Increasingly, cell-based therapy with autologous progenitor populations, such as endothelial progenitor cells (EPC), are being utilized for treatment of vascular diseases. However, both the number and functional capacity are diminished when cells are derived from patients with established risk factors for coronary artery disease (CAD). Herein, we report that inhibition of glycogen synthase kinase 3 (GSK) can improve both the number and function of endothelial progenitor cells in patients with CAD or diabetes mellitus (DM) leading to greater therapeutic benefit. Specifically, use of various small molecule inhibitors of GSK (GSKi) results in a 4-fold increased number of EPCs. Moreover, GSKi treatment improves the functional profile of EPCs through reductions in apoptosis, improvements in cell adhesion through up-regulation of very-late antigen-4 (VLA-4), and by increasing paracrine efficacy by increasing vascular endothelial growth factor (VEGF)secretion. Therapeutic improvement was confirmed in vivo by increased reendothelialization(RE) and reductions of neointima (NI) formation achieved when GSKi-treated cells were administered following vascular injury to CD-1 nude mice. Because cell-based therapy is technically challenging, we also tested a strategy of local delivery of GSKi at the site of arterial injury through GSKi-eluting stents. In vitro, GSKi elution increased EPC attachment to stent struts. In vivo, GSKi-eluting stents deployed in rabbit carotid arteries resulted in systemic mobilization of EPCs, improved local RE, and important reductions in in-stent NI formation. Finally, we tested the ability of GSKi to improve EPC-mediated arterial repair in patients with DM. As in patients with CAD, GSKi treatment improved EPC yield and diminished in vitro apoptosis. Utilizing a proteomics approach, we identified Cathepsin B (catB) as a differentially regulated protein necessary for reductions in apoptosis. Indeed, antagonism of catB prevented GSKi improvements in GSKi treated EPC mediated arterial repair in a xenotransplant wire injury model. Thus, our data demonstrates that GSKi treatment results in improvements in EPC number and function in vitro and in vivo resulting in enhanced arterial repair following mechanical injury. Accordingly, GSK antagonism is an effective cell enhancement strategy for autologous cell-based therapy with EPCs from high risk patients such as CAD or DM.

Coronary artery disease (CAD) is the leading cause of death worldwide. Treatment with coronary interventions, long-term treatment and life style changes can reduce symptoms and improve prognosis. The aim of this thesis was to investigate aspects of invasive treatment for multivessel coronary artery disease, and to investigate adherence to prevention guidelines one year after myocardial infarction.  We used the national quality registry SWEDEHEART to collect data on long term treatment one year after myocardial infarction for 51 620 patients < 75 years of age. For 17 236 of the patients, we collected LDL-cholesterol measurements from SWEDEHEART and defined use of lipid lowering drugs from the Prescribed Drug Register. We developed a questionnaire for post-PCI-patients to investigate patients’ understanding of cause and treatment of coronary artery disease. For 23 342 PCI-patients with multivessel coronary artery disease, SWEDEHEART-data was linked to Swedish health data registries to determine one year outcome for patients undergoing incomplete vs. complete revascularization.   Lipid control (LDL-cholesterol < 1.8 mmol/L) was attained by one in four patients one year after myocardial infarction, whereas blood pressure control (< 140 mmHg) was attained by two thirds of patients. Lipid and blood pressure control was lower for women but there was no gender difference in smoking cessation rate: 56 %. Over 90 % of patients were treated with a statin after myocardial infarction but treatment was intensified for only one in five patients with LDL-cholesterol above target. The questionnaire study revealed that non-modifiable factors such as age and heredity were more often seen as cause of coronary artery disease than modifiable life style factors. Only one in five patients perceived CAD as a chronic illness, requiring life style changes. Two thirds of PCI-patients with multivessel disease underwent incomplete revascularisation, and this was associated with a twofold risk for the combination of death, myocardial infarction and repeat revascularization up to one year, compared to patients who underwent complete revascularization. We conclude that  long term treatment after myocardial infarction is suboptimal in relation to guideline recommendations. Assessment of patients’ views on CAD and better health education post PCI may facilitate life style changes. Further studies need to investigate whether complete revascularization will improve outcome for PCI-patients with multivessel disease.

Research shows that the interaction between the weather conditions and human health exists and this interaction has a very wide range, from subjective well-being to death. With respect to reactions to weather variations, people can be divided into weather-resistant and weather-sensitive. However, there is the lack of standardised tools to evaluate weather sensitivity. People with heart disease and people with sensitive nervous system are considered to be more sensitive to weather change than others. There are evidences that psychological distress and Type D personality are both associated with development and progression of coronary artery disease. Also, it is hypothesized that individual differences such as personality traits may have an effect on sensitivity to weather. The aim of this study was to examine and to evaluate associations between weather parameters and subjective well-being of patients with coronary artery disease. The objectives of the study: 1) to examine the validity of Type D personality assessment instrument used in this study; 2) to develop and test the psychometric properties of self-assessment diary for weather sensitivity in patients with coronary artery disease; 3) to evaluate associations between the subjective well-being of patients with coronary artery disease and the weather parameters; 4) to evaluate associations between anxiety, depression and personality and the subjective weather-related well-being in patients with coronary artery disease. / Moksliniai tyrimai rodo, kad egzistuoja sąveika tarp orų pokyčių ir žmonių sveikatos ir ši sąveika sudaro labai platų spektrą – nuo subjektyvios savijautos pablogėjimo iki mirties. Dėl reakcijų į orų pokyčius, žmonės gali būti suskirstyti į dvi grupes – jautrius orų pokyčiams ir atsparius. Tačiau standartizuotų instrumentų, kurie leistų įvertinti jautrumą orams ir atskirti jautrius orų pokyčiams asmenis, ypač skirtingų susirgimų grupėse, trūksta. Sergantieji širdies ligomis ir asmenys išgyvenantys psichologinį distresą priskiriami prie vienų iš jautriausių orų pokyčiams. Įrodyta, kad tiek psichologinis distresas, tiek asmenybės D tipas yra susiję su išeminės širdies ligos išsivystymu ir progresavimu. Be to, pastaraisiais metais keliamos hipotezės, kad individualūs skirtumai, tokie kaip asmenybės bruožai, taip pat gali įtakoti jautrumą orams. Darbo tikslas buvo išnagrinėti ir įvertinti sergančiųjų išemine širdies liga subjektyvios savijautos sąsajas su orais ir jos ryšį su asmenybės bruožais, nerimo ir depresijos simptomais. Darbo uždaviniai: 1) validizuoti tyrime naudojamą instrumentą asmenybės D tipui vertinti; 2) sukurti savikontrolės dienyną jautrumui orams įvertinti ir atlikti jo psichometrinę analizę; 3) nustatyti sąsajas tarp sergančiųjų išemine širdies liga subjektyvios savijautos ir orų, 4) įvertinti sergančiųjų išemine širdies liga subjektyvios orų sąlygotos savijautos sąsajas su nerimu, depresija ir asmenybės bruožais.

The aim of the thesis was to study cardiovascular side effects of radiotherapy (RT) in breast cancer (BC). In a study base of 25,171 women with BC diagnosed 1970-2000, we found a statistically significant 12% increase of stroke, compared to the stroke incidence in the background population. A case-control study of 282 cases with BC followed by a stroke and 1:1 matched controls with BC but not stroke was performed. In women irradiated to internal mammary chain (IMC) and supraclavicular lymph nodes (SCL) vs. a pooled group of women not irradiated or irradiated to targets other than IMC and SCL, a statistically significant increase of stroke with an odds ratio of 1.8 was observed. There were no associations between BC laterality, targets of RT, and hemisphere location of stroke. The radiation targets IMC and SCL, showed a statistically significant trend for an increased risk of stroke with daily fraction dose. A study of 199 patients with BC, examined by coronary angiography, detected a four- to seven-fold increase of high grade coronary artery stenosis in mid and distal left anterior descending artery (LAD), including distal diagonal branch, when comparing women with irradiated left-sided BC to those with right-sided. An increase of clinically significant coronary artery stenosis was found in pre-specified hotspot areas for radiation among women irradiated to the left breast/chest wall or to the IMC. Thus, the coronary arteries should be regarded as organs at risk in RT of BC. In a study of 15 BC patients treated with 3D conformal RT, a marked difference in dose distribution in mid and distal LAD between left- and right-sided BC was demonstrated. Irradiated right-sided BC mainly received low doses of scattered and transmitted radiation to the coronary arteries. On the contrary, tangential RT to the left breast without regional lymph node irradiation yielded coronary artery max doses of approximately 50 Gray to distal LAD, probably not safe concerning late radiation vascular effects. To conclude, we found cardiovascular side effects in women irradiated for BC, resulting in stroke and coronary artery disease, and showed an association between the targets for RT and the anatomical location of these vascular events.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 5 uppsatser.

Thesis (Ph.D. )--University of Tennessee Health Science Center, 2007. / Title from title page screen (viewed on May 16, 2008 ). Research advisor: Gerald I. Byrne, Ph.D. Document formatted into pages (xi, 114 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 65-107).

Thesis (M.Sc.). / Written for the Dept. of Biochemistry. Title from title page of PDF (viewed 2009/06/25). Includes bibliographical references.

Trata-se de estudo transversal sem modelo de intervenção, que tem como objeto a atenção à saúde na prevenção secundária da doença coronariana a pacientes com ou sem tratamento ambulatorial especializado. O objetivo primário foi: Avaliar se há diferença na atenção à saúde entre pacientes portadores de doença arterial coronariana em sua forma aguda ou crônica com ou sem acompanhamento ambulatorial especializado. Os objetivos secundários foram: a) apresentar o perfil de cada grupo de pacientes a partir de dados sócio-demográficos e econômicos; b) descrever as característica clínicas dos pacientes e identificar a que fatores de risco cada grupo de pacientes está exposto; c) descrever a regularidade na utilização de medicamentos e como se dá o acesso à mesma; d) identificar o tipo e principais dificuldades enfrentadas pelo paciente para seguir o tratamento. Para a coleta de dados foi utilizado formulário desenvolvido e previamente testado para atender os objetivos propostos para o estudo, além de informações coletadas diretamente do prontuário do paciente. A coleta de dados foi realizada em três unidades públicas de saúde localizadas no município do Rio de Janeiro. A amostra selecionada foi composta por 112 pacientes divididos igualmente entre os dois grupos existentes na pesquisa. Os dados foram transcritos para planilha do programa Statistic Package for the Social Science e análise realizada através dos testes estatísticos de diferença entre proporção, odds-ratio e qui-quadrado. Quanto ao perfil sócio-demográfico e econômico verificou-se diferença estatística significativa quanto ao grau de instrução entre os grupos I e II, com predomínio de pacientes de nível fundamental incompleto para o grupo I e médio completo no grupo II (p=0,0434), foi também verificada diferença significativa entre os grupos relacionada ao rendimento mensal, embora o maior percentual encontrado em ambos os grupos tenha sido observado na faixa de dois salários mínimos, uma vez que o grupo II apresentou maior concentração de renda entre a faixa de dois a três salários mínimos (p=0,0044). Ao que se refere aos fatores de risco para doença coronariana, observou-se diferença estatística entre os grupos para a variável tabagismo (p= 0,0001) e sedentarismo (p=0,0025). Verificou-se para pacientes do grupo I valor estatístico significativo quanto a regularidade em utilizar medicamentos (p=0,0010). Concluiu-se, portanto, que o acompanhamento de pacientes pós-síndrome coronariana aguda em ambulatório especializado de coronariopatias apresentou benefícios significativos quando comparado ao grupo de pacientes não cobertos por este tipo de assistência. Verificou-se ainda que o enfermeiro poderá contribuir e atuar amplamente para a prevenção secundária da doença coronariana, enquanto membro da equipe multidisciplinar. / This transverse study has been made without an intervention model and its subject is the health attention level throughout the secondary prevention of the coronary artery disease in patients with and without specialized outpatient treatment. The primary objective was: assessing the difference in the treatment given to acute and chronicle patients with coronary artery disease who are with or without specialized outpatient treatment follow-up. The secondary objectives were: a) presenting the profile of each group of patients, considering their socio-demographic and economic data; b) describing the patients clinical characteristics and identifying to which risk factors each group of patients is exposed to; c) describing the regularity in the use of medicines and how one can access it; d) identifying type and main difficulties found by patients to follow their treatment. Data collection has been done through a specially created and previously tested form so as to attend the proposed objectives of this study, besides through information directly collected from the patients record table. This data collection has been made in three municipal public health treatment unities located in Rio de Janeiro. The selected sample has been composed of 112 patients equally divided into the two existing groups in the research. The data has been transcribed into the Statistic Package for the Social Science table and the analysis has been made through statistical tests of difference among proportion, odds-ratio and chi-square. Concerning the socio-demographic and economic profile, a significant statistical difference has been considered according to the education level between the groups I and II, with a predominant number of patients with incomplete basic educational level in group I and with complete college education in group II (p=0,0434). A significant difference concerning monthly income between the groups has also been proved, although the highest percentage found in both groups was observed in the range of two minimum wages, group II had a higher concentration of income among the range of two to three minimum wages (p = 0.0044). Regarding risk factors for coronary disease, there was a statistical difference between groups for the variables smoking (p = 0.0001) and lack of exercise (p = 0.0025). It was found that, for patients in Group I as statistically significant value in using medication regularly (p = 0.0010). It was concluded therefore that the monitoring of patients after acute coronary syndrome in the specialized coronary artery disease outpatient treatment showed significant benefits when compared to patients not covered by this type of assistance. It was also found that nurses can contribute and act widely for the secondary prevention of coronary disease, as a member of the multidisciplinary team.

TÍTULO: Associação entre Distúrbios Respiratórios do Sono, Estresse Oxidativo e Doença Arterial Coronariana. INTRODUÇÃO: Evidências sugerem associação entre a doença arterial coronariana (DAC) e os distúrbios respiratórios do sono (DRS), porém o mecanismo que explica essa associação é incerto. Episódios repetitivos de hipóxia e reoxigenação vivenciados pelos indivíduos com DRS levam ao aumento de espécies reativas de oxigênio (ERO). ERO no interior dos eritrócitos podem ser detoxificadas pelas enzimas antioxidantes glutationa peroxidase (GPx), catalase (CAT) e superóxido dismutase (SOD). Ainda no citoplasma as ERO podem ser detoxificadas pela vitamina C ou ácido úrico. O estresse oxidativo é caracterizado por um desequilíbrio entre os níveis de ERO e antioxidantes. Este desequilíbrio promove lesão oxidativa em biomoléculas, mecanismo este associado à fisiopatologia da DAC. OBJETIVOS: Verificar a relação entre o índice de apnéia hipopnéia (IAH) e a presença de DAC. Verificar a associação entre IAH, DAC e a atividade das enzimas antioxidantes: SOD, CAT, GPx e antioxidantes não enzimáticos, ácido úrico e vitamina C. Avaliar a relação entre IAH, DAC e os produtos de danos oxidativos em lipídios, proteínas. Entre os marcadores de estresse oxidativo identificar preditores para DAC. MATERIAIS E MÉTODOS: Estudo transversal. Entre junho de 2007 e maio de 2008 na Hemodinâmica do Hospital de Clínicas de Porto Alegre, triamos consecutivamente 519 indivíduos encaminhados para angiografia diagnóstica ou terapêutica. Incluímos 14 pacientes com DAC (≥ 50% diminuição do lúmen da coronária) e 30 controles com < 50% de obstrução. O IAH foi mensurado por meio de polissonografia portátil. Verificamos presença de DAC através da angiografia coronariana. A quantificação dos grupos carbonil no hemolisado e no plasma e as atividades das enzimas antioxidantes SOD, CAT e GPx foram verificadas por método espectrofotométrico. Mensuramos malondialdeído (MDA) e vitamina C por cromatografia líquida de alta eficiência. RESULTADOS: Este é o primeiro trabalho que evidencia correlação entre IAH e o aumento de carbonilação de proteínas eritrocitárias. Além disso, os resultados obtidos mostram que os indivíduos portadores de DAC apresentam níveis maiores de grupos carbonil no hemolisado quando comparados aos indivíduos controles. Em um modelo de regressão multivariado ajustado para idade, sexo e índice de massa corporal, buscando verificar preditores para DAC, verificamos que o aumento de uma unidade de carbonil aumenta 1,7% o risco para desenvolvimento de DAC, já uma unidade do IAH aumenta em 3,9% o risco de desenvolvimento de DAC. Não foi encontrada correlação entre IAH e os marcadores MDA, carbonil no plasma e os antioxidantes: SOD, CAT, GPx vitamina C e ácido úrico. Não verificamos correlação entre DAC e os marcadores MDA, carbonil no plasma e entre os antioxidantes SOD, CAT , GPx e ácido úrico. Pacientes com CAD significativa apresentaram níveis menores de vitamina C. Correlação positiva foi observada entre os níveis de vitamina C e a concentração de proteínas carboniladas no plasma. CONCLUSÃO: Foi evidenciado que a carbonilação de proteínas eritrocitárias e o IAH tem importância na fisiopatologia da DAC. Da mesma forma a vitamina C parece ter importância na prevenção da DAC. / INTRODUCTION: Evidences suggest association between Coronary Artery Disease (CAD) and Sleeping Disordered Breathing (SDB), however the mechanism is uncertain. Repetitive episodes of hypoxia and reoxygenation experienced by individuals with SDB lead to an increase of Reactive Oxygen Species (ROS). ROS inside the erythocytes may be scavenging by glutathione peroxidase antioxidants enzymes (GPx), catalase (CAT) and superoxide dismutase (SOD). In the cytoplasm ROS may be inhibited by vitamin C, or uric acid. Oxidative stress is characterized by an unbalance between ROS and antioxidants. These unbalance promotes oxidative damage in biomolecules, this mechanism is associated to the CAD physiopathology . OBJECTIVE: Verify the relation between apnea hypopnea index (AHI) and CAD. Verify association between AHI, CAD and antioxidants enzymes activity: SOD, CAT, GPx and non enzymatic antioxidants, uric acid, and vitamin C. Evalute the relation between AHI, CAD and oxidative damage products in lipids and proteins. Among the oxidative stress markers identify the predictors for CAD. MATERIALS AND METHODS: Cross sectional study. Between June and May 2008 in the hemodinamic ward of Clinicas Hospital of Porto Alegre, we consecutively screened 519 individuals sent for diagnostic or therapeutic angiography. We included 14 cases with CAD (≥ 50% narrowing of coronary lumen) and 30 controls with < 50% narrowing. The AHI was measured by portable polisomnography. We found the presence of CAD through coronary angiography. Carbonyl groups quantification in the hemolysed and plasma and antioxidants enzyme activities of SOD, CAT and GPx were verified by spectophotometric method. Malondyaldeyde (MDA) and vitamin C were measured by HPLC. RESULTS: This work is the first one that shows correlation between AHI and increased erythrocytes protein carbonylation. In the same way evidences that individuals with significant CAD compared to controls present higher levels of carbonyl groups in the hemolysates. In a multivaried regression model adjusted to age, gender and body mass index to verify predictors for CAD, we verified that the carbonyl unit increased 1.7% the risk for development of CAD, while one unit of IAH increased in 3.9% the risk to develop CAD. We did not find correlation between AHI and the markers MDA, plasma carbonyl and the antioxidants: SOD, CAT, GPx vitamin C and uric acid. We didn’t verify correlation between CAD and the markers MDA, plasma carbonyl and the others antioxidants SOD, CAT , GPx and uric acid. Patients with significant CAD had lower levels of vitamin C. Positive correlation was observed between vitamin C and erythrocyte carbonyl concentration. CONCLUSION: We evidenced that erythrocytes protein carbonylation and AHI are important in the physiopathology of CAD. In the same way vitamin C appears important factor in CAD prevention.

FDA approval of drug-eluting stents (DES) in 2002, was based on data obtained from several pivotal, short-term (< one year) randomized control trials that evaluated their efficacy in reducing in-stent restenosis when used in treatment of coronary artery lesions compared with bare metal stents (BMS). These trials excluded patients with complex coronary lesions. When the FDA approved use of DES in treatment of coronary artery lesions, the on-label indications only applied to a very limited subset of simple lesions. Immediate advantages of DES were observed in clinical practice for on-label indications, specifically in their ability to significantly reduce in-stent restenosis after PCI. The increased short-term safety and efficacy seen in on-label clinical cases soon led clinicians to expand the use DES to more complex lesions. These complex indications, not included in the pivotal FDA trials, are considered off-label. Off-label indications include bifurcation lesions, ostial lesions, lesions greater in length and diameter than those approved by the FDA, implantation in saphenous vein grafts, and lesions in the left main coronary artery. Currently, DES use for treatment of lesions presenting off-label indications may comprise as much as 60% of clinical cases. However, early evidence that DES may play a role in adverse safety outcomes, has led many to question the use of DES outside their on-label indications. This paper sought to evaluate some of the current research investigating first generation DES use in four different off-label indications: coronary artery bypass graft lesions, saphenous vein graft lesions, ostial lesions, and chronic total coronary occlusions. In particular, it looked at studies, which compared the efficacy and clinical outcomes of DES and BMS treatment of each of the different lesion types. The results of this evaluation were very promising in that of the four specific off-label indications evaluated, all of them showed to be superior in reduction of neointimal growth and subsequent in-stent restenosis. Additionally, DES treatment of left main coronary artery lesions, saphenous vein graft lesions, and chronic total coronary occlusions showed to be superior in reducing the incidence rate of major adverse cardiac events and target vessel revascularization over various follow-up durations. The only scenario that DES did not prove to be superior to BMSs was the treatment of ostial lesions. Long-term randomized control trials with large study populations should be performed to further elucidate the effects of DES treatment of specific off-label lesions.