Thesis (Ph. D.)--University of Missouri--Columbia, 2005. / "July 2005." Typescript. Vita. Includes bibliographical references (leaves 152-167). Also issued on the Internet.

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Introdução: os determinantes prognósticos da doença arterial coronária (DAC) incluem tanto a anatomia como a morfologia da placa, havendo uma forte correlação entre essas duas características. Pouco se sabe sobre os desfechos cardiovasculares nos pacientes com sintomas estáveis, assim como sobre o papel dos escores realizados através da angiotomografia das artérias coronárias (TCCor) no prognóstico de longo prazo. Objetivos: avaliar o prognóstico de longo prazo para eventos cardiovasculares nos pacientes sintomáticos com suspeita de DAC que realizaram TCCor em dois estudos prospectivos - CORE 64 e CORE 320. Métodos: foram incluídos 222 pacientes, com idades entre 45 e 85 anos, com indicação clínica de cateterismo por suspeita de doença arterial coronária, submetidos a TCCor no Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo e participantes dos estudos multicêntricos CORE64 e CORE 320. 23 (9,5%) pacientes foram excluídos por perda de seguimento. Foram avaliadas a presença e a extensão da DAC através dos escores tomográficos (SIS, SSS, Gensini e Leaman). Os pacientes foram classificados quanto à presença de DAC não obstrutiva (estenose < 50%) e DAC obstrutiva (estenose > 50%); presença ou ausência de eventos cardiovasculares maiores (MACE). MACE foi definido como evento composto por: IAM não fatal; revascularização miocárdica (realizada acima de 30 dias da inclusão do paciente); óbito cardiovascular; hospitalizações por insuficiência cardíaca (IC) e morte súbita revertida ou arritmias não fatais. Resultados: MACE ocorreu em 73 dos 199 pacientes. 9 (4,5%) apresentaram óbito cardiovascular, 14 (7,0%) IAM não fatal, 31 (15,5%) submeteram a revascularização miocárdica tardia, 11 (5,5%) hospitalizações por IC e 8 (4,0%) morte súbita revertida ou arritmias não fatais. Na análise multivariada, quando adicionados ao modelo clínico isolado, todos os escores tomográficos, com exceção de SIScalc, SISmista e Gensini, correlacionaram-se com a presença de MACE. O modelo que adicionou DAC obstrutiva foi o que apresentou a melhor performance diagnóstica, quando comparado ao modelo clínico isolado (?2 35,6 vs 21,2, p < 0,001). Após ajuste para a presença de DAC obstrutiva, o SISnãocalc permaneceu de forma independente associado a MACE, apresentando benefício incremental sobre o modelo clínico e a severidade da DAC (?2 39,5 vs 21,2, p < 0,001 comparado ao modelo clínico; e ?2 39,5 vs 35,6, p=0,04 comparado ao modelo clínico + severidade DAC). Pacientes com DAC não obstrutiva e SISnãocalc > 3 tiveram altas taxas de eventos (HR 4,27, 95% CI 2,17-4,40, p < 0,001). Conclusões: escores tomográficos predizem eventos cardiovasculares no seguimento de longo prazo nos pacientes sintomáticos com suspeita de DAC. Nossos achados sugerem que, entre os pacientes com DAC obstrutiva, a presença de mais de 3 segmentos com placas não calcificadas está associada ao aumento do risco cardiovascular no longo prazo / Background: The prognostic determinants of coronary artery disease (CAD) include luminal obstruction severity, plaque burden and components, which can be assessed by coronary artery computed tomography angiography (CTA) scores. The role of CTA scores in the long-term prognosis of patients with stable symptoms is unknown. Aim: To evaluate the long-term prognosis value of CTA scores for cardiovascular events in symptomatic patients with suspected CAD referred for coronary CTA in two multicenter prospective studies - CORE 64 and CORE 320. Methods: Two hundred and twenty-two participants from Heart Institute (InCor) University of Sao Paulo Medical School of CORE64 and CORE320 studies, referred for clinically indicated invasive coronary angiography (ICA) for suspected or known CAD were enrolled. Coronary CTA were categorized as non-obstructive or obstructive CAD (greater than 50% stenosis), presence and extent of calcified, noncalcified and partially calcified plaques, using coronary CTA modified scores including all plaques or specific plaque types scores (Segmental Involvement Score - SIS, Segmental Stenosis Score - SSS, Gensini and CTA modified Leaman). The primary endpoint was major adverse cardiac events (MACE), defined as a composite of cardiovascular death, non-fatal acute coronary syndrome, hospitalization for heart failure, late revascularization (beyond 30 days of index conventional coronary angiography), non-fatal significant ventricular arrhythmia or cardiac arrest. Results: During a median follow-up of 6.8 (6.3-9.1) years, 73 patients met the composite end points of MACE. Cardiovascular death occurred in 9 (4.5%), non-fatal ACS in 14 (7.0%), revascularization in 31 (15.5%), hospitalization for heart failure in 11 (5.5%) and non-fatal significant VA or cardiac arrest in 8 (4.0%) patients. When individually added to clinical model on multivariate analysis, all CTA features remained significant, with the exception of SIS of calcified and mixed plaque (SISCalc, SICMixed) and Gensini score. Compared to the clinical model, the highest model improvement was observed when added obstructive CAD (?2 35.6 vs 21.2, p < 0.001). Moreover, CTA multivariate models demonstrated comparable incremental values for the prediction of MACE (X2 > 30), including the extent of non-calcified plaques (SISNoncalc). After further adjustment for the presence of obstructive CAD, SISNoncalc remained independently associated with MACE, presenting incremental prognostic value over clinical data and CAD severity (?2 39.5 vs 21.2, p < 0.001 for comparison with clinical model; and X2 39.5 vs 35.6, p=0.04 for comparison with clinical + CAD severity). Patients with obstructive CAD and SISNoncalc > 3 were likely to experience events (HR 4.27, 95% CI 2.17-4.40, p < 0.001). Conclusions: Coronary CTA scores predict cardiovascular events in long-term follow-up in symptomatic patients with suspected or known CAD. Among patients with obstructive CAD, the presence of more than 3 non-calcified plaques segments is associated with increased cardiovascular risk in the long term

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / "May 2001." Typescript. Vita. Includes bibliographical references (leaves 176-195). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri--Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 121-137).

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Introdução: os determinantes prognósticos da doença arterial coronária (DAC) incluem tanto a anatomia como a morfologia da placa, havendo uma forte correlação entre essas duas características. Pouco se sabe sobre os desfechos cardiovasculares nos pacientes com sintomas estáveis, assim como sobre o papel dos escores realizados através da angiotomografia das artérias coronárias (TCCor) no prognóstico de longo prazo. Objetivos: avaliar o prognóstico de longo prazo para eventos cardiovasculares nos pacientes sintomáticos com suspeita de DAC que realizaram TCCor em dois estudos prospectivos - CORE 64 e CORE 320. Métodos: foram incluídos 222 pacientes, com idades entre 45 e 85 anos, com indicação clínica de cateterismo por suspeita de doença arterial coronária, submetidos a TCCor no Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo e participantes dos estudos multicêntricos CORE64 e CORE 320. 23 (9,5%) pacientes foram excluídos por perda de seguimento. Foram avaliadas a presença e a extensão da DAC através dos escores tomográficos (SIS, SSS, Gensini e Leaman). Os pacientes foram classificados quanto à presença de DAC não obstrutiva (estenose < 50%) e DAC obstrutiva (estenose > 50%); presença ou ausência de eventos cardiovasculares maiores (MACE). MACE foi definido como evento composto por: IAM não fatal; revascularização miocárdica (realizada acima de 30 dias da inclusão do paciente); óbito cardiovascular; hospitalizações por insuficiência cardíaca (IC) e morte súbita revertida ou arritmias não fatais. Resultados: MACE ocorreu em 73 dos 199 pacientes. 9 (4,5%) apresentaram óbito cardiovascular, 14 (7,0%) IAM não fatal, 31 (15,5%) submeteram a revascularização miocárdica tardia, 11 (5,5%) hospitalizações por IC e 8 (4,0%) morte súbita revertida ou arritmias não fatais. Na análise multivariada, quando adicionados ao modelo clínico isolado, todos os escores tomográficos, com exceção de SIScalc, SISmista e Gensini, correlacionaram-se com a presença de MACE. O modelo que adicionou DAC obstrutiva foi o que apresentou a melhor performance diagnóstica, quando comparado ao modelo clínico isolado (?2 35,6 vs 21,2, p < 0,001). Após ajuste para a presença de DAC obstrutiva, o SISnãocalc permaneceu de forma independente associado a MACE, apresentando benefício incremental sobre o modelo clínico e a severidade da DAC (?2 39,5 vs 21,2, p < 0,001 comparado ao modelo clínico; e ?2 39,5 vs 35,6, p=0,04 comparado ao modelo clínico + severidade DAC). Pacientes com DAC não obstrutiva e SISnãocalc > 3 tiveram altas taxas de eventos (HR 4,27, 95% CI 2,17-4,40, p < 0,001). Conclusões: escores tomográficos predizem eventos cardiovasculares no seguimento de longo prazo nos pacientes sintomáticos com suspeita de DAC. Nossos achados sugerem que, entre os pacientes com DAC obstrutiva, a presença de mais de 3 segmentos com placas não calcificadas está associada ao aumento do risco cardiovascular no longo prazo / Background: The prognostic determinants of coronary artery disease (CAD) include luminal obstruction severity, plaque burden and components, which can be assessed by coronary artery computed tomography angiography (CTA) scores. The role of CTA scores in the long-term prognosis of patients with stable symptoms is unknown. Aim: To evaluate the long-term prognosis value of CTA scores for cardiovascular events in symptomatic patients with suspected CAD referred for coronary CTA in two multicenter prospective studies - CORE 64 and CORE 320. Methods: Two hundred and twenty-two participants from Heart Institute (InCor) University of Sao Paulo Medical School of CORE64 and CORE320 studies, referred for clinically indicated invasive coronary angiography (ICA) for suspected or known CAD were enrolled. Coronary CTA were categorized as non-obstructive or obstructive CAD (greater than 50% stenosis), presence and extent of calcified, noncalcified and partially calcified plaques, using coronary CTA modified scores including all plaques or specific plaque types scores (Segmental Involvement Score - SIS, Segmental Stenosis Score - SSS, Gensini and CTA modified Leaman). The primary endpoint was major adverse cardiac events (MACE), defined as a composite of cardiovascular death, non-fatal acute coronary syndrome, hospitalization for heart failure, late revascularization (beyond 30 days of index conventional coronary angiography), non-fatal significant ventricular arrhythmia or cardiac arrest. Results: During a median follow-up of 6.8 (6.3-9.1) years, 73 patients met the composite end points of MACE. Cardiovascular death occurred in 9 (4.5%), non-fatal ACS in 14 (7.0%), revascularization in 31 (15.5%), hospitalization for heart failure in 11 (5.5%) and non-fatal significant VA or cardiac arrest in 8 (4.0%) patients. When individually added to clinical model on multivariate analysis, all CTA features remained significant, with the exception of SIS of calcified and mixed plaque (SISCalc, SICMixed) and Gensini score. Compared to the clinical model, the highest model improvement was observed when added obstructive CAD (?2 35.6 vs 21.2, p < 0.001). Moreover, CTA multivariate models demonstrated comparable incremental values for the prediction of MACE (X2 > 30), including the extent of non-calcified plaques (SISNoncalc). After further adjustment for the presence of obstructive CAD, SISNoncalc remained independently associated with MACE, presenting incremental prognostic value over clinical data and CAD severity (?2 39.5 vs 21.2, p < 0.001 for comparison with clinical model; and X2 39.5 vs 35.6, p=0.04 for comparison with clinical + CAD severity). Patients with obstructive CAD and SISNoncalc > 3 were likely to experience events (HR 4.27, 95% CI 2.17-4.40, p < 0.001). Conclusions: Coronary CTA scores predict cardiovascular events in long-term follow-up in symptomatic patients with suspected or known CAD. Among patients with obstructive CAD, the presence of more than 3 non-calcified plaques segments is associated with increased cardiovascular risk in the long term

Cardiovascular disease (CVD) is the leading cause of death for people of most ethnicities on a global scale, and countless research efforts on the pathology of CVD has been well-characterized over the years. However, advancement in modern technologies, such as nanotechnology, has generated environmental and occupational health concerns within the scientific community. Current investigation of nanotoxicity calls into question the negative effects nanomaterials may invoke from their environmental, commercial, and therapeutic usage. As a result, further research is needed to investigate and characterize the toxicological implications associated with nanomaterial-exposure and CVD. We investigated the toxicity of multi-walled carbon nanotubes (MWCNT) and titanium dioxide (TiO2), which are two prominently used nanomaterials that have been previously linked to upregulation of inflammatory and atherogenic factors. However, the mechanistic pathways involved in these nanomaterials mediating detrimental effects on the heart and/or coronary vasculature have not yet been fully determined. Thus, we utilized two different routes of exposure in rodent models to assess alterations in proinflammatory and proatherogenic signaling pathways, which are represented in contrast throughout the dissertation. In our MWCNT study, we used C57Bl/6 mice exposed to MWCNTs (1 mg/m3) or filtered air (FA-Controls), via inhalation, for 6 hr/d for 14d. Conversely, intravenous TiO2 was administered to F344 male fisher rats, following 24h and 28d post-exposure to a single injection of TiO2-NPs (1 mg/kg), compared to control animals. MWCNT-exposed endpoints investigated the alterations in cholesterol transport, such as lectin-like oxidized low-density lipoprotein receptor (LOX)-1 and ATP-binding cassette transporter (ABCA)-1, inflammatory markers [tumor necrosis factor (TNF)-α], interleukin (IL)-1β/IL-6, nuclear-factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signaling factors involved in activation of the pathway, as well as intracellular/vascular adhesion molecule(s) (VCAM-1, ICAM-1), and miRNAs (miR-221/-21/-1), associated with CVD, were analyzed in cardiac tissue and coronary vasculature. Cardiac fibrotic deposition, matrix-metalloproteinases (MMP)-2/9, and reactive oxygen species (ROS) were also assessed. TiO2-exposure endpoints also involved alterations on cholesterol transport proteins via LOX-1 and ABCA-1, factors of inflammation, namely intracellular macrophages and interleukin (IL)-1β, MMP-2/9 activity and protein expression, fibrotic deposition, and ROS generation were analyzed via quantitative detection or histologically in both cardiac tissue and coronary vasculature. Results from both studies found alterations in fibrotic deposition, upregulation in LOX-1 expression and MMP-2/9 activity, and ROS generation; with a concurrent decrease in ABCA-1 expression in cardiac tissue and coronary vasculature. Individually, MWCNT-exposed endpoints had shown induction of cardiac TNF-α, MMP-9, IκB Kinase (IKK)-α/β, and miR-221 mRNAs; as well as increased coronary expression of TNF-α and VCAM-1. TiO2 studies found increases in IL-1β and MMP-9 protein expression, as well as intracellular macrophage induction. Both studies also found, through pre-treatment of NADPH oxidase inhibitor, apocynin, resulted in attenuation of nanomaterial-exposure mediated ROS production; with nitric oxide synthase inhibitor, L-NNA, also showing attenuation, but only in our MWCNT-exposed inhalation study. The results from both studies have demonstrated, through different routes of administration, exposures, and rodent models; that exposure to nanomaterials can mediate signaling pathways involved in initiation and/or progression of CVD.

Objetivo: checar se poluentes do ar urbano de São Paulo induzem alterações sangüíneas e cardiopulmonares. MM: camundongos Balb/c foram expostos por 7, 14, 21, 30 e 45 dias em 3 câmaras: Limpa (controle), Intermediária (seletiva ao PM) e Suja (ar externo). Após exposição, os animais foram ventilados (FlexiVent) e coletados dados de mecânica pulmonar, sangue, coração e pulmão. Foram registrados PM, CO, SO2 e NO2 diários. Resultados: aos 21 e 45 dias coincidentes com picos de poluição houve aumento da resistência de via aérea (45d p=0,012), leucocitose (21d p < 0,001 e 45d p=0,039) e vasoconstricção pulmonar (21d p=0,034) nos animais da Câmara Suja, sem alteração de coronárias. Nenhum poluente excedeu limites de qualidade de ar / Objective: verify if air pollution of São Paulo city induces alterations in blood and cardiopulmonary systems. MM: Balb/c mice were exposed during 7, 14, 21, 30 and 45 days to 3 chambers: Clean (control), Intermediate (PM only) and Dirty (external air). After exposure, animals were ventilated (FlexiVent) and collected lung mechanics data and blood, heart and lung. PM, CO, SO2 e NO2 were measured daily. Results: on day 21 and 45, coincidently to peak of pollutions, there was proximal airway resistance increase (45d p=0.012), leukocytosis (21d p < 0.001 and 45d p=0.039) and vasoconstriction of peribronchiolar arterioles (21d p=0.034) in animals of Dirty Chamber with no alterations of coronaries. Neither pollutants exceeded the standard limits