Made available in DSpace on 2016-08-19T18:16:03Z (GMT). No. of bitstreams: 1 dissertacao MARIANA AQUINO DOS SANTOS COSTA.pdf: 1654276 bytes, checksum: 6d130b62fd3570f64c41058397343cfb (MD5) Previous issue date: 2011-11-23 / Introduction: Coronary artery disease, is one of the leading causes of mortality in the world. The apolipoproteins appear as a new parameter, more sensitive and specific, and does not require fasting 12:00 for blood collection. The C-reactive protein is the most inflammatory marker studied, because the presence has been detected in inflamed tissue, arteries with atherosclerosis and infarcted cardiac muscle.Objetives: The purpose of this survey was to establish changes in lipid profile and PCR inflammatory marker, as in a group of patients undergoing coronary angiography and corrate them with the severity of the coronary disease.Methods:Cross-sectional study conducted with 292 patients in hemodynamic service of Hospital Universitário Presidente Dutra. After signing the free term, patients responded to a structured questionnaire, checking blood pressure, weight, height, abdominal circumference and hip and then followed by a collection of blood for the performance of biochemical assay. To evaluate the relationship between clinical and laboratory variables and the coronary disease applied the T test of Student and Mann-Whitney, the test of Chi-square and logistic regression to identify predictors of coronary disease.To correlate lipids, apolipoproteins and severity of the coronary disease, it used the one-way ANOVA and Kruskal-Wallis.Results:The group with coronary disease presented age, triglycerides, CT/HDL-c and VLDL-c major and hip circumference, HDL-c less than the group without coronary disease, with statistical significance. Women showed triglycerides, CT/HDL-c and VLDL-c major and hip circumference and weight less than women without coronary disease. Relation between the levels of C-reactive protein and coronary disease, 19.68% of the patients were in the range of low risk, 23,9% with moderate risk and 56.38% with high risk. Conclusion: Were predictors for coronary disease the males, increasing age and VLDL-c and the reduction of Apo A. The higher values of C-reative, triglycerides and VLDL-c and lower levels of HDL-c and Apo A, the greater the severity of the coronary artery disease. / Introdução: A doença arterial coronariana constitui uma das principais causas de mortalidade no mundo. As apolipoproteínas surgem como um novo parâmetro, mais sensíveis e específicas, além de não necessitar de jejum de 12 horas para coleta de sangue. A proteína C reativa é o marcador inflamatório mais estudado, sua presença já foi constatada em tecidos inflamados, artérias com aterosclerose e músculo cardíaco infartado. Objetivo: O propósito desta pesquisa foi estabelecer alterações no perfil lipídico e na proteína C reativa, como marcador inflamatório, em um grupo de pacientes submetidos à angiografia coronariana e correcioná-los com a gravidade da doença arterial coronariana. Métodos: Estudo transversal realizado com 292 pacientes no serviço de hemodinâmica do Hospital Universitário Presidente Dutra. Após assinarem o termo de consentimento livre e esclarecido, os pacientes responderam a um questionário estruturado, verificaram a pressão arterial, peso, altura, circunferência abdominal e do quadril e em seguida coletaram sangue para a realização das dosagens bioquímicas. Para avaliar a relação entre as variáveis clínicas e laboratoriais e a doença coronariana aplicou-se o teste t de Student e Mann-Whitney, o teste do qui-quadrado e regressão logística para identificar os preditores de doença coronariana. Para correlacionar lipídeos, apolipoproteínas e a gravidade da doença coronariana, usou-se a ANOVA one-way ou Kruskal-Wallis.Resultados:O grupo com doença coronariana apresentou idade, triglicérides, razão CT/HDL-c e VLDL-c maior e circunferência quadril, HDL-c menor que o grupo sem doença coronariana, com significância estatística.As mulheres apresentaram triglicérides, razão CT/HDL-c e VLDL-c maior e peso e circunferência quadril menor que as mulheres sem doença coronariana.Com relação entre os níveis de proteína C reativa e doença coronariana, 19,68% dos pacientes encontravam-se na faixa de baixo risco, 23,9% risco moderado e 56,38% com risco elevado.Conclusão:Foram preditores para doença coronariana, o sexo masculino, aumento da idade e do VLDL-c e a redução da apolipoproteína A. Maior a gravidade da doença coronariana, quanto mais elevado os níveis de proteína C reativa, triglicérides e VLDL-c e menores os níveis de HDL-c e apolipoproteína A.

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<p>The aim was to contribute to the optimal use of the resting ECG by exploring, in middle-aged and elderly men, the development and regression of ECG abnormalities; the prognostic value of the ECG for cardiovascular disease compared to conventional risk factors; and the impact of age at baseline and follow-up time for prediction of cardiovascular disease.</p><p>It was based on the Uppsala Study of Adult Men cohort that was started in 1970. Participants were examined at ages 50, 70, 77, and 82, with annual updates on mortality and in-hospital morbidity using national registries. </p><p>The studies indicated that the prevalence of silent MI and frequency of regression of major Q/QS patterns may be higher than previously believed. Considering that persistent T wave abnormalities and ST segment depression carried twice as high a risk for future cardiovascular disease (CVD) mortality as new or reverted abnormalities, the results suggested that serial electrocardiograms (ECG) would contribute to proper risk assessment. Also, the inclusion of ischemic ECG findings significantly increased the predictive power of the Framingham score at age 70 for CVD. </p><p>While hypertension and dyslipidemia were consistent long-term risk factors for myocardial infarction at ages 50 and 70, the length of follow-up period and age at baseline affected the predictive power of ECG abnormalities, fasting insulin, BMI, and smoking. </p><p>For stroke, midlife values for blood pressure and ECG abnormalities retained prognostic value over long follow-up periods, even though they improved when re-measured in elderly participants. ApoB/apoA1 ratio, driven by apoA1, was associated with stroke in elderly but not middle-aged men. Hyperinsulinemia and diabetes mellitus were more specifically associated with ischemic stroke than with any-cause stroke. </p><p>In summary, the resting ECG carried prognostic information beyond conventional risk factors. Even though the low prevalence of ECG abnormalities at the age of 50 calls into question the role of the ECG as a screening tool, the additional risk information it carries with it justifies its regular and repeated registration above the age of 50. </p>

The aim was to contribute to the optimal use of the resting ECG by exploring, in middle-aged and elderly men, the development and regression of ECG abnormalities; the prognostic value of the ECG for cardiovascular disease compared to conventional risk factors; and the impact of age at baseline and follow-up time for prediction of cardiovascular disease. It was based on the Uppsala Study of Adult Men cohort that was started in 1970. Participants were examined at ages 50, 70, 77, and 82, with annual updates on mortality and in-hospital morbidity using national registries. The studies indicated that the prevalence of silent MI and frequency of regression of major Q/QS patterns may be higher than previously believed. Considering that persistent T wave abnormalities and ST segment depression carried twice as high a risk for future cardiovascular disease (CVD) mortality as new or reverted abnormalities, the results suggested that serial electrocardiograms (ECG) would contribute to proper risk assessment. Also, the inclusion of ischemic ECG findings significantly increased the predictive power of the Framingham score at age 70 for CVD. While hypertension and dyslipidemia were consistent long-term risk factors for myocardial infarction at ages 50 and 70, the length of follow-up period and age at baseline affected the predictive power of ECG abnormalities, fasting insulin, BMI, and smoking. For stroke, midlife values for blood pressure and ECG abnormalities retained prognostic value over long follow-up periods, even though they improved when re-measured in elderly participants. ApoB/apoA1 ratio, driven by apoA1, was associated with stroke in elderly but not middle-aged men. Hyperinsulinemia and diabetes mellitus were more specifically associated with ischemic stroke than with any-cause stroke. In summary, the resting ECG carried prognostic information beyond conventional risk factors. Even though the low prevalence of ECG abnormalities at the age of 50 calls into question the role of the ECG as a screening tool, the additional risk information it carries with it justifies its regular and repeated registration above the age of 50.

Η απολιποπρωτεΐνη Ε (apoE) είναι κύριο συστατικό των VLDL λιποπρωτεϊνών και των υπολειμμάτων χυλομικρών και είναι υπεύθυνη για την απομάκρυνση των αθηρογενετικών λιποπρωτεϊνών από την κυκλοφορία. In vivo και in vitro μελέτες έχουν δείξει ότι μεταλλάξεις στην apoΕ που εμποδίζουν την πρόσδεση των λιποπρωτεϊνών που περιέχουν την apoΕ στον υποδοχέα της LDL (LDLr), συνδέονται με υψηλά επίπεδα χοληστερόλης στο πλάσμα και προκαλούν πρώιμη αθηροσκλήρωση σε ανθρώπους και πειραματόζωα. Στον άνθρωπο υπάρχουν τρεις κύριες φυσικές ισομορφές της apoE που ονομάζονται E2, E3, E4 και είναι αποτέλεσμα μεταλλάξεων στα αμινοξικά κατάλοιπα 112 και 158. Προηγούμενες μελέτες σε πειραματόζωα έχουν δείξει πως η apoE διαμεσολαβεί στην εμφάνιση διατροφικά επαγόμενης παχυσαρκίας. Σκοπός της εργασίας είναι να αξιολογήσουμε το ρόλο της κάθαρσης των λιποπρωτεϊνών που περιέχουν apoE μέσω του υποδοχέα LDLr στην εμφάνιση παχυσαρκίας, καθώς οι ισομορφές Ε3, Ε4 έχουν πολύ μεγαλύτερη συγγένεια για τον LDLr από την Ε2 ισομορφή. Τα πειραματόζωα που χρησιμοποιήθηκαν ήταν πειραματικά ποντίκια αγρίου τύπου C57BL/6, ποντίκια με καθολική έλλειψη στην apoE (apoE-/- ) και ποντίκια που εκφράζουν την ανθρώπινη E2, E3, E4 ισομορφή αντίστοιχα. Τα πειραματόζωα τρέφονταν με δίαιτα δυτικού τύπου για ένα χρονικό διάστημα 24 εβδομάδων ενώ παράλληλα πραγματοποιήθηκαν βιοχημικές και μεταβολικές μελέτες. Παρατηρήσαμε πως τα ποντίκια που εκφράζουν την apoE2, παρά την χαμηλή συγγένεια που έχουν ως προς τον LDLr, αύξησαν το βάρος τους περισσότερο και εμφάνισαν υψηλότερες τιμές χοληστερόλης και τριγλυκεριδίων στο αίμα σε σχέση με τις υπόλοιπες ισομορφές. Γεγονός που αποδεικνύει πως η κάθαρση των λιπιδίων του αίματος δεν σχετίζεται με την εμφάνιση παχυσαρκίας στα πειραματικά μοντέλα ποντικών. Αντίθετα οι δοκιμασίες ανοχής στη γλυκόζη που πραγματοποιήθηκαν έδειξαν πως τα apoE3 +/+ ποντίκια εμφάνισαν τη χειρότερη ανοχή στη γλυκόζη, ενώ οι apoE2 +/+ , apoE4 +/+ ομάδες ποντικών είχαν στατιστικά παρόμοιες καμπύλες. Σύμφωνα με τα παραπάνω προκύπτει πως εμφάνιση διαβήτη και διατροφικά επαγόμενης παχυσαρκίας είναι ανεξάρτητα πεδία που πρέπει να μελετηθούν ξεχωριστά. / Apolipoprotein E (apoE) is a major component of VLDL and chylomicron remnants and is responsible for the removal of atherogenic lipoproteins from the circulation. In vivo and in vitro studies have shown that apoE mutations that prevent the binding of apoE-containing lipoproteins to LDLr, are associated with high plasma cholesterol levels and cause premature atherosclerosis in humans and animals. In humans, there are three main natural isoforms of apoE called E2, E3, E4 and is the result of mutations in amino acid residues 112 and 158. Given that previous animal studies have shown that apoE mediates the development of diet-induced obesity, the aim of this study was the evaluation of the role of apoE-containing lipoprotein's clearance by the LDLr in the development of obesity. Taking into account that the E3, E4 isoforms have higher LDLr affinity compared to the E2 isoform, we focused on the role of different apoE isoforms in these metabolic diseases. The animals we used in this study were apoE-deficient mice (apoE-/-), mice expressing human E2 (apoE2+/+), E3 (apoE3+/+), E4 (apoE4+/+) isoform and wild type C57BL/6 mice as a control group. The animals were fed western type diet for a 24-week period while biochemical and metabolic studies were performed. We observed that mice expressing apoE2, despite having low LDLr affinity, had higher body weight compared to C57BL/6 and exhibited higher plasma cholesterol and triglyceride levels compared to the other isoforms. This observation demonstrates that the clearance of blood lipids is not associated with obesity in experimental mouse models. Conversely, the glucose tolerance tests carried out showed that the apoE3+/+ mice had the worst glucose tolerance, followed by apoE4+/+ and the apoE2+/+ mice groups (apoE3+/+>>apoE4+/+≥apoE2+/+) suggesting that in case of glucose tolerance the clearance of apoE-containing lipoproteins may be a factor. Based on the above, diet-induced obesity and diabetes are, probably, independent fields that should be studied separately.

Apolipophorin-III is a hemolymph protein known for its role in lipid transport. Apolipophorin-III isolated from the hemolymph of last instar larvae of Galleria mellonella bound to the surface of the insect pathogenic Gram-negative bacterium Xenorhabdus nematophilus and to the lipid A moiety of its lipopolysaccharide. This binding reduced the toxicity of the lipopolysaccharide to hemocytes and decreased the inhibitory effect of the lipopolysaccharide on phenoloxidase. Apolipophorin-III also bound to the Gram-positive bacterium Micrococcus lysodeikticus; this enhanced the activity of hen egg lysozyme on the organism as well as the lytic activity of G. mellonella cell-free hemolymph. / The involvement of apolipophorin-III in the immune responses of G. mellonella larvae to lipoteichoic acids, surface components of Gram-positive bacteria, was examined. Lipoteichoic acids from Bacillus subtilis, Enterococcus hirae and Streptococcus pyogenes caused a dose- and time-dependent drop in the total counts of circulating hemocytes and a partial or complete depletion of plasmatocytes depending on the species of lipoteichoic acid. All lipoteichoic acids tested activated phenoloxidase in vitro; however, in vivo, only B. subtilis lipoteichoic acid elevated the phenoloxidase activity while the other two suppressed it. Binding of apolipophorin-III to lipoteichoic acids was demonstrated. Apolipophorin-III prevented the complete depletion of plasmatocytes and depressed the activation of phenoloxidase by lipoteichoic acid from B. subtilis. The concentration of apolipophorin-III in hemolymph two hours post injections of lipopolysaccharides or lipoteichoic acids into larvae of G. mellonella did not change with respect to control insects that received phosphate-buffered saline. The concentration of apolipophorin-III in hemolymph at the end of the feeding larval stage was 8--12 mg/mL of hemolymph. Apolipophorin-III was present in significant amounts in the prepupal, pupal and adult stages. The protein was detected immunologically in hemocyte lysates, plasma and fat body. Non-denaturing polyacrylamide gels and immunoblots of fresh hemolymph suggested that apolipophorin-III is associated with a 77 kDa protein.

Graduation date: 2000

With the severity of cardiovascular disease (CVD) and the related mortality rate to this disease, new methods are necessary for risk assessment and treatment prior to the onset of the disease. The current paradigm in CVD risk assessment has shifted towards the multivariate approach over the individual use of traditional risk factors or lipid measurements. Through a combination of analytical techniques and multivariate statistical analysis, a novel method of cardiovascular risk assessment was developed. The analytical techniques employed include density gradient ultracentrifugation (DGU) and matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) applied to human serum. These techniques provided detailed information about the characterization of the lipoproteins and their structural components, specifically the apolipoproteins belonging to high density lipoproteins (HDL). This information when combined with multivariate statistical analysis provided a method that accurately identified the presence of CVD in clinical studies between cohorts of subjects that had been previously diagnosed with CVD and cohorts of subjects that had been identified as healthy controls (CTRL) based on a clear angiography. The lipoprotein density profiles were divided into subclasses based on their density and measured using a fluorescent probe to tag the lipoprotein particles. Use of multiple ethylenediaminetetraacetic acid (EDTA) based solutes allowed for the manipulation of the density gradient formation in order to separate the lipoproteins by specific density ranges in order to achieve better baseline separation of the profiles. Application of the integrated fluorescence intensities for each subclass of lipoprotein to linear discriminant analysis/sliced inverse regression (LDA/SIR) and quadratic discriminant analysis (QDA) yielded an advanced and accurate form of risk assessment for CVD. This method was found to be highly accurate as well as identify potential atherogenic lipoprotein subclasses through studying the LDA/SIR prediction equation generated. It was also shown that the LDA/SIR equation could be used to monitor medical treatment and lifestyle change for their effects on the risk assessment model. Further study into the atherogenicity of HDL through analysis of the apolipoproteins using MALDI-MS led to identification of potential risk factors that could be added to the statistical analyses. These risk factors included mass differences in the Apolipoprotein A-I (Apo A-I) and Apolipoprotein C-I (Apo C-I) between CVD and CTRL samples as well as the presence of specific mass peaks related to Apolipoprotein A-II (Apo A-II) that were primarily found in the CVD samples. These differences, in addition to the lipoprotein density profile data, were found to increase the potential accuracy of CVD risk assessment. The combination of these methods has shown great potential in the assessment of CVD risk as well as the ability to increase researchers' understanding of the nature of VD and how to treat it.

[Truncated abstract] The metabolic syndrome is characterized by cardiovascular risk factors including dyslipidemia, insulin resistance, visceral obesity, hypertension and diabetes. The dyslipidemia of the metabolic syndrome includes elevated plasma triglyceride and apolipoprotein (apo) B levels, accumulation of small, dense low-density lipoprotein (LDL) particles and low high-density lipoprotein (HDL) cholesterol concentration. However, the precise mechanisms for this dyslipoproteinemia, specifically low plasma HDL cholesterol, are not well understood. This thesis therefore, focuses on HDL, its structure, function and metabolism. However, lipoprotein metabolism is a complex interconnected system, which includes forward and reverse cholesterol transport pathways. Hence, this thesis also examines and discusses the metabolism of apoB-containing lipoproteins. This thesis tests the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that lipid regulating therapies can improve these kinetic abnormalities. The aims were first, to compare and establish the clinical, metabolic and kinetic differences between metabolic syndrome and lean subjects; and second, to determine the regulatory effects of statin therapy, specifically, rosuvastatin on lipoprotein transport in the metabolic syndrome. Five observation statements were derived from the general hypothesis and examined in the studies described below. The findings are presented separately as a series of original publications. Study 1 Twelve men with the metabolic syndrome and ten lean men were studied in a case-control setting. ... These findings explain the HDL raising effects of rosuvastatin in the metabolic syndrome. Collectively, these studies suggest that the dyslipidemia of the metabolic syndrome results from increased production rates of VLDL and LDL particles, reduced fractional catabolic rates of these lipoproteins, together with accelerated catabolism of HDL particles. Treatment with rosuvastatin increases the catabolic rates of all apoB-containing lipoproteins and at a higher dose, decreases LDL apoB production. These effects are consistent with inhibition of cholesterol synthesis leading to an upregulation of LDL receptors. Rosuvastatin decreases the fractional catabolism of HDL particles. The effects of rosuvastatin on HDL kinetics may be related to a reduction in triglyceride concentration and cholesterol ester transfer protein activity. These findings are consistent with the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that statin therapy improves these kinetic abnormalities.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.