Cette pathologie est également associée à des altérations cognitives, perceptuelles et de la qualité de vie. La physiopathologie de la schizophrénie reste mal connue. Récemment, des travaux ont mis en avant le rôle central des processus inflammatoires chroniques dans la physiopathologie de ce trouble psychiatrique. En particulier, il a été montré que la CRP (Protéine C-Réactive), marqueur inflammatoire chronique aspécifique et facile à doser dans une prise de sang, est augmentée dans la schizophrénie. La CRP est reliée à la symptomatologie clinique et aux altérations cognitives des patients souffrant de schizophrénie. Mais le lien entre altérations perceptuelles et de la qualité de vie et CRP reste à explorer. / Schizophrenia is an illness characterized by positive symptoms (delusions and hallucinations), negative symptoms (reduced emotional expression, alogia, apragmatism, reduced social engagement) and disorganized symptoms (cognitive and affective). This pathology is also associated to cognitive and perceptual alterations and to quality of life alterations. The physiopathology of schizophrenia is still unclear. Recently, papers put forward the central role of chronic inflammatory process in pathophysiology of this psychiatric disorder. In particular, CRP (C-Reactive Protein), a nonspecific marker of chronic inflammation and easy to measure with blood sample, was shown to be increased in schizophrenia. CRP is connected to clinical symptomatology and to cognitive alterations in patients with schizophrenia. However the connection between alterations of perception, quality of life and CRP remains to be explored.

Ageing is accompanied by a progressive decline in skeletal muscle mass and strength which may lead to impaired ability to perform activities of daily living in older adults. Although the exact cause of the gradual decline in muscle mass is unknown, identifying efficient strategies aiming to prevent age-related loss of muscle mass and strength is important in order to promote healthy ageing. The overall aim of this thesis was to explore the effects of resistance training alone or combined with a healthy diet on skeletal muscle mass and function of healthy recreationally active older women and to determine mechanisms by which elevated systemic inflammation may contribute to the age-related decline of muscle mass in older adults. The combination of resistance training and a healthy diet induced gains in leg lean mass as well as greater gains in dynamic explosive force than resistance training alone in healthy recreationally active older women. The observed gains in leg lean mass were accompanied by increases in the size of type IIA muscle fibres together with down-regulation in gene expression of a pro-inflammatory factor (IL-1β) and upregulation in gene expression of a regulator of cellular growth (mTOR) in skeletal muscle of older women. Additionally, reduced muscle protein synthesis and size of muscle cells may mediate the detrimental effects of elevated circulating markers of inflammation on muscle mass in older adults. In conclusion, the present thesis depicts mechanistic links between elevated systemic marker of inflammation and muscle mass and provides new information on the effects of combined resistance training and healthy diet on muscle mass and strength in a group of healthy recreationally active older women. This knowledge is instrumental for development of strategies aiming to prevent age-related loss of muscle mass and function.

Periodontite crônica e perda dentária tornaram-se ferramentas úteis para estudar a hipótese de que a infecção/inflamação aumenta o risco de doenças cardiovasculares. Tem se demonstrado que a periodontite e suas consequências (perdas dentárias) têm o poder de elevar os marcadores inflamatórios sistêmicos, incluindo a proteína C-reativa, a qual é uma proteína aguda plasmática que é reconhecida como um preditor de infarto e se encontra aumentada em infecções. Com base no entendimento que o processo inflamatório sistêmico é o fator ligante entre as duas condições, o objetivo deste estudo foi analisar a associação entre edentulismo, perda dentária e parâmetros clínicos de periodontite crônica com inflamação sistêmica medida através de níveis de proteína C-reativa. Este estudo transversal controlado faz parte de um macro-projeto do Instituto de Cardiologia do Rio Grande do Sul que num estudo tipo consórcio incluiu 130 pacientes que receberam indicação para realizar cineangiocoronariografia. Os pacientes selecionados foram examinados entre dezembro de 2016 e outubro de 2017 e passaram por exame periodontal completo constando de índice de placa visível (IPV), sangramento à sondagem (SS), perda de inserção (PI), profundidade de sondagem (PS) em todos os dentes presentes nos seis sítios e também coletado o número de dentes perdidos e coleta de exames sanguíneos. A amostra foi dividida em 2 grupos: edêntulos (24,6%) e dentados (75,3%), sendo que maioria era homens (67,7%), com idade média de 63,30(±10,7) brancos (80%), com educação fundamental (70%), sedentários (62%), diabéticos (52%), hipertensos (74%) e com pelo menos um evento cardiovascular anterior (52%). As médias ± desvio-padrão de PS foram de 3,36±1,25; para PIos valores foram de 5,42±1,85; IPV médio de 0,39±0,25; e SS médio de 0,34±0,23, com uma média de 13,44±7,95 dentes. No modelo de regressão logística observou-se o efeito independente da perda dentária após ajustada para fumo e sexo. Conclui-se que a perda dentária está associada a incremento do risco cardíaco medido por inflamação sistêmica. / Chronic periodontitis and tooth loss have become useful tools for studying the hypothesis that infection/inflammation increases the risk of cardiovascular disease. It has been shown that periodontitis and its consequences (tooth loss) have the power to elevate systemic inflammatory markers; one of these markers is C-reactive protein is an acute plasma protein that is recognized as a predictor of myocardial infarction and is increased in infections. Based on the understanding that the systemic inflammatory process is the linking factor between the two conditions the objective of this study was to analyze the association between edentulism, tooth loss and clinical parameters of chronic periodontitis with systemic inflammation measured through C-reactive protein levels. This controlled cross-sectional study is part of a macro-project of the Instituto de Cardiologia do Rio Grande do Sul, which in a consortium-type study included 130 patients who were indicated to perform coronary angiography. The selected patients were examined between December 2016 and October 2017 and underwent complete periodontal examination consisting of visible plaque index (VPI), bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL), in six sites per tooth of all teeth present in addition to blood tests. The sample was divided into 2 groups: edentulous (24,6%) and dentate (75,3%)individuals. The majority were men (67.7%), with mean age of 63.30 (± 10.7) whites (80%), hypertensive (74%) and with at least one previous cardiovascular event (52%). The means and standard deviation of PD were 3.36 ±1.25; for CAL mean values of 5.42 ±1,85; Mean VPI was of 0.39 ± 0.25; and BOP presented 0.34 ± 0.23 as mean, with a mean of 13.44 ± 7.95 teeth present. In logistic regression model, we observed the independent effect of tooth loss after adjustment for smoking and sex. It is concluded that tooth loss is associated with increased cardiac risk as measured by systemic inflammation.

No description available.

C-reactive protein (CRP) is a part of the innate immune system, is synthesized in the liver, its blood level increases in inflammatory states, and it binds to Streptococcus pneumoniae. The conformation of CRP is altered under conditions mimicking an inflammatory milieu and this non-native CRP also binds to immobilized/aggregated/pathogenic proteins. Experiments in mice have revealed that one of the functions of CRP is to protect against pneumococcal infection. For protection, CRP must be injected into mice within two hours of administering pneumococci, thus, CRP is protective against early-stage infection but not against late-stage infection. It is unknown how CRP protects or why CRP does not protect against late-stage infection. The hypotheses are that the protection requires complement activation by CRP-pneumococci complexes and that CRP cannot protect if pneumococci have time to recruit complement inhibitor factor H on their surface to become complement attack-resistant. To test these hypotheses, we generated CRP mutants by site-directed mutagenesis: a mutant that binds to pneumococci but does not activate complement and a mutant that binds to immobilized factor H. We found that mutant CRP incapable of activating complement was not protective against infection and that mutant CRP capable of binding to factor H was protective against both early and late stage infections. Additional experiments showed that CRP enhances the effects of the antibiotic clarithromycin in reducing bacteremia in infected mice. Moreover, we observed that mutant CRP capable of binding to factor H bound to several proteins immobilized on plastic, suggesting that CRP recognizes a pattern, probably an amyloid-like structure, on immobilized proteins. Indeed, mutant CRP, after binding to amyloid b peptides, prevented the formation of pathogenic amyloid fibrils. Lastly, employing a hepatic cell line, we investigated the mechanism of CRP expression in response to pro-inflammatory cytokines. We found that the transcription factor C/EBPb and two C/EBP-binding sites on the CRP promoter were critical for inducing CRP expression. We conclude that complement activation is necessary for CRP-mediated protection against infection, that CRP functions in two structural conformations, that CRP and clarithromycin act synergistically, that CRP has anti-amyloidogenic properties, and the increased CRP expression requires C/EBPb.

C-reactive protein (CRP) is an acute phase protein of the innate immune system that has been evolutionarily conserved. Human CRP is known to exist in two different pentameric conformations; native CRP and non-native CRP that possess differential ligand recognition functions. The structure of CRP evolved from arthropods to humans, in terms of subunit composition, disulfide bonds, and glycosylation pattern. Along with change in structure, the gene expression pattern of CRP also evolved from a constitutive protein in lower invertebrates to an acute phase protein in humans. The objective of this study was to determine the function of a non-native pentameric CRP, that binds to atherogenic LDL, in atherosclerosis and compare the ligand recognition functions of human pentameric CRP with an evolutionary distant CRP for understanding the evolution of the structure of CRP. Additionally, in vitro reporter gene assays were used to gain further insight into the regulation of human CRP gene expression by an IL-6 inducible transcription factor, STAT3. We observed that CRP, in its non-native pentameric conformation, binds to atherogenic LDL and slows the progression of atherosclerosis in a site-specific manner in high fat diet fed LDLR-/- mice. Further, we observed that the ligand recognition function of CRP from an evolutionary conserved species, Limulus polyphemus, is different than that of native pentameric human CRP, but overlaps that of non-native pentameric human CRP. Lastly, we screened the proximal 300 bp region of the CRP promoter and identified a novel STAT3 binding site at position -134 located upstream of the previously identified, transcriptionally active STAT3 site at -108. In conclusion, non-native pentameric human CRP is an atheroprotective molecule whose ligand recognition functions exhibit similarity with CRP from an evolutionarily distant species. IL-6 mediated transcriptional regulation of human CRP is modulated, in part, by STAT3 binding to two distinct positions on the CRP promoter.

The connection between C-reactive protein (CRP) and atherosclerosis lies on three grounds. First, the concentration of CRP in the serum, which is measured by using highly sensitive (a.k.a. 'hs') techniques, correlates with the occurrence of cardiovascular disease. Second, although CRP binds only to Fcγ receptor-bearing cells and, in general, to apoptotic and damaged cells, almost every type of cultured mammalian cells has been shown to respond to CRP treatment. Many of these responses indicate proatherogenic functions of CRP but are being reinvestigated using CRP preparations that are free of endotoxins, sodium azide, and biologically active peptides derived from the protein itself. Third, CRP binds to modified forms of low-density lipoprotein (LDL), and, when aggregated, CRP can bind to native LDL as well. Accordingly, CRP is seen with LDL and damaged cells at the atherosclerotic lesions and myocardial infarcts. In experimental rats, human CRP was found to increase the infarct size, an effect that could be abrogated by blocking CRP-mediated complement activation. In the Apob 100/100 Ldlr -/- murine model of atherosclerosis, human CRP was shown to be atheroprotective, and the importance of CRP-LDL interactions in this protection was noted. Despite all this, at the end, the question whether CRP can protect humans from developing atherosclerosis remains unanswered.

Human C-reactive protein (CRP), injected intravenously into mice or produced inside mice by a human transgene, protects mice from death following administration of lethal numbers of Streptococcus pneumoniae. The protective effect of CRP is due to reduction in the concentration of bacteria in the blood. The exact mechanism of CRP-dependent killing of pneumococci and the partners of CRP in this process are yet to be defined. The current efforts to determine the mechanism of action of CRP in mice are directed by four known in vitro functions of CRP: 1. the ability of pneumococcal C-polysaccharide-complexed CRP to activate complement pathways, 2. the ability of CRP to bind to Fcγ receptors on phagocytic cells, 3. the ability of CRP to bind to immobilized complement regulator protein factor H which can also be present on pneumococci, and, 4. the ability of CRP to interact with dendritic cells. CRP-treated dendritic cells may well be as host-defensive as CRP alone. An interesting condition for the protective function of CRP is that CRP must be given to mice within a few hours of the administration of pneumococci. CRP does not protect mice if given later, suggesting that CRP works prophylactically but not as a treatment for infection. However, full knowledge of CRP may lead to the development of CRP-based treatment strategies to control pneumococcal infection. Also, because CRP deficiency in humans has not yet been reported, it becomes important to investigate the deficiency of the mechanism of action of CRP in CRP-positive individuals.