In order to identify patients with severe coronary artery disease (CAD) and at a higher risk of future cardiac events after uncomplicated myocardial infarction, 105 consecutive patients were studied prospectively. There were 93 men and 12 women with a mean age of 56 +/- 8.2 years. Treadmill testing, exercise radionuclide ventriculography, thallium-201 myocardial imaging and selective coronary arteriography were performed 6-8 weeks after infarction. Patients were grouped into those who had single and multiple vessel disease. Multiple regression analysis of 18 noninvasive indices was carried out using generalized linear interactive modelling (GLIM) and the results were compared with the severity of underlying CAD and the clinical outcome after a mean follow-up period of 18.8 +/- 3. 4 months. At the end of the follow-up period, patients were categorized into those who had no cardiac events, minor and major cardiac events. Multivariate analysis produced an algorithm from three factors found to be most predictive of the severity of CAD. These included ST-segment depression on exercise, total score of rest and exercise regional wall motion and the presence of significant redistribution on thallium-201 imaging. The sensitivity of this algorithm for predicting multiple vessel disease was 42%, with a specificity of 94%, and a predictive accuracy of 69%. However, the total score of regional wall motion abnormalities was the single most predictive factor of major cardiac events with a sensitivity of 94%, a specificity of 57%, and predictive accuracy of 63%. None of the other factors produced additional prognostic information. Therefore, exercise radionuclide ventriculography appears to be the investigation of choice in assessing prognosis after myocardial infarction.

No description available.

Intimal hyperplasia in the proximal portion of the right coronary artery was investigated by using longitudinal sections of the artery, to determine the amount of intimal and medial thickness, and the amount of deviation from the normal of the internal elastic lamina. One hundred and one samples in the 0-30 year age range were used and the results correlated with other known information about the individuals. Findings: 1. Intimal thickness increases directly as age increases. 2. There was a sex difference in the 16-30 year age group (males greater than females), but not under 15 years. 3. Intimal thickness increases significantly as the amount of internal elastic lamina change increases. 4. Medial thickness increases significantly with increasing age. 5. Intimal thickness increases significantly as medial thickness, heart mass and body mass increase, and increases at a more rapid rate than any of the three. 6. The amount of elastic lamina change increases significantly with age only between 1 and 30 years. These findings are correlated with the possible factors in the etiology of intimal hyperplasia. / Medicine, Faculty of / Graduate

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.

No description available.

Vitamin C (ascorbate or Asc) is an essential vitamin for humans. The transport of oxidized ascorbate occurs via Na^+-dependent vitamin C transporters (SVCTI/SVCT2). Ascorbate is a powerful antioxidant that may be beneficial in scavenging the reactive oxygen species associated with cardiovascular diseases. The objectives of this thesis were: to identify the SVCT isoform(s) expressed in pig coronary artery smooth muscle and endothelium, to determine if preloading cultured pig coronary artery smooth muscle cells with ascorbate protects them against oxidative stress, and to overexpress SVCT2 in these cells to see if an increase in ascorbate reserve helps protect the cells even more. Pig coronary artery smooth muscle tissue and cells cultured from the same tissue express SVCT2 and not SVCT1. Cultured pig coronary artery endothelial express SVCT2, however the limited amount of fresh endothelium isolated, restricted us from determining the isoform present in the fresh tissue. Ascorbate preloading (200 (mu)M overnight) did not decrease the damage caused by hydrogen peroxide as measured by oxidation of dichlorodihydrofluorescein diacetate or mitochondrial reductase activity. The mRNA and ^14C-Asc uptake was marginally greater in pig coronary artery smooth muscle cells stably transfected with a linear pcDNA3.1 SVCT2 plasmid than mock transfected controls. The ^14C-Asc uptake was 1.5 times greater than mock transfected cells after 60 min. A new SVCT2 plasmid, that contained SVCT2 coding region only, did not show greater ^14C-Asc accumulation compared to the plasmid that had the entire SVCT2 cDNA in transiently transfected HEK293T cells. This thesis is a beginning towards further study on the molecular and physiological role ascorbate plays in the coronary artery. / Thesis / Master of Science (MS)

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

Thesis (M.Sc.)--Memorial University of Newfoundland, 2003. / Restricted until October 2004. Bibliography: leaves 95-101.

published_or_final_version / abstract / Pharmacology / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine