Não há evidência conclusiva da vantagem da revascularização cirúrgica do miocárdio (RCM) ou angioplastia percutânea coronária (APC) sobre o tratamento clínico (TC) em pacientes sintomáticos, com doença arterial coronária (DAC) multiarterial e função ventricular esquerda (FVE) preservada. O objetivo deste estudo foi comparar os resultados em longo prazo da RCM ou APC com o TC em pacientes portadores de DAC em múltiplos vasos e FVE preservada. Os desfechos primários do estudo foram a combinação de morte por qualquer origem, infarto do miocárdio não fatal (IAM) e angina refratária com necessidade de intervenção mecânica. O desfecho secundário foi o estado anginoso ao final do estudo. Todos os eventos foram analisados de acordo com o princípio de intenção de tratar. De 2.077 pacientes elegíveis para randomização dentre 20.769 pacientes avaliados para participar do estudo, 611 foram efetivamente randomizados para se submeterem à RCM (n=203), APC (n=205) ou TC (n=203). Em 10 anos de seguimento desfechos primários ocorreram em 37,9% dos pacientes submetidos à RCM em comparação a 56,1% dos submetidos à APC e 69% dos que receberam TC (p<0,0001). Não foi encontrada nenhuma diferença com relação à morte por qualquer origem entre RCM (25,1%), APC (23,9%) e TC (31%) (p=0,230). Intervenção mecânica por causa de angina refratária foi necessária em 38,9% dos que receberam TC, comparada a 40% dos submetidos à APC e 7,4% dos que se submeteram à RCM (p<0,0001). Em adição, 20,7% dos pacientes que receberam TC tiveram IAM, em comparação a 13,2% dos submetidos à APC e 9,9% dos submetidos à RCM (p=0,008). Pacientes submetidos à TC tiveram maior incidência de morte por origem cardíaca (20,7%) do que os submetidos à APC (14,1%) e RCM (10,8%) (p=0,021), no entanto, essa diferença só foi significativa entre RCM e TC (p=0,009). Nenhuma diferença significativa foi encontrada na incidência de AVE entre os três grupos de tratamento (p=0,303). Ao final do seguimento, angina estava presente em 14,8% dos pacientes alocados para TC em comparação a 9,3% dos submetidos à APC e 6,4% dos submetidos à RCM (p=0,022). A RCM reduziu de modo significativo e independente a incidência de eventos combinados em comparação ao TC (HR=0,449; IC95%=0,346 - 0,583) e à APC (HR=0,560; IC95%=0,431 0,726), sobretudo à custa de redução da intervenção mecânica em comparação ao TC (HR=0,162; IC95%=0,113-0,232) e à APC (HR=0,150;IC95%=0,111-0,228). A RCM também reduziu significativamente a incidência de IAM e o estado anginoso em comparação ao TC (HR=0,467; IC95%=0,280 0,780; p=0,013 e HR=0,397; IC95=0,200 0,785; p=0,009, respectivamente). O estudo revelou que os três tipos de tratamento alcançaram índices elevados e semelhantes de sobrevivência em 10 anos de seguimento. Todavia, a cirurgia foi superior ao tratamento clínico na prevenção do infarto do miocárdio não fatal, na diminuição da incidência de angina e na prevenção da intervenção mecânica guiada por angina refratária. A angioplastia e o tratamento clínico mostraram resultados semelhantes em relação ao alívio dos sintomas anginosos e na prevenção dos eventos combinados definidos como morte por qualquer origem, infarto do miocárdio não fatal e a necessidade de intervenção mecânica / There was no conclusive evidence that coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) is superior to medical therapy (MT) alone in symptomatic patients with multivessel coronary artery disease (CAD), and preserved left ventricular function. The objective of this study is to compare the long-term results of CABG or PCI versus MT in patients with multivessel CAD and preserved left ventricular function. The primary end-points were the combination (MACE) of overall mortality, non fatal acute myocardial infarction (AMI), and refractory angina requiring revascularization. Secondary end-point was the angina status at the end of follow-up. All events were analyzed according to the intention to treat principle. From 2.077 eligible patients for randomization among 20.769 patients screened for the trial, 611 could be randomized to CABG (n=203), PCI (n=205), and MT (n=203). At 10-year follow-up, MACE occurred in 69% of patients who underwent MT, compared to 56% treated with PCI, and 37.9% receiving CABG (p<0.0001). There were no statistical differences in overall mortality among the three groups (31% in MT, 23.9% in PCI, and 25.1% in CABG; p=0.230). Mechanical intervention driven by refractory angina were necessary in 38.9% of patients in the MT, compared to 40% in the PCI, and 7.4% in the CABG group (p<0.0001). In addition, non-fatal acute myocardial infarction (AMI) were experienced by 20.7% of patients receiving MT, in comparison to 13.2% of patients submitted to PCI and 9.9% of those submitted to CABG (p=0.008). Patients who underwent MT had higher cardiac mortality (20.7%), than patients receiving PCI (14.1%) or CABG (10.8%) (p=0.021), however this difference was significant only between CABG and MT (p=0,009). No statistical differences were observed in the incidence of stroke among the three groups of treatment (p=0.303). At the end of follow-up angina was present in 14.8% of MT patients, compared to 9.3% of PCI patients, and 6.4% of CABG patients (p=0.022). CABG independently reduced the incidence of MACE in comparison to MT (HR=0.449; CI95%=0.346 0.583) and PCI (HR=0.560; CI95%=0.431 0.726). This reduction is mainly driven by reduction in the rate of mechanical intervention in comparison to MT (HR=0.162; CI95%=0.113-0.232), and PCI (HZ=0.150; CI95%=0.111-0.228). CABG also reduced the incidence of AMI and angina status in comparison to MT (HR=0.150; IC95%=0.280 0.780; p=0.013; HR=0.397; IC95%=0.200 0.785; p=0.009, respectively). Our study has shown that the three treatment options yielded comparable and elevated rates of survival in 10-year follow-up. However, CABG was superior to MT in the prevention of AMI, in the reduction of the angina incidence, and in the prevention of mechanical intervention. Angioplasty and MT have shown similar results in relation to angina alleviation and prevention from MACE defined as the combination of all cause mortality, AMI, and the need of mechanical intervention

INTRODUÇÃO: A trombose venosa profunda é uma doença de alta incidência, e uma das principais causas de insuficiência venosa profunda. O tratamento clássico, com heparina e anticoagulante oral, não tem ação direta sobre o tempo de remoção do trombo. O tratamento trombolítico seletivo por cateter permite rápida remoção do coágulo com complicações inferiores a administração sistêmica do fibrinolítico. OBJETIVO: Comprovar a eficácia da infusão seletiva de rt-PA em baixas doses no tratamento da trombose venosa profunda iliacofemoral aguda e na prevenção do desenvolvimento dos sinais, sintomas e alterações hemodinâmicas tardios relacionados à síndrome pós-trombótica.METODO: Em pacientes portadores de trombose venosa profunda iliacofemoral aguda, implantou-se um cateter reto multiperfurado no segmento venoso acometido, e infundiuse dose contínua de 1,0 mg/hora de rtPA diluído. O controle do procedimento foi feito por flebografia transcateter a cada 12-18h. RESULTADOS: Quinze pacientes foram selecionados. Houve fibrinólise efetiva em 12 dos 15 casos (80%), com restabelecimento da perviedade iliacofemoral. O tempo médio de infusão do rt-PA foi de 41 horas. Houve correlação entre o grau de fibrinólise e a magnitude da melhora clínica (p < 0,05). Não ocorreram complicações maiores, tais como embolia pulmonar ou hemorragias graves. Quatro pacientes apresentaram episódios de retrombose. O grupo foi seguido por um período de 45 a 131 semanas (mediana de 99). Nos oito pacientes em que a fibrinólise foi efetiva e não houve retrombose, a incidência de seqüelas clínicas e de refluxo valvular venoso ao duplex-scan foi inferior a observada nos sete pacientes com falha terapêutica ou retrombose (p < 0,01 nas duas amostras). A diferença na incidência de recanalização venosa completa também foi estatisticamente significativa (p < 0,05) em favor do grupo com fibrinólise efetiva. CONCLUSÕES: A terapêutica trombolítica seletiva com rt-PA em baixas doses é eficaz e segura no tratamento agudo da trombose venosa iliacofemoral. A evolução clínica e ultrassonográfica tardia foram significativamente superiores nos pacientes em que a terapêutica foi efetiva / INTRODUCTION: Deep venous thrombosis keeps being a high incidence disease and one of the leading causes of chronic venous insufficiency. The classic therapy with heparin and oral anticoagulation doesn\'t have direct action over thrombus removal time. Seletive catheter-directed thrombolysis allows an early thrombus removal with a lower rate of complications than systemic thrombolysis. OBJECTIVES: To prove the efficacy of catheterdirected low-dose rt-PA infusion in the treatment of acute iliofemoral deep vein thrombosis and in the prevention of late clinical and haemodinamic sequelae of post-thrombotic syndrome. METHODS: In selected patients with acute iliofemoral deep venous thrombosis, a straight multiside-hole catheter was introduced through the thrombotic venous segments. A low-dose (1mg/h) rt-PA continuous infusion was initiated and control transcatheter phlebography was taken every 12-18 hours. RESULTS: Fifteen patients were selected. Effective fibrinolysis was achieved in 12 of 15 cases (80%), with iliofemoral patency obtained. The medium time of rt-PA infusion was 41 hours. Statistic correlation between lysis grade and clinical improvement was observed (p < 0,05). There were no episodes of major complications such as transfusion-needed hemorrhage or pulmonary embolism. Four patients presented with rethrombosis. The group was followed by a period of 45 to 131 weeks (median 99). In the eight patients in witch lytic therapy was well succeeded and venous patency was kept, the incidence of clinical signs and symptoms of venous insufficiency and duplex-scan findings of valvular reflux was statistically lower than in the seven patients with acute therapeutic failure or rethrombosis (p < 0,01 for both). There was also difference in findings of complete venous recanalization between the two groups (p < 0,05), showing benefit to the group with effective therapy. CONCLUSIONS: Low-dose rt-PA fibrinolytic therapy is safe and effective in the treatment of iliofemoral acute venous thrombosis. The clinical and ultrasound late evolution was superior in patients in witch lytic therapy was effective

3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG CoA) reductase is a 97 kDa glycoprotein located in the endoplasmic reticulum responsible for cholesterol biosynthesis in mammalian liver and intestine. HMG CoA reductase inhibitors (statins) (e.g. simvastatin, mevastatin and parvastatin) are used clinically to treat and prevent coronary artery diseases by reducing plasma LDL-cholesterol level. Recent studies have demonstrated that statins can provide beneficial effects (pleiotropic effects) beyond its lipid-lowering activity. However, the modulatory effects of statins on ion channels activities have not been fully explored. Hence, this study is designed to demonstrate the existence of the HMG CoA reductase in various human isolate cardiovascular preparations and the modulatory effect(s) of simvastatin on both large-conductance calcium-activated (BKCa) and ATP-sensitive (IKATP) potassium channels of porcine isolated coronary vascular smooth muscle cells. / In conclusion, our results demonstrated the biochemical existence of HMG CoA reductase in various human isolated cardiovascular preparations and porcine isolated coronary artery. Simvastatin modulates the BKCa and IKATP channels of the porcine isolated coronary artery via different and multiple cellular mechanisms. / In this study, we demonstrated the biochemical existence of the HMG CoA reductase in various human isolated cardiovascular preparations and porcine isolated coronary artery. In addition, we demonstrated that simvastatin modulates both the BKCa channels and IKATP channels of porcine isolated coronary artery via different mechanisms. Acute application of simvastatin (100 nM) slightly enhanced whereas simvastatin (&ge; 1 muM) inhibited the BKCa amplitude of porcine coronary artery smooth muscle cells. The classical HMG CoA reductase-mevalonate cascade is important in mediating the inhibitory effect of simvastatin observed at low concentrations (1 and 3 muM), whereas an increased PKC-delta protein expression and activation is important in simvastatin (10 muM)-mediated inhibition of BKCa channels. In contrast, the basal activity of the IKATP channels was not affected by simvastatin (1, 3 and 10 muM). However, acute application of simvastatin (1, 3 and 10 muM) inhibited the opening of the IKATP channels by cromakalim and pinacidil in a PP2A-dependent manner (sensitive to okadaic acid, a PP2A inhibitor). The okadaic acid-sensitive, simvastatin-mediated inhibitory effect on IKATP channel is mediated by an activation of AMPK in a Ca2+-dependent manner. Activation of AMPK probably increased the activity of the Na+/K+ ATPase and subsequently caused an influx of glucose via the SGLT1 down the Na + concentration gradient for the ouabain-sensitive, glucose-dependent activation of PP2A. / Seto, Sai Wang. / Adviser: Yiu-Wa Kwan. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3456. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 221-254). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Não há evidência conclusiva da vantagem da revascularização cirúrgica do miocárdio (RCM) ou angioplastia percutânea coronária (APC) sobre o tratamento clínico (TC) em pacientes sintomáticos, com doença arterial coronária (DAC) multiarterial e função ventricular esquerda (FVE) preservada. O objetivo deste estudo foi comparar os resultados em longo prazo da RCM ou APC com o TC em pacientes portadores de DAC em múltiplos vasos e FVE preservada. Os desfechos primários do estudo foram a combinação de morte por qualquer origem, infarto do miocárdio não fatal (IAM) e angina refratária com necessidade de intervenção mecânica. O desfecho secundário foi o estado anginoso ao final do estudo. Todos os eventos foram analisados de acordo com o princípio de intenção de tratar. De 2.077 pacientes elegíveis para randomização dentre 20.769 pacientes avaliados para participar do estudo, 611 foram efetivamente randomizados para se submeterem à RCM (n=203), APC (n=205) ou TC (n=203). Em 10 anos de seguimento desfechos primários ocorreram em 37,9% dos pacientes submetidos à RCM em comparação a 56,1% dos submetidos à APC e 69% dos que receberam TC (p<0,0001). Não foi encontrada nenhuma diferença com relação à morte por qualquer origem entre RCM (25,1%), APC (23,9%) e TC (31%) (p=0,230). Intervenção mecânica por causa de angina refratária foi necessária em 38,9% dos que receberam TC, comparada a 40% dos submetidos à APC e 7,4% dos que se submeteram à RCM (p<0,0001). Em adição, 20,7% dos pacientes que receberam TC tiveram IAM, em comparação a 13,2% dos submetidos à APC e 9,9% dos submetidos à RCM (p=0,008). Pacientes submetidos à TC tiveram maior incidência de morte por origem cardíaca (20,7%) do que os submetidos à APC (14,1%) e RCM (10,8%) (p=0,021), no entanto, essa diferença só foi significativa entre RCM e TC (p=0,009). Nenhuma diferença significativa foi encontrada na incidência de AVE entre os três grupos de tratamento (p=0,303). Ao final do seguimento, angina estava presente em 14,8% dos pacientes alocados para TC em comparação a 9,3% dos submetidos à APC e 6,4% dos submetidos à RCM (p=0,022). A RCM reduziu de modo significativo e independente a incidência de eventos combinados em comparação ao TC (HR=0,449; IC95%=0,346 - 0,583) e à APC (HR=0,560; IC95%=0,431 0,726), sobretudo à custa de redução da intervenção mecânica em comparação ao TC (HR=0,162; IC95%=0,113-0,232) e à APC (HR=0,150;IC95%=0,111-0,228). A RCM também reduziu significativamente a incidência de IAM e o estado anginoso em comparação ao TC (HR=0,467; IC95%=0,280 0,780; p=0,013 e HR=0,397; IC95=0,200 0,785; p=0,009, respectivamente). O estudo revelou que os três tipos de tratamento alcançaram índices elevados e semelhantes de sobrevivência em 10 anos de seguimento. Todavia, a cirurgia foi superior ao tratamento clínico na prevenção do infarto do miocárdio não fatal, na diminuição da incidência de angina e na prevenção da intervenção mecânica guiada por angina refratária. A angioplastia e o tratamento clínico mostraram resultados semelhantes em relação ao alívio dos sintomas anginosos e na prevenção dos eventos combinados definidos como morte por qualquer origem, infarto do miocárdio não fatal e a necessidade de intervenção mecânica / There was no conclusive evidence that coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) is superior to medical therapy (MT) alone in symptomatic patients with multivessel coronary artery disease (CAD), and preserved left ventricular function. The objective of this study is to compare the long-term results of CABG or PCI versus MT in patients with multivessel CAD and preserved left ventricular function. The primary end-points were the combination (MACE) of overall mortality, non fatal acute myocardial infarction (AMI), and refractory angina requiring revascularization. Secondary end-point was the angina status at the end of follow-up. All events were analyzed according to the intention to treat principle. From 2.077 eligible patients for randomization among 20.769 patients screened for the trial, 611 could be randomized to CABG (n=203), PCI (n=205), and MT (n=203). At 10-year follow-up, MACE occurred in 69% of patients who underwent MT, compared to 56% treated with PCI, and 37.9% receiving CABG (p<0.0001). There were no statistical differences in overall mortality among the three groups (31% in MT, 23.9% in PCI, and 25.1% in CABG; p=0.230). Mechanical intervention driven by refractory angina were necessary in 38.9% of patients in the MT, compared to 40% in the PCI, and 7.4% in the CABG group (p<0.0001). In addition, non-fatal acute myocardial infarction (AMI) were experienced by 20.7% of patients receiving MT, in comparison to 13.2% of patients submitted to PCI and 9.9% of those submitted to CABG (p=0.008). Patients who underwent MT had higher cardiac mortality (20.7%), than patients receiving PCI (14.1%) or CABG (10.8%) (p=0.021), however this difference was significant only between CABG and MT (p=0,009). No statistical differences were observed in the incidence of stroke among the three groups of treatment (p=0.303). At the end of follow-up angina was present in 14.8% of MT patients, compared to 9.3% of PCI patients, and 6.4% of CABG patients (p=0.022). CABG independently reduced the incidence of MACE in comparison to MT (HR=0.449; CI95%=0.346 0.583) and PCI (HR=0.560; CI95%=0.431 0.726). This reduction is mainly driven by reduction in the rate of mechanical intervention in comparison to MT (HR=0.162; CI95%=0.113-0.232), and PCI (HZ=0.150; CI95%=0.111-0.228). CABG also reduced the incidence of AMI and angina status in comparison to MT (HR=0.150; IC95%=0.280 0.780; p=0.013; HR=0.397; IC95%=0.200 0.785; p=0.009, respectively). Our study has shown that the three treatment options yielded comparable and elevated rates of survival in 10-year follow-up. However, CABG was superior to MT in the prevention of AMI, in the reduction of the angina incidence, and in the prevention of mechanical intervention. Angioplasty and MT have shown similar results in relation to angina alleviation and prevention from MACE defined as the combination of all cause mortality, AMI, and the need of mechanical intervention

INTRODUÇÃO: A trombose venosa profunda é uma doença de alta incidência, e uma das principais causas de insuficiência venosa profunda. O tratamento clássico, com heparina e anticoagulante oral, não tem ação direta sobre o tempo de remoção do trombo. O tratamento trombolítico seletivo por cateter permite rápida remoção do coágulo com complicações inferiores a administração sistêmica do fibrinolítico. OBJETIVO: Comprovar a eficácia da infusão seletiva de rt-PA em baixas doses no tratamento da trombose venosa profunda iliacofemoral aguda e na prevenção do desenvolvimento dos sinais, sintomas e alterações hemodinâmicas tardios relacionados à síndrome pós-trombótica.METODO: Em pacientes portadores de trombose venosa profunda iliacofemoral aguda, implantou-se um cateter reto multiperfurado no segmento venoso acometido, e infundiuse dose contínua de 1,0 mg/hora de rtPA diluído. O controle do procedimento foi feito por flebografia transcateter a cada 12-18h. RESULTADOS: Quinze pacientes foram selecionados. Houve fibrinólise efetiva em 12 dos 15 casos (80%), com restabelecimento da perviedade iliacofemoral. O tempo médio de infusão do rt-PA foi de 41 horas. Houve correlação entre o grau de fibrinólise e a magnitude da melhora clínica (p < 0,05). Não ocorreram complicações maiores, tais como embolia pulmonar ou hemorragias graves. Quatro pacientes apresentaram episódios de retrombose. O grupo foi seguido por um período de 45 a 131 semanas (mediana de 99). Nos oito pacientes em que a fibrinólise foi efetiva e não houve retrombose, a incidência de seqüelas clínicas e de refluxo valvular venoso ao duplex-scan foi inferior a observada nos sete pacientes com falha terapêutica ou retrombose (p < 0,01 nas duas amostras). A diferença na incidência de recanalização venosa completa também foi estatisticamente significativa (p < 0,05) em favor do grupo com fibrinólise efetiva. CONCLUSÕES: A terapêutica trombolítica seletiva com rt-PA em baixas doses é eficaz e segura no tratamento agudo da trombose venosa iliacofemoral. A evolução clínica e ultrassonográfica tardia foram significativamente superiores nos pacientes em que a terapêutica foi efetiva / INTRODUCTION: Deep venous thrombosis keeps being a high incidence disease and one of the leading causes of chronic venous insufficiency. The classic therapy with heparin and oral anticoagulation doesn\'t have direct action over thrombus removal time. Seletive catheter-directed thrombolysis allows an early thrombus removal with a lower rate of complications than systemic thrombolysis. OBJECTIVES: To prove the efficacy of catheterdirected low-dose rt-PA infusion in the treatment of acute iliofemoral deep vein thrombosis and in the prevention of late clinical and haemodinamic sequelae of post-thrombotic syndrome. METHODS: In selected patients with acute iliofemoral deep venous thrombosis, a straight multiside-hole catheter was introduced through the thrombotic venous segments. A low-dose (1mg/h) rt-PA continuous infusion was initiated and control transcatheter phlebography was taken every 12-18 hours. RESULTS: Fifteen patients were selected. Effective fibrinolysis was achieved in 12 of 15 cases (80%), with iliofemoral patency obtained. The medium time of rt-PA infusion was 41 hours. Statistic correlation between lysis grade and clinical improvement was observed (p < 0,05). There were no episodes of major complications such as transfusion-needed hemorrhage or pulmonary embolism. Four patients presented with rethrombosis. The group was followed by a period of 45 to 131 weeks (median 99). In the eight patients in witch lytic therapy was well succeeded and venous patency was kept, the incidence of clinical signs and symptoms of venous insufficiency and duplex-scan findings of valvular reflux was statistically lower than in the seven patients with acute therapeutic failure or rethrombosis (p < 0,01 for both). There was also difference in findings of complete venous recanalization between the two groups (p < 0,05), showing benefit to the group with effective therapy. CONCLUSIONS: Low-dose rt-PA fibrinolytic therapy is safe and effective in the treatment of iliofemoral acute venous thrombosis. The clinical and ultrasound late evolution was superior in patients in witch lytic therapy was effective

Lam Lop Chi. / Thesis submitted in: August 2005. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 114-126). / Abstracts in English and Chinese. / Acknowledgements --- p.I / Abstract in English --- p.II-IV / Abstract in Chinese --- p.V-VI / List of Abbreviations --- p.VII-IX / List of Figures --- p.X / List of Tables --- p.XI-XII / Table of Contents --- p.XIII-XV / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Background --- p.1 / Chapter 1.2 --- Risk factors --- p.6 / Chapter 1.3 --- Overseas guidelines in CAD management --- p.11 / Chapter 1.4 --- Angioplasty in CAD intervention --- p.15 / Chapter 1.5 --- Prevention or Intervention? --- p.21 / Chapter 1.6 --- Economic impact on PCI --- p.24 / Chapter 1.7 --- Cost of illness --- p.28 / Chapter 1.8 --- Hypothesis --- p.30 / Chapter 1.9 --- Objectives --- p.30 / Chapter Chapter 2 --- Cost of AMI Study / Chapter 2.1 --- Background --- p.31 / Chapter 2.2 --- Objective --- p.32 / Chapter 2.3 --- Method --- p.32 / Chapter 2.4 --- Results --- p.35 / Chapter 2.5 --- Discussion --- p.49 / Chapter 2.6 --- Study limitations --- p.58 / Chapter 2.7 --- Conclusions --- p.58 / Chapter Chapter 3 --- Angina study / Chapter 3.1 --- Background --- p.60 / Chapter 3.2 --- Objective --- p.76 / Chapter 3.3 --- Hypothesis --- p.76 / Chapter 3.4 --- Method --- p.76 / Chapter 3.5 --- Results --- p.79 / Chapter 3.6 --- Discussion --- p.93 / Chapter 3.7 --- Study limitations --- p.101 / Chapter 3.8 --- Conclusions --- p.101 / Chapter Chapter 4 --- Overall Discussion --- p.103 / Chapter Chapter 5 --- Conclusions --- p.112 / References --- p.114 / Appendix --- p.127