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.

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, 2005. / Bibliography: leaves 68-79.

Thesis (M.N.)--Memorial University of Newfoundland, 2004. / Bibliography: leaves 96-101.

The purpose of this study W8S to explore and describe the experience of waiting for coronary artery bypass graft (CABG) surgery from the perspective of the individual who h8s a prolonged wait for this surgery. A phenomenological approach was used to guide the study. Data were collected through 17 semi-structured, audio-taped interviews with 7 men and 2 women awaiting CABG surgery. Analysis occurred concurrently with data collection. It was found that there were three interrelated core facets of the experience: the illness, the prospective surgery, and the wait. Each facet held distinct meaning: the illness represented a loss of normalcy and a threat to life; the surgery, both an opportunity to regain normalcy and a threat; and the wait, a "no control" situation which enhanced the losses and threats of the other facets, engendered further losses, and delayed the expected gain from surgery. Within each facet, representative emotional reactions, and coping strategies were identified. The findings indicate that these clients require regular contact and that nursing care must address all three facets of the experience. / Applied Science, Faculty of / Nursing, School of / Graduate

A 41‐year‐old man presenting with unstable angina was found to have diffuse coronary ectasia with a partially occluding thrombus in the proximal left anterior descending artery. Anticoagulation with heparin followed by warfarin resulted in relief of angina and resolution of thrombosis at follow‐up angiography 3.5 months later. The patient remains well after three years. Nonatherosclerotic ectatic coronary arteries are prone to thrombosis possibly because of spasm, intimal damage, and blood current eddies. We believe that chronic warfarin therapy may be indicated in many patients with coronary ectasia.

No description available.

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?