No description available.

No description available.

No description available.

Patients with established coronary artery disease (CAD) remain at elevated risk of major adverse cardiac events (MACE). Specifically, stented coronary artery remains the highest-risk coronary lesion with annualized adverse event rates as high as 8-12% in the following year largely due to in-stent restenosis (ISR) and stent thrombosis. Plasminogen activator inhibitor-1 (PAI-1), an anti-fibrinolytic protein, has previously been associated with CAD with known mechanism of action to regulate the pathophysiological changes associated with in-stent restenosis and stent thrombosis. Moreover, extracellular vesicles (EVs) originating from circulating blood and vascular cells are increasingly being utilized as biomarkers and mediators of vascular disease. We first demonstrate the analytical and biochemical performance of plasma PAI-1 in patients with established CAD. Specifically, PAI-1 performs similarly to established biomarkers including C-reactive protein and NT-proBNP with an analytical (CVa = 4.1%), intra-individual (CVi = 44.0%), and inter-individual (CVg = 118.6%) coefficients of variation. Following this, we demonstrate that plasma PAI-1 is not associated with MACE in one-year follow-up, but reduced levels of PAI-1 remain associated with unplanned revascularization. Subsequently, we sought to evaluate the relationship between PAI-1 and EVs in humans with platelets being a common source of origin. In the largest study of EV to-date in CAD (n=489), we demonstrate the strong predictive ability of PAI-1 platelet-derived EVs (PAI-1+ PEV) with MACE following revascularization. Patients with high circulating levels of PAI-1+ PEV had higher rates of MACE (262.3 vs. 103.0 events per 1,000 person-years; hazard ratio (HR) 2.19; 95% CI, 1.07-4.52; and HR 2.67; 95% CI, 1.22-5.84, discovery and validation cohorts, respectively). Furthermore, we reveal that high PAI-1+ PEV fractions did not enhance thrombogenicity but promoted a pro-inflammatory vascular smooth muscle cell (VSMC) state by enhancing proliferation and migration, through up-regulation of pro-inflammatory genes such as KLF4. Inhibition of the PAI-1-LRP-1 interaction by TM5275 dampened the pro-inflammatory VSMC response, whereas inhibition of the PAI-1-vitronectin interaction by tiplaxtinin had no such effect. Our data reveals the potential of PAI-1+ PEV as a biomarker in the post-revascularization population and postulates the mechanism in an in vitro model of VSMCs. Accordingly, our data demonstrates the potential of PAI-1 PEV as a strong biomarker following revascularization and PAI-1 inhibition by TM5275 is a promising strategy to reduce the pro-inflammatory VSMC state associated with ISR.

Elevated homocysteine (Hcy) concentration has been identified as an independent risk factor for premature CAD. Associations between Hcy concentrations and established cardiovascular risk factors have occasionally, but not consistently, been demonstrated. Plasma fibrinogen and total Hcy concentrations, along with other risk factors, folate and Bvitamin supplements, and medications, were recorded for 40 males (mean age ± SD: 65 ± 9.8 yr) with CAD. Physical activity was assessed using the Modifiable Activity Questionnaire (MAQ), a written questionnaire which appraises leisure and occupational activities by recall for a 12 month period. Univariate analyses revealed those subjects on beta-blocker therapy (n = 12) had lower fibrinogen concentrations than those not on these medications (n = 28) (277.7 ± 16.7 vs. 316.1 ± 10.9 mg/dl , respectively, p = 0.04). A trend existed for those on beta-blockade to also have lower Hcy concentrations (8.3 ± 0.66 vs 9.7 ± 0.43 µmol/L, respectively, p = 0.058). Subjects in the upper tertile of physical activity had significantly lower fibrinogen concentrations than those in the lower tertile (274.7 ± 38 mg/dl vs. 320.2 ± 63, respectively, p = 0.05). Homocysteine concentration was found to be positively associated with age (p = 0.0008). No significant associations were established with multivariate analyses among fibrinogen, Hcy, physical activity, age, BMI, B-vitamin and folate supplements, beta-blocker therapy, total cholesterol, HDL, LDL, triglycerides, and TC/HDL ratio. These results support the hypothesis that hyperhomocysteinemia is an independent risk factor for CAD. Future studies should consider the favorable effects of beta-blockade, which may be a confounding factor, on Hcy and fibrinogen concentrations. Knowledge of associations may contribute toward understanding of the pathogenesis of CAD. / Master of Science

No description available.

Patients that have suffered from a heart attack, has a condition called coronary artery disease. This condition is partly inherited, by lifestyle choices such as diet, smoking and exercise account for as much as 80 % of the disease progression and outcome. Today a great majority of patients with coronary artery disease choose not to participate in an exercise-based rehabilitation programme after an event, even though exercise has shown to reduce mortality rates by more than 25 %. What if we could encourage patients with coronary artery disease to engage in exercise-based rehabilitation treatment outside a hospital environment?

Ph.D., Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, 2008. / In many developing countries with advanced stages of the nutrition transition, the burden of coronary artery disease (CAD) has shifted from the rich to the poor. Much of this transition is caused by changes in lifestyle, in particular: dietary changes, an increase in weight and obesity, a decrease in physical activity, high levels of stress, and increasing tobacco and alcohol consumption. However, we have come to appreciate a prominent role for inflammation in atherosclerosis and its complications. Globalization, urbanization and Westernization of lifestyle will increase the socioeconomic burden posed by non-communicable diseases in middle-to-low-income countries. In South Africa, it is mainly the African population that is experiencing rapid urbanization and the nutrition transition. Reliable ischaemic heart disease (IHD) mortality data are not available for the black population of South Africa. The purpose of this thesis was: to determine whether factors such as inflammation, postprandial lipaemia and hyperglycaemia are important determinants in black patients with documented CAD (with no previous known history of diabetes mellitus) and their age matched controls; to assess the prevalence of the metabolic syndrome (MS) in black patients and abnormal glucose regulation on black patients with CAD; and to compare the metabolic syndrome prevalence rates using the National Cholesterol Education Program Adult Treatment III (NCEP: ATP III) and International Diabetes Federation (IDF) definitions. Socio-economic status, anthropometric data, glucometabolic variables, LDL particles and MS prevalence rates were measured using 40 patients and 20 controls. The patients were selected consecutively on the basis of a coronary angiogram performed during the preceding 24 months. All subjects had significant CAD, which was defined as more than 50% lesions in one or more major coronary arteries. Subjects with severe hypercholesterolaemia, defined as an untreated total cholesterol level over 7.5 mmol/l, were excluded from the study. Those subjects with diabetes mellitus or HIV/AIDS were excluded from the study. Paper 1, titled ‘Metabolic syndrome, undiagnosed diabetes mellitus and insulin resistance are highly prevalent in urbanized South African blacks with coronary artery disease’, demonstrated a high prevalence of MS in black patients with established CAD. To our knowledge, this is the first report from South Africa that documents the prevalence of the syndrome in black patients with CAD. Almost all of our patients had previously diagnosed hypertension (95%). The second most frequent risk factor was an elevated glucose concentration, which was seen in half the patient cohort. The importance of obesity, particularly abdominal obesity expressed as waist circumference (WC), is well documented as a risk factor for MS. An unexpected outcome of our study was that half of the patients had abnormal glucose regulation, despite the exclusion of previously diagnosed DM. This high prevalence was revealed by the oral glucose tolerance test (OGTT). Paper 2 compares the MS prevalence estimates, as defined by NCEP: ATP III and IDF, amongst urbanized black South Africans with CAD. The IDF proposed a single unifying definition in 2005, as different definitions used different sets of criteria; this led to confusing and inconsistent estimations of MS prevalence. The new definition standardizes the criteria for the diagnosis of MS and offers a fresh assessment of the syndrome. The main findings that arose from the study were that both definitions generated similar prevalence estimates of MS and the two definitions similarly identified the presence or absence of MS in more than 80% of patients. This study demonstrated that postprandial lipaemia and hyperglycemia were common in black CAD patients. Small dense LDL particles were highly associated with CAD. Fasting triglyceride concentrations was the strongest determinant. Prolonged exposure of the endothelium to TG–rich atherogenic remnant particles might be the reason why postprandial increases in TG account for greater CAD risk. Paper 3 assessed postprandial lipaemia in black CAD patients with and without metabolic syndrome. This study was the first to contribute information about postprandial lipaemia and hyperglycaemia in urbanized South African blacks with CAD. Fasting lipid profiles and postprandial responses to the oral fat load were similar in patients with and without metabolic syndrome. A possible explanation might be that because patients in both groups had established CAD, they exhibited some of the underlying features of CAD, such as atherogenic dyslipidaemia. The main finding was that postprandial lipaemia was common in black CAD patients, including patients with metabolic syndrome. Fasting triglycerides concentration was the strongest determinant. Small, dense LDL particles were highly associated with CAD. Paper 4 reports on the assessment of postprandial hyperglycaemia in urbanized blacks with and without CAD. Results showed that glucose AUC was significantly higher in the patients than in control subjects and 120 min. glucose, followed by 0 min. glucose concentration, were the strongest determinants of postprandial hyperglycaemia. Our study demonstrated that as glucose tolerance declined across the normal glucose tolerance, impaired glucose tolerance and diabetes mellitus categories, peak glucose concentrations occurred later in the oral glucose tolerance test; insulin and proinsulin responses were also delayed. A comparison between CAD patients and control subjects drawn from the same ethnic population verified that abnormal glucose tolerance and insulin resistance were more prevalent in the patients with CAD. Paper 5 aimed at investigating whether carotid intima-media thickness (CIMT) is a predictor of CAD in South African black patients. The results showed that CIMT correlated with evidence of angiographically proven CAD. The findings of this study need to be considered within the context of its limitations, i.e. the low number of women and some bias towards only hospital referred CAD patients. It was not our intention to recruit more men than women, but because CAD is more prevalent in men, the majority of participants happened to be male. Performance of the OGTT and hyperinsulinaemic euglycaemic clamp technique is time consuming and requires considerable laboratory resources; therefore a relatively small number of patients and control subjects were studied. These limitations do not detract from the overall conclusions. Paper 6 evaluated markers of inflammation in black CAD patients, some of whom had MS. Leptin was the only marker that increased with additional MS criteria. Elevated hs- CRP concentrations indicated an inflammatory state in CAD patients. Association of leptin with BMI, waist circumference (WC) and hs-CRP revealed a close link with MS, obesity and inflammation in urban black South African CAD patients. Paper 7 investigated the role of diet, socio-demographics and physical activity in a black South African population with CAD, compared to a healthy control group. While diet is known to be affected by urbanisation, differences in dietary intake were observed between the two urban groups, despite the similarity in their socio-demographic profile. The study highlighted the clinical relevance of MS, its likely impact on morbidity and mortality, and that its identification is, therefore, important in risk assessment of patients with CAD. Increasing recognition of MS is, therefore, an initial step in addressing the metabolic problems associated with the syndrome. Furthermore, it was shown that a preponderance of small, dense LDL particles was highly associated with CAD in black patients. Although CAD prevalence is still low at this stage, it is likely to increase rapidly among urban dwellers as they adopt a Western lifestyle.

Orientador: Haroldo Wilson Moreira / Banca: Haroldo Wilson Moreira / Banca: Luiz Carlos de Mattos / Banca: Moacir Fernandes de Godoy / Banca: Paulo Inácio da Costa / Banca: Amauri Antiquera Leite / Resumo: A doença arterial coronariana representa uma das principais causas de morbidade e mortalidade das populações, principalmente naquelas que habitam regiões desenvolvidas. Os considerados fatores de risco para o desenvolvimento dessa doença são bastante conhecidos e analisados, sendo verificada uma importância cada vez maior com relação aos riscos genéticos e a verificação da associação de sistemas polimórficos humanos com a propensão a desenvolver uma determinada doença. A partir desses estudos foi possível imaginar a ocorrência dos denominados marcadores genéticos, onde os autores realizam uma tentativa com vistas às possibilidades de correlacionar esses marcadores com a doença analisada. Foi propósito do presente trabalho estabelecer e verificar a validade para o nosso laboratório de uma metodologia molecular capaz de caracterizar a mutação G1691A no gene do fator V da coagulação, a mutação G20210A no gene da protrombina e as mutações C677T e G1793A no gene da metilenotetrahidrofolato redutase. Com essa possibilidade, verificar e correlacionar as freqüências dessas mutações em portadores de doença arterial coronariana, de não portadores de doença arterial coronariana e em doadores de sangue em uma parcela da população paulista. Para tanto foram estabelecidos três grupos de estudo constituídos por moradores da região de São José do Rio Preto, Estado de São Paulo, sendo dois deles classificados por cinecoronariografia como portadores de doença arterial coronariana e como não portadores de doença arterial coronariana, enquanto um terceiro grupo foi constituído por doadores de sangue da mesma região. A idade dos pacientes variava dos 36 aos 84 anos de idade, enquanto a do terceiro grupo variava dos 18 aos 55 anos de idade... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The coronary artery disease is a major cause of morbidity and mortality of people, especially those who inhabit the developed regions. The considered risk factors for the development of this disease are quite known and analyzed, being observed an increasingly regard to the risks of genetic and a verification of human polymorphic systems' association to the propensity to develop a particular disease. From these studies it was possible to imagine the occurrence of so-called genetic markers, where the authors hold an attempt to view the possibilities of these markers be correlated to the disease examined. The purpose of this work was to establish and verify the validity of a molecular methodology capable of characterizing the mutation in G1691A in the gene of the clotting factor V, the mutation in the gene G20210A prothrombin and of the mutations in the gene C677T and G1793A of methylene-tetrahydrofolate reductase. With this option, check and correlate the frequency of these mutations in individuals with coronary artery disease, in non individuals with coronary artery disease and in blood donors in a share of the Paulista population. Hence, three groups of study were established, consisting in residents of the region of Sao Jose do Rio Preto, São Paulo, two of them classified by coronary angiography as bearers of coronary artery disease and non bearers individuals with coronary artery disease, while a third group was set by donors of blood in the same region. The patients' ages ranged from 36 to 84 years old, while the third group ranged from 18 to 55 years old. The genomic DNA was extracted with Amersham Pharmacia Biotech's Kit, and the characterization of alleles involved in the change G1691A (factor V Leiden), the prothrombin G20210A, and G1793A of MTHFR C677T determined by gene amplification, followed by the performance of restriction enzyme, in accordance with established protocol... (Complete abstract click electronic access below) / Doutor

Le traitement combiné des facteurs de risque, notamment d’une hypertension artérielle et d’un diabète, reste insuffisant pour obtenir une réduction substantielle de la morbidité et de la mortalité cardiovasculaire. Ce risque résiduel peut être considéré comme le reflet d’une maladie artérielle infra clinique. La rigidité aortique et l’amplification de la pression pulsée sont des marqueurs hémodynamiques de l’atteinte artérielle et peuvent être étudiés de manière non invasive. L’objectif de ce travail a été dans un premier temps de décrire la maladie artérielle infra clinique et ses déterminants au sein de deux cohortes de patients à risque cardiovasculaire, hypertendus et/ou diabétiques et patients suivis pour une infection au virus de l’immunodéficience humaine (VIH). L’apport de la mesure non invasive de la rigidité aortique dans l’estimation du risque chez des patients diabétiques de type 2 a été évalué au sein d’une troisième cohorte. La deuxième partie de ce travail a été orientée vers le dépistage de la maladie coronaire. L'apport de la rigidité aortique dans l’amélioration de la valeur prédictive positive des examens de dépistage a été étudié dans le cadre d’un bilan cardiovasculaire réalisé en hôpital de jour. La conclusion principale de ce travail est que la maladie artérielle infra clinique permet d’une part de cibler le patient à haut risque et, d’autre part, d’améliorer le dépistage de la maladie coronaire à l’échelle individuelle. Le suivi de l’évolution, sous traitement, du degré de rigidité aortique et du niveau de pression pulsée centrale, en parallèle avec l’incidence des événements cardiovasculaires, doit permettre désormais de préciser l’importance de ces paramètres dans la prise en charge thérapeutique au-delà du contrôle des facteurs de risque « traditionnels ». / The combined treatment of risk factors, in particular hypertension and diabetes, appears insufficient to achieve substantial reduction in cardiovascular (CV) morbidity and mortality. This residual risk may be indicative of adverse responses of subclinical arterial damage, illustrated by aortic stiffness and pressure wave reflection. These hemodynamic parameters are considered to be associated with central pulse pressure level. Central blood pressure appears closely related to the developpment and complications of atherosclerosis as well as microvascular organ damage. Firstly, the objective of this work was to study subclinical arterial damage by noninvasive measurement of aortic stiffness and pressure wave reflection, and their determinants, in two cohort of patients with increased CV risk, hypertensive and/or diabetic patients and patients with HIV infection. In a third cohort, composed of patients with type 2 diabetes, we studied aortic stiffness as a independant maker of CV disease. Secondly, we investigate whether noninvasive aortic stiffness assessment improves diagnostic accuracy of coronary artery disease (CAD) screnning. The contribution of aortic stiffness in improving the detection of CAD was studied as part of a complete CV evaluation. The main conclusion of this work is that assessment of subclinical arterial damage provides a clinically useful tool to individualize high-risk patients and to improve CAD screening. Prospective evaluation of aortic stiffness and central pulse pressure in parallel with incidence of CV events would clarify the importance of these hemodynamic parameters in the management of the residual risk.