O treinamento físico aeróbico induz atenuação de disfunções cardiometabólicas que acometem mulheres menopausadas e/ou diabéticas. Entretanto, estudos envolvendo treinamento resitido ou combinado (aeróbio + resistido) são escassos e controversos. Dessa forma, os objetivos do presente estudo foram avaliar os efeitos metabólicos, cardiovasculares e autonômicos da privação dos hormônios ovarianos na presença ou não de diabetes induzido por estreptozotocina em ratas, bem os efeitos do treinamento físico aeróbio dinâmico, resistido dinâmico, ou combinado nesta condição. Ratas Wistar (200-220g) foram dividas em um grupo controle sedentário (ES), um grupo diabético sedentário (DS) e 5 grupos ooforectomizados (retirada bilateral dos ovários) (n=8), sendo um euglicêmico sedentário (EOS) e os demais diabéticos (estreptozotocina, 50 mg/kg, iv): sedentário (DOS), submetido a treinamento físico (TF) aeróbio em esteira (DOTA), a TF resistido em escada (DOTR), ou a TF combinado, em escada e esteira em dias alternados (DOTC). Após as 8 semanas de TF, a função e a morfometria cardíaca foram avaliadas pelo ecocardiograma e, no dia seguinte, os animais foram canulados para registro da pressão arterial (PA) e avaliação da sensibilidade barorreflexa (SB). A análise da variabilidade da frequência cardíaca (FC) e da PA sistólica (PAS) foi realizada no domínio do tempo e da frequência. Os resultados demonstraram aumento de 9% no peso corporal e 10% na PA, e redução de SB (21% nas respostas taquicárdicas) no grupo EOS. Os animais diabéticos apresentaram redução de 19% no peso corporal e na capacidade física (22% no teste máximo em esteira e 19% na carga máxima na escada); redução de 8% na massa e 18% na espessura relativa da parede do ventrículo esquerdo (VE), aumento de 11% na cavidade do VE, de 31% no tempo de relaxamento isovolumétrico e 34% no índice de desempenho miocárdico; além de redução de na PA, na FC, na SB e na banda AF-IP. A associação de diabetes com ooforectomia induziu exacerbação de algumas disfunções, como aumento de 9% na glicemia e de 20% no índice de desempenho miocárdico (IDM); redução de 14% na velocidade de encurtamento do VE e 14% na FC (DOS vs. DS). O treinamento induziu aumento de 77% na capacidade de corrida no grupo DOTA, aumento de 60% na carga máxima no DOTR, e aumento em ambos os parâmetros no DOTC (75% na corrida e 58% na carga máxima). Todos os animais treinados apresentaram reversão da hipotensão e da bradicardia de repouso, associadas a aumento na VAR-IP (DOTA: 79%, DOTR: 79%, DOTC: 65%), normalização da banda de BF-IP, e redução no índice de desempenho miocárdico (DOTA: 16%, DOTR: 15%, DOTC: 31%) (vs. DOS). Os grupos DOTA e DOTC (mas não o DOTR) apresentaram maior SB (respostas taquicárdicas e bradicárdicas), atenuação das alterações morfométricas do VE, e na variabilidade da PA sistólica (vs. DOS). Além disso, o grupo DOTR apresentou aumento de 14% na massa, e redução de 14% na velocidade de encurtamento do VE e de 15% no IDM em relação ao grupo DOS. O grupo DOTC demonstrou redução adicional de 18% no IDM e em relação ao DOTA. A mortalidade foi maior no grupo DOS em comparação aos grupos treinados. Concluindo, os resultados evidenciam que o treinamento físico dinâmico aeróbio, resistido ou combinado induziu benefícios na capacidade física, cardíacos, hemodinâmicos e autonômicos após a privação dos hormônios ovarianos em ratas diabéticas. No entanto, o treinamento físico combinado promoveu efeitos adicionais em relação aos treinamentos aeróbio ou ao resistido nesta condição. / Aerobic exercise training induces attenuation of cardiometabolic disorders that affect postmenopausal and/or diabetic women. However, there few and controversial studies involving resistance or combined training (aerobic + resistance) in these conditions. Thus, the objectives of this study were to evaluate the metabolic, cardiac, hemodynamic and autonomic effects of ovarian hormones deprivation in the healthy and streptozotocin-induced diabetic rats, as well as the effects of dynamic aerobic, resistance or combined exercise training in this condition. Female Wistar rats (200-220g) were divided into (n = 8 each group) a sedentary control group (ES), a sedentary diabetic group (SD) and 5 ovariectomized groups (bilateral ovaries removal): sedentary euglycemic (EOS), sedentary diabetic (DOS), trained diabetic by an aerobic protocol on a treadmill (DOTA), by a resistance protocol in ladder (DOTR), or by a combined protocol in ladder+treadmill on alternate days (DOTC). After 8 weeks of training, cardiac morphometric and function were evaluated by echocardiography. On the next day, the animals were cannulated to arterial pressure (AP) recording and baroreflex sensitivity (BS) evaluation. Heart rate (HR) and systolic AP variability were analyzed in the time and frequency domains. The results showed increased of 9% in body weight and 10% in AP, and BS (21% in tachycardic responses) reduction in the EOS group. Diabetic animals showed a reduction of 19% in body weight and in physical capacity (22% in the maximal test on a treadmill and 19% in the maximum load on the ladder), reduction of 8% in mass and of 18% in relative wall thickness of the left ventricle (LV), increase of 11% in LV cavity, 31% in the isovolumetric relaxation time and 34% in myocardial performance index (MPI); in addition to reduction in AP, in HR, BS, and in PI-HF band. The association of diabetes with ovariectomy induced exacerbation of some dysfunctions, such as increased of 9% in blood glucose and 20% in MPI, reduction of 14% in the LV velocity of shortening and 14% in HR (DOS vs. DS). Exercise training induced an increase of 77% in the run capacity in the DOTA group, 60% in the maximum load in DOTR group, and increases in both parameters in DOTC (75% in run and 58% in the maximum load). All trained animals showed reversal of hypotension and bradycardia at rest DOTA: 79%, DOTR: 79%, DOTC: 65%), associated with increased HR variance and normalization of the LF band of pulse interval (PI), and reduced MPI (DOTA: 16%, DOTR: 15%, DOTC: 31%) (vs. DOS). The DOTA and DOTC groups (but not DOTR) had higher BS (tachycardic and bradycardic responses), and attenuation in the LV morphometric changes and in SAP variability (vs. DOS). Furthermore, the DOTR group showed an increase of 14% in mass and a reduction of 14% in LV velocity of shortening and of 15% in MPI in relation to DOS group. The DOTC group showed additional reduction of 18% in MPI and in relation to DOTA. Mortality was higher in DOS group when compared to trained group. In conclusion, the results showed that dynamic aerobic, resistance or combined exercise training induced benefits in physical capacity, cardiac, hemodynamic and autonomic parameters after ovarian hormone deprivation in diabetic rats. However, the combined exercise training promoted additional effects than aerobic or resistance training in this condition.

Os idosos constituem a parcela da população, que mais cresce atualmente. Este segmento populacional requer cuidados médicos e terapêuticos frequentes e consomem cerca de três vezes mais medicamentos que indivíduos jovens. Deste modo necessitam de uma avaliação detalhada da farmacocinética e farmacodinâmica do fármaco a ser utilizado para uma menor ocorrência de efeitos adversos. O objetivo foi fenotipar o CYP2D6 em pacientes idosos cardiopatas classificados como metabolizadores extensivos ou lentos do metoprolol, desenvolver e validar o método de análise do tartarato de metoprolol e seu metabólito em urina utilizando a cromatografia liquida de alta eficiência (HPLC) e identificar possíveis correlações entre fatores antropométricos, raciais e comorbidades apresentadas com a razão metabólica metoprolol/-OH metoprolol em urina. A casuística foi composta por 130 indivíduos idosos, considerados acima de 60 anos, voluntários, com algum tipo de cardiopatia previamente identificada, com função renal e hepática normais. Todos indivíduos foram submetidos a uma coleta de urina de 0-8h após a administração de um comprimido de 100 mg de tartarato de metoprolol para a determinação do metoprolol e -OH metoprolol com a finalidade de estabelecer a sua razão metabólica e fenotipar esses indivíduos de acordo com os resultados da razão da concentração metoprolol/-OH metoprolol em urina utilizando a HPLC com detecção por fluorescência, sendo fenotipados como metabolizadores lentos os pacientes que tiveram resultados > 12,6 e como metabolizadores extensivos aqueles avaliados com resultados 12,6. A maior porcentagem de pacientes estudados situou-se na faixa etária de 60 a 70 anos (média de 71,8 ± 6,2), mediana de 71,0, valor mínimo de 60 e máximo de 93 anos. Cento e quatro pacientes (80,0%) reportaram ser da raça branca, 13 (10,0%) da raça negra, 1 (0,8%) da raça amarela e 12 (9,2%) da raça parda. Cento e um pacientes (77,7%) eram do sexo feminino. Os pacientes investigados utilizavam em média 5,9 + 2,1 tipos de medicamentos, variando de 1 a 11 fármacos utilizados concomitantemente. Observou-se uma média de 5,1 + 3,2 comorbidades concomitantes, variando de 1 a 14 patologias associadas. Três pacientes (2,3%) foram fenotipados como metabolizadores lentos do metoprolol, diferenciando dos 7 a 10% de metabolizadores lentos existentes na população caucasiana. Foi detectada diferença estatisticamente significativa na razão metabólica metoprolol/-OH metoprolol segundo a quantidade de medicamentos utilizada pelos idosos (p=0,017) e segundo a utilização de bebida alcoólica (p=0,045). Conclui-se que a maioria dos indivíduos estudados eram do sexo feminino, a proporção de metabolizadores de idosos cardiopatas classificados como PM foi menor do que a que é encontrada em caucasianos, a variável quantidade de medicamentos utilizados esteve relacionada de maneira significativa à taxa de metabolização do tartarato de metoprolol observada nestes idosos cardiopatas e a variável ingestão de bebida alcoólica mostrou correlação significativa com o valor da razão metoprolol/-OH metoprolol no presente estudo. / These days, elderly people constitute the most important part of the increasing population. This population segment requires frequent medical and therapeutic cares, and spends three times more drugs than the young individuals. For that reason, a detailed pharmacokinetic and pharmacodynamic evaluation of the administrated drug must be accomplished aiming to avoid side effects. The objective of this study was to phenotype CYP2D6 in elderly cardiopatic patients classified as extensive or poor metoprolol metabolizers, aiming to develop and validate the method for analysis of metoprolol tartrate and its metabolite in urine using high performance liquid chromatography (HPLC), and to identify possible correlations between anthropometric, racial factors, and comorbidities presented with the urine metabolic ratio of metoprolol/-OH-metoprolol. The casuistry was composed by 130 elderly individuals over 60 years old, volunteer, carrying any type of pre identified cardiomyopathy, with normal renal and hepatic functions. Aiming the evaluation of the urine metabolic ratio of metoprolol/-OH-metoprolol, the individuals were submitted to a urine collection 0-8h after administration of tablets of 100 mg of metoprolol tartrate for phenotyping after the results of the concentration metoprolol/-OH-metoprolol using HPLC and fluorescence detection, being phenotyped as poor metabolizers the patients that presented ratio > 12.6, and extensive metabolizers 12.6. Mostly studied patients percentage age was 60-70 years old (mean of 71.8 ± 6.2) - median 71.0; the maximum value was 93, and the minimum value was 60 years old. One hundred and four patients (80.0%) reported being Caucasian, 13 (10.0%) Black, 1 (0.8%) Asian, and 12 (9.2%) Half-black. One hundred and one patients (77.7%) were female. The studied patients used approximately 5.9 + 2.1 types of drugs, varying of 1 to 11 concomitant drugs used. We could observe the mean of concomitant comorbidities of 5.1 + 3.2 varying of 1 to 14 associated pathologies. Three patients (2.3%) were phenotyped as poor metoprolol metabolizers differentiating of those 7 to 10% poor metabolizers existent in Caucasian population. A significant statistical difference was detected in the metabolic ratio metoprolol/-OH-metoprolol according to the quantity of drug used by elderly patients (p=0.017), and alcohol users (p=0.045). It could be concluded that mostly of studied individuals was female. The proportion of elderly cardiopatic metabolizers classified as PM was lower than the Caucasian ones. The quantity of drugs used was significantly related to the metabolism ratio of metoprolol tartatre observed on those elderly cardiopatic patients, and the variable alcohol ingestion showed significant relation to the value of ratio metoprolol/-OH-metoprolol in the present study.

Estudo descritivo-transversal de abordagem quantitativa, com o objetivo de identificar os indicadores clínicos e bioquímicos de risco cardiovascular entre pessoas com diagnóstico de Transtornos Alimentares (TAs). A população foi composta por 22 usuários em seguimento ambulatorial, em dois hospitais universitários situados no interior paulista e na capital, no período de março de 2013 a fevereiro de 2014. Para a coleta de dados, realizou-se uma entrevista para identificação das variáveis sociodemográficas: idade, sexo, cor da pele, estado familiar conjugal, escolaridade e renda familiar. Os dados clínicos foram coletados por meio de avaliação antropométrica: estatura, peso, circunferência abdominal (CA), cálculo do índice de massa corporal (IMC); aferição das dobras cutâneas: tríceps, bíceps, subescapular e suprai líaca; medida indireta da pressão arterial (PA) e do Índice Tornozelo Braquial (ITB) e cálculo do percentual de gordura corporal. Foram realizados exames laboratoriais para a dosagem de proteína C reativa, colesterol total e frações, triglicérides, homocisteína, vitamina B12 e ácido fólico. Os dados foram agrupados em categorias, e as variáveis quantitativas foram expressas como média e desvio-padrão. Os testes estatísticos foram realizados por meio do aplicativo Statistical Package for the Social Science (SPSS), versão 16.0 e pelo R i386 versão 3.0.0, adotando-se o nível de significância de ?=0,05. Para a análise da associação entre a classificação do IMC (eutrófico e baixo peso) com as variáveis clínicas, antropométricas e bioquímicas, uti lizou-se o Teste Exato de Fisher. Os participantes possuíam idade média de 28,41 ± 7,51 anos, 95,5% eram do sexo feminino, 86,4%, brancos, 72,7% viviam sem cônjuge, 45,5% eram estudantes e 31,9%, trabalhadores com vínculo empregatício, 31,8% declararam ensino superior em curso ou incompleto, com média de 12,45 ± 2,94 anos de estudo, 59,1% informaram renda fami liar entre três e quatro salários-mínimos; 59,1% apresentaram o diagnóstico médico de anorexia nervosa (AN), com média de tempo de tratamento de 3,23 ± 2,34 anos; 59,1% eram eutróficos, com média de IMC de 19,19 ± 2,90 Kg/m2 ; 86,4% apresentaram valores de CA normais; 95% com ITB normal, 70% com delta ITB (diferença entre os ITBs) normal; 95,4% com cifras de PA inferiores a 120x80 mmHg, 18,2% com pulso radial inferior a 60 batimentos por minuto; 9,1% com pressão de pulso >50 mmHg. A soma das quatro dobras cutâneas foi de 62,05 ± 19,92 mm, e o percentual de gordura foi de 28,95 ± 5,65; 47,6% classificaram-se como acima da média para o risco de morbidade, devido à alta porcentagem de gordura corporal, de acordo com as dobras cutâneas. Quanto aos exames bioquímicos, 42,1% apresentaram aumento nos níveis do colesterol total; 33,3%, aumento do LDL-C, 10,5%, aumento nos níveis de triglicérides, 18,2%, aumento da homocisteína, 31,8%, aumento do ácido fólico, 4,5%, da PCR e 9,0% estavam com níveis de vitamina B12 maiores ou menores do que os valores de referência. Houve associação estatisticamente significante para a associação entre o IMC e o diagnóstico de AN e bulimia nervosa, p=0,002. Concluímos que as pessoas com TA apresentaram indicadores clínicos e bioquímicos de risco cardiovascular, devendo ser adotadas medidas e ações preventivas que priorizem a promoção da saúde neste grupo de indivíduos / This is a cross-sectional descriptive study with quantitative approach that aim to find out the clinical and biochemical indicators of cardiovascular risk among people diagnosed with eating disorders (ED). The population was composed of 22 users an outpatient follow-up from two university hospitals located on the countryside and capital of São Paulo during the period from March 2013 to February 2014. The data collection occurred through interview to identify socio-demographic variables such as age, sex, skin color, marital status, education, and family income. The clinical data collected from anthropometric assessment were height, weight, waist circumference (WC), and body mass index (BMI); skinfold-thickness measurement: triceps, biceps, subscapular and suprai liac; indirect measurement of blood pressure (BP) and ankle-brachial index (ABI); body fat percentage. Laboratory examinations were carried out to identify the presence of C-reactive protein (CRP), cholesterol (total or individual components), triglycerides, homocysteine, vitamin B12, and folic acid. The data were grouped into categories and the quantitative variables were expressed as median and standard deviation. It was used SPSS (Statistical Package for the Social Science), version 16.0 and R i386 version 3.0.0 and the significance level adopted was ?=0.05. It was used the Fisher Exact Test for association analysis between BMI classification (eutrophic and low weight) with clinical, anthropometric and biochemical variables. The average age of participants was 28.41 ± 7.51 years, female (95.5%), white (86.4%), not living with a partner (72.7%), students (45.5%), employment relationship (31.9%), bachelor degree in progress or incomplete (31.8%) with average study of 12.45 ± 2.94 years, and family income between three and four minimum wages (59.1%); the medical diagnosis presented that 59.1% of persons had anorexia nervosa (AN) with an average treatment time of 3.23 ± 2.34 years; eutrophics (59.1%) with BMI average of 19.19 ± 2.90 Kg/m2 ; normal WC values (86.4%); normal ABI (95%), normal delta-ABI (70%) is the difference between the ABI; BP levels below 120x80 mmHg (95.4%), radial pulse less than 60 beats per minute (18.2%); pressure pulse > 50 mmHg (9.1%).The sum of four skinfold thicknesses was 62.05 ± 19.92 mm and body fat percentage was 28.95 ± 5.65; 47.6% was classified average above of morbidity risk due to high level of body fat based on skinfold thicknesses. The biochemical tests showed increase of levels as follows: total cholesterol (42.1%); LDL-C (33.3%), triglycerides (10.5%), homocysteine (18.2%), folic acid (31.8%), CRP (4.5%), and 9.0% presented vitamin B12 levels higher or lower than the reference values. There was a statistically significant association between BMI and the diagnosis of AN and bulimia nervosa, p=0.002. We conclude that persons with ED present clinical and biochemical indicators of cardiovascular risk. Therefore, preventive actions that prioritize the health promotion should be considered in this group

Endothelial dysfunction (ED) is associated with many cardiovascular conditions including hypertension and hyperhomocysteinemia. The decreased bioavailability of nitric oxide and increased oxidative stress are the hallmarks of ED. Apart from the mainstream Western medicine treatment, Chinese medical interventions have also demonstrated their capacity in dealing with a great variety of cardiovascular conditions. The effectiveness of acupuncture on hypertension has been recognized by the World Health Organization but the underlying mechanisms have hitherto remained largely obscure. A commonly prescribed Chinese herb, the Root of Rhodiola rosea has been used to treatment a wide range of cardiovascular conditions but its effect on ED is also unclear. In this thesis, we have explored the effects and the underlying mechanism of these two important Chinese medical interventions. / In the first part, we have performed an acupuncture study on hypertensive animals. Eighteen weeks old adult Wistor Kyoto Rats (WKYs) and Spontaneously Hypertensive Rats (SHRs) were divided into WKY control, SHR control, Sham-acupuncture and real acupuncture groups. Electroacupuncture was performed on acupoints ST36 and LR3 in the real acupuncture group for 6 weeks. The blood pressure at the end of the treatment was lowered in acupuncture group when compared with SHR control and sham-acupuncture group. Serum angiotensin II level in SHR controls was higher than that in WKY control and acupuncture treatment significantly attenuated it. Dihydroethidium (DHE) imaging showed that the reactive oxygen species (ROS) level was reduced in the aortas and carotid arteries of acupuncture treated SHR. Biochemical assays showed that acupuncture inhibited the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and enhanced antioxidant capacity. In functional studies, the endothelial dependent relaxation of aorta rings and carotid arteries to acetylcholine were improved in acupuncture group. SHRs received acupuncture also expressed a elevation of eNOS and peNOS level and inhibition of nitrotyrosine level in Western blotting assay. The nitrate/nitrite level in aortic tissue was also increased by acupuncture. The findings concluded that one of the possible mechanisms of acupuncture in lowering blood pressure involved the improvement of oxidative stress, nitric oxide bioavailability and endothelium functions. / In the second part, we have studied the effects of salidroside, an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties on homocysteine induced ED. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. DHE imaging revealed that salidroside inhibited homocysteine-induced elevation in ROS production in both aortas and cultured endothelial cells. Western blot analysis showed that salidroside increased the phosphorylation of eNOS which was diminished by homocysteine in endothelial cells. Moreover, salidroside inhibited the NOX2 expression which was promoted by homocysteine in aorta tissue. The findings suggested that salidroside was effective in preserving the NO bioavailability and reducing ROS level, thereby protecting against homocysteine-induced impairment of ED. / We have successfully demonstrated the two Chinese medicine modalities, i.e. acupuncture and salidroside, a naturally occurring chemical compound isolated from Rhodiola rosea, delivered beneficial effects on ED, and both of them exert anti-oxidative effects for their action. Our experimental findings have enhanced the prospective of using Chinese medical interventions to manage oxidative stress-associated cardiovascular conditions and also helped put the clinical use of Chinese medical interventions on a more scientific footing. / 內皮功能失調與很多心血管系統疾病，包括高血壓和高半胱氨酸過高症有著十分密切的關系，一氧化氮供應減少與氧化應激增加均為這病理現象的一個特徵。除了主流的西方醫學治療方法外，中醫藥也一直表現出對各種心血管系統疾病有著明顯的療效。其中以針灸治療高血壓雖然己被世界衛生組織認可為一有效之療法，然而其療效原理卻並未被完全了解。另外，中草藥當中的紅景天，其對心血管疾病的療效亦非常顯著，唯其對內皮功能失調之影響卻仍有待查証。在這部論文當中，作者將會對以上兩項中醫藥治療方法的原理作出深入探討。 / 在第一部份的實驗當中，作者對自發性高血壓的大鼠施行了針灸治療。把十八週歲的自發性高血壓大鼠與京都種大鼠分為1)京都種大鼠對照組 2)自發性高血壓大鼠對照組 3)假針組針針刺組。針刺組中所使用的方案乃於足三里和太沖施行為期六週的電針治療。治療後針刺組的血壓相對於高血壓大鼠對照組和假針組均有明顯下降。同時針刺組大鼠血液中的血管緊張素II亦明顯降低。顯微鏡螢光造影發現於主動脈與頸動脈組織中，超氧化因子數量於針刺後均低於另外兩組高血壓大鼠對照組與假針組。另外實驗結果亦發現尼克酰胺腺嘌呤二核苷酸磷酸氧化酶的活動於針刺後下降，而抗氧化總容量則有所提升。另一方面，血管功能測試則顯示在針刺組內，由乙酰胆碱所引發的血管舒張比對照所產生的有所增加。而內皮一氧化氮酶和磷化皮內皮一氧化氮酶於血管中的表達則於針刺治療後有所增加，反觀硝基酪氨酸的含量則於針刺後減少。針刺對於血管組織中的亚硝酸盐/硝酸盐含量均有刺激作用。綜合而言，針刺能透過抑制氧化應激從而增加血管中一氧化氮的含量，最後達至內皮功能改善而降低血壓。 / 在第二部份，作者對中藥紅景天內其中一種活性成份紅景天苷對半胱氨酸所引起的內皮功能損傷進行研究。血管功能測試顯示半胱氨酸抑制了由乙酰胆碱所引發的血管舒張，而紅景天苷則能有效逆轉該抑制作用。顯微鏡螢光造影則發現紅景天苷能壓制由半胱氨酸所刺激的超氧化因子，另一方面能增加由半胱氨酸所抑制的磷化皮內皮一氧化氮酶的表達。尼克酰胺腺嘌呤二核苷酸磷酸氧化酶為超氧化因子的其中一個主要來源，半胱氨酸被發現會對其當中NOX2亞組的表達有刺激作用，而紅景天苷則能減少其表達。實驗結果顯示紅景天苷對半胱氨酸所引起的內皮功能損傷有顯著保護作用，其原理則與減少氧化因子從而增加一氧化氮的含量有密切關系。 / 整體而言，本論文成功顯示針灸與紅景天苷兩項中醫藥治療方案均能夠透過抑制超氧化因子而改善內皮功能捐傷。實驗結果加強了中醫藥於治療氧化應激相關的心血管疾病的應用，為中醫藥發展提供堅實的科學基礎。 / Leung, Sin Bond. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references. / Abstracts also in Chinese. / Title from PDF title page (viewed on 01, November, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

目的1)發現與中風相闋的視網膜特徵2) 利用視網膜特徵建立統計模型對老年人中風風險進行分類。 / 方法:配對病例對照研究。病例為中風患者，一部分中風患者來自於糖尿病眼病的篩查項目，另外一部分是腦內科的中風患者。對照是沒有中風的老年人。對照來自糖尿病眼病篩查項目內沒有患中風的患者及在眼科門診沒有中風及特殊眼病的患者。對照與病例在年齡及是否患有糖尿病進行匹配。所有研究對象均來自香港威爾斯親王醫院。我們收集所有研究對象的中風危險因素，包括年齡，性別，吸煙，及是否患有糖尿病，高血壓，缺血性心髒病，心房顫動，高血脂。所有研究對象的彩色視網膜照片都被採集。我們應用軟件“ImageJ"分析並記錄視網膜動靜脈直徑，血管分叉係數，分叉角度，分叉對稱性，視乳頭周長。我們也記錄其他視網膜特徵，如動靜脈壓跡，出血，硬性滲出，動脈阻塞及血管彎曲性。獨立t檢驗用於對連續變量的單因素分析，卡方檢驗用於對分類變量的單因素分析。Logistic 回歸用於建立統計模型對中風風險進行分類。所有統計方法均應用SPSS16.0 軟件。 / 結果:本研究納入122 中風患者及122 例患者做對照。每組分別有81 例糖尿病患者， 41 例非糖尿病患者。視網膜特徵包括動靜脈直徑，血管彎曲度，出血，硬性滲出，動靜脈壓跡在兩組中有顯著性差異。我們建立風險模型對兩組患者進行風險分類。分類準確度最高達的模型裡面包括的因子有：1)中風相關危險因素包括:高血壓，糖尿病，心房顫動2) 視網膜特徵包括:動脈直徑，血管彎曲性，出血，動靜脈壓跡跟靜脈對稱性；3) 視網膜特徵間的交立作用包括:動脈直徑與靜脈對稱性，動脈直徑與出血，靜脈對稱性與血管彎曲度。分類的準確度為80 .4%。只包括視網膜特徵的分類模型的準確度為74.5% 。 / 結論:彩色視網膜照相可成為中風風險的分類工具。與中風相關的視網膜特徵包括血管直徑，血管彎曲度，血管對稱性，出血，動靜脈壓跡。視網膜特徵與中風之間的聯繫存在交互作用。 / Objective: 1) To detect retina characteristics that associated with stroke; 2) To develop a statistics model with variables of retina characteristics for classifying patients with stroke from those without stroke in aged population. / Method: Matched case control study. Patients with stroke from the diabetic retinopathy screening program and stroke patients from Acute Stroke Unit were selected as stroke cases. Controls (patients without history of stroke) with matched diabetes status and age were selected from the diabetic retinopathy screening program and eye outpatient clinics. All subjects in this study were from Prince of Wales Hospital, Hong Kong. Risk factors of stroke from all subjects were collected, including age, gender, diabetes, hypertension, hyperlipidemia, history of ischemic heart disease, atrial fibrillation and smoking. Color retina images of each subject were collected and analyzed. The retina characteristics, including diameters of arterioles and venules, bifurcation coefficients, bifurcation angles, branch symmetry, optic disc perimeter were extracted from the color retina images by software "ImageJ". Other retina characteristics including arteriole-venule nicking, hemorrhages, exudates, arteriole occlusion, and vessel tortuosity were also recorded. Independent t test and Chi-squire test were used to compare the continuous and categorical retina characteristics respectively between patients with stroke and those without stroke. Logistic model combining the risk factors of stroke and retina characteristics was established to classify patients with stroke from those without stroke. All data analysis was by SPSS 16.0. / Results: there were 122 stroke cases and 122 controls recruited in this study. There were 41 patients without diabetes and 81 patients with diabetes in each group. Retina characteristics including diameters of arterioles and venules, vessel tortuosity, hemorrhages, exudates, arteriole-venule nicking were significantly different between the two groups. We established risk models to classify patients with stroke from those without stroke. The risk model with highest accuracy of classification included 1) stroke risk factors including hypertension, diabetes and atrial fibrillation; 2) retina characteristics, including arteriole diameters, vessel tortuosity, hemorrhages, arteriolevenule nicking and venule symmetry; 3)interaction between retina characteristics, including arteriole diameters by venule symmetry, arteriole diameters by hemorrhage,and venule symmetry by vessel tortuosity. The accuracy of classification was 80.4%. Using retinal characteristics alone achieved an accuracy of 74.5%. / Conclusion: color retina images are a potential tool for stroke risk stratification. Useful characteristics found in the retinal images included vessel diameters, vessel tortuosity, vessel symmetry, hemorrhage, arteriole-venule nicking. The association between the retinal characteristic and stroke was modified by other retinal characteristics. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Li, Qing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 139-148). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.iii / Acknoledgements --- p.v / Chapter Chapter 1 --- Introduction and review of the Literature --- p.1 / Chapter Section 1: --- Stroke prevention and risk assessment tools --- p.1 / Chapter Section 2: --- Rationale of relationship of vascular circulation between retina and brain --- p.9 / Chapter Section 3: --- Manifestation of hypertensive retinopathy and diabetic retinopathy --- p.12 / Chapter Section 4: --- Retina characteristics related to stroke --- p.15 / Chapter Section 5: --- How to make retina as a tool of risk stratification for stroke --- p.28 / Chapter Section 6: --- Rationale to do study to further explore the useful information in color retina images to make it as tool for stroke risk stratification --- p.31 / Chapter Chapter 2 --- Research hypothesis and general design --- p.33 / Chapter Chapter 3 --- Methods of retia characteristics extraction --- p.34 / Chapter Chapter 4 --- A Study of the Reliability of manual measurement of Retinal characteristics using ImageJ --- p.46 / Chapter Chapter 5 --- A study of comparison of retina characteristics between patients with stroke and patients without stroke --- p.55 / Chapter Section 1: --- Method --- p.56 / Chapter Section 2: --- Result-univariate analysis --- p.62 / Chapter Section 3: --- Results-stratification analysis --- p.68 / Chapter Section 4: --- Result-risk model building for stroke risk stratification --- p.79 / Chapter Chapter 6: --- Discussion --- p.118 / Chapter Chapter 7: --- Limitation of this study --- p.133 / Chapter Chapter 8: --- Future development and application of the study results --- p.134 / Appendix --- p.136 / Reference --- p.139

Introdução: A atrite reumatoide (AR) é uma doença Inflamatória crônica de etiologia desconhecida que afeta principalmente as articulações. A evolução da doença está associada com a incapacidade funcional, aumentando o risco de doenças cardiovasculares (DCV) e disfunção endotelial e rigidez arterial. Objetivo: Avaliar os efeitos de uma única sessão de exercício aeróbico de alta intensidade na função endotelial mediada pelo fluxo (DMF), avaliar a dor no pré exercício e após uma semana de intervenção através da escala visual analógica (EVA) e rigidez arterial em pacientes 26 com AR. Métodos: Estudo quase experimento, com 22 pacientes portadores de AR leve a moderada. Foram realizados teste ergoespirométrico, ecografia braquial para determinar a dilatação mediada pelo fluxo (DMF) e a avaliação da rigidez arterial por determinação da velocidade de onda de pulso (VOP), pré, pós e uma hora após a aplicação de um protocolo de treinamento intervalado de alta intensidade (TIAI). Resultados: A média de idade dos participantes é de 59,2 + 7,6 anos e há predominância do sexo feminino (91%). Apresentaram DAS28 de 4,1+ 1,0 (atividade moderada), e HAQ de 1+ 0,6 pontos (deficiência moderada). O VO2 Máximo encontrado foi de 21,19 + 3,89 ml/Kg/min. Os valores de DMF nos três momentos foram: basal com hiperemia reativa (10,59+0,47) e com nitroglicerina spray sublingual (12,66+0,89), no pós imediato (10,69+ 0,39) e com nitroglicerina (12,93+0,58), e 1 hora após (10,93+0,29) e com o medicamento (13,20+0,46), em relação a escala analógica visual de dor (EVA) observamos no basal uma dor de (3,45+0,80) e pós uma semana de intervenção (2,50+0,51). Conclusão: Concluímos que o TIAI com portadores de AR não foi significativo em relação às porcentagens de DMF, mas quando observamos outras medidas como a VOP, Pressão Arterial, Pressão de Pulso e o Índice de Aumentação, e os pacientes não apresentaram dor após uma semana de intervenção, sendo assim o exercício parece ser eficiente, sugerindo que pode ser uma estratégia útil para a prevenção de DCV em pacientes com AR. / Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology that mainly affects the joints. The evolution of the disease is associated with functional disability, increasing the risk of cardiovascular diseases (CVD) and endothelial dysfunction and arterial stiffness. Objective: To evaluate the effects of a single high-intensity aerobic exercise session on flow-mediated endothelial function (DMF), evaluate pain in pre-exercise and after one week of intervention using visual analogue scale (VAS) and arterial stiffness in patients with AR. Methods: Almost experimental study with 22 patients with mild to moderate RA. An ergospirometric test, brachial ultrasound was performed to determine the flow-mediated dilatation (FMD) and the evaluation of arterial 53 stiffness by determination of the pulse wave velocity (VOP), pre, post and one hour after the application of an interval training protocol high intensity (TIAI). Resultados: A média de idade dos participantes é de 59.2 + 7.6 anos e há predominância do sexo feminino (91%). Apresentaram DAS28 de 4.1+ 1.0 (atividade moderada), e HAQ de 1+ 0.6 pontos (deficiência moderada). O VO2 Máximo encontrado foi de 21.19 + 3.89 ml/Kg/min. Os valores de DMF nos três momentos foram: basal com hiperemia reativa (10.59+0.47) e com nitroglicerina spray sublingual (12.66+0.89), no pós imediato (10.69+ 0.39) e com nitroglicerina (12.93+0.58), e 1 hora após (10.93+0.29) e com o medicamento (13.20+0.46), em relação a escala analógica visual de dor (EVA) observamos no basal uma dor de (3.45+0.80) e pós uma semana de intervenção (2.50+0.51). Conclusion: We conclude that the TIAI with RA patients was not significant in relation to DMF percentages, but when we observed other measures such as OPV, Blood Pressure, Pulse Pressure and Increasing Index, and patients did not present pain after one week the exercise appears to be efficient, suggesting that it may be a useful strategy for the prevention of CVD in patients with RA.

Introdução: A influência dos polimorfismos da óxido nítrico sintase endotelial (eNOS) na resposta ao exercício físico ainda não foi esclarecida na literatura. Objetivos: Verificar o efeito do treinamento multicomponente sobre parâmetros de saúde de mulheres com idade entre 50 e 80 anos, bem como a influência dos genótipos e haplótipos (interação) das variantes genéticas da eNOS [-786T>C, 894G>T (Glu298Asp) e íntron 4b/a] neste mesmo contexto. Método: 52 participantes realizaram a avaliação da pressão arterial sistólica (PAS) e diastólica (PAD), índice de massa corporal (IMC), circunferência da cintura (CC) e porcentagem de gordura. Análises sanguíneas foram realizadas para genotipagem e avaliação do perfil lipídico (colesterol total, triglicerídeos, HDL-c e LDL-c), das concentrações de nitrito (NO2), malondialdeído (MDA), glutationa (GSH) e capacidade antioxidante total (CAT). A aptidão física foi avaliada pelos testes de caminhada de seis minutos (resistência aeróbia), flexão e extensão de cotovelo e sentar e levantar (força muscular). A intervenção de treinamento multicomponente (várias capacidades e habilidades motoras) durou 12 semanas e foi realizada 2x/sem, 90 min por sessão e Borg de 13 a 15 (um pouco intenso a intenso). A análise estatística foi realizada levando em conta a amostra total e também de acordo com os grupos normotenso e hipertenso, utilizando modelos de regressão de efeitos mistos. Resultados: Na análise sem divisão pelos genótipos, foi possível observar melhoras em todas as variáveis, com exceção da GSH, CC e perfil lipídico. Na análise isolada de cada polimorfismo, foi possível observar redução significativa da PAS e PAD em todos os grupos com o sem o alelo polimórfico, mas vale ressaltar que o grupo sem o alelo polimórfico nas três variantes genéticas, descritivamente, apresentou melhor resposta (?%) na PAS e PAD, e que isto, na posição -786T>C levou à diferença entre os grupos após a intervenção. Sobre a NO2, todos os grupos apresentaram melhora, com exceção dos grupos com o alelo polimórfico no Glu298Asp e íntron 4b/a (\"GluAsp+AspAp\" e \"4b4a+4a4a\"). Os polimorfismos não influenciaram na resposta do MDA, CAT e aptidão física, já que todos os grupos apresentaram melhora. O haplótipo H1 (três subgrupos sem o alelo polimórfico) foi o único a apresentar melhora em todas as variáveis estudadas, enquanto o haplótipo H8 (três subgrupos com os alelos polimórficos) somente apresentou diminuição do MDA e aumento da aptidão física. O efeito do treinamento multicomponente na análise sem divisão pelos genótipos e de acordo com os grupos normotenso e hipertenso foi parecida, mas levando em consideração os subgrupos com o alelo polimórfico nas três variantes genéticas da eNOS não apresentaram resposta na PAD e NO2 no grupo hipertenso e o subgrupo com o alelo polimórfico no íntron 4 b/a (\"4b4a+4a4a\") não apresentou melhora na PAD, NO2 e CAT no grupo normotenso, enquanto os subgrupos correspondentes sem o alelo polimórfico apresentaram melhora. Conclusão: Os polimorfismos da eNOS podem influenciar a resposta ao treinamento multicomponente, e, consequente prevenção e controle da PA / Introduction: The influence of endothelial nitric oxide synthase (eNOS) polymorphisms on the response to exercise training remain unclear. Objectives: To verify the effects of multicomponent training on health parameters in older adult women, as well as the influence of the genotypes and haplotypes (interaction) of eNOS genetic variants [-786T>C, 894G>T (Glu298Asp) and intron 4b/a] in the same context. Methods: Fifty-two participants underwent systolic (SBP) and diastolic blood pressure (DBP), body mass index (BMI), waist circumference (WC), and fat percentage assessments. Blood samples were used for genotyping and to assess lipid profile (total cholesterol, triglycerides, HDL-c, and LDL-c), nitrite concentration (NO2), malondialdehyde (MDA), glutathione (GSH), and total antioxidant capacity (TAC). Physical fitness was assessed by six-minute walk (aerobic resistance), elbow flexion and extension, and sit and stand up (muscle strength) tests. The multicomponent training intervention (various capacities and motor skills) was performed for 12 weeks, twice a week, for 90 min per session and a Borg Scale intensity of 13-15 (a little intense to intense). Statistical analysis was performed taking into account the total sample and also according to the normotensive and hypertensive groups using linear mixed effects models. Results: In the analysis without division by genotypes, it was possible to observe improvements in all variables, except for GSH, WC, and lipid profile. In the isolated analysis of each polymorphism, a significant reduction was observed in SBP and DBP in both groups, ancestral and variant genotypes, although it is worth mentioning that the ancestral genotype in the three genetic variants, descriptively, presented trends towards a better response (?%) in SBP and DBP, and this in position -786T>C led to the difference between the groups after the intervention. Regarding NO2, all groups demonstrated improvement, except for variant genotypes in Glu298Asp and intron 4b/a (\"GluAsp+AspAsp\" and \"4b4a+4a4a\"). Polymorphisms did not influence the MDA, TAC, or physical fitness response, since all groups showed improvement. The haplotype H1 (three ancestral genotypes) was the only one to show improvement in all the variables studied, whereas the haplotype H8 (three variant genotypes) demonstrated only a decrease in MDA and an increase in physical fitness. The effect of multicomponent training in the analysis without division by genotypes and according to the normotensive and hypertensive groups was similar, but considering the genotypes, the variant genotypes in the three genetic variants of eNOS did not present a response in DBP or NO2 in the hypertensive group and the variant genotypes in the intron 4 b/a (\"4b4a + 4a4a\") did not show improvement in DBP, NO2, or TAC in the normotensive group, while the corresponding ancestral genotypes demonstrated improvement. Conclusion: eNOS polymorphisms can influence the response to multicomponent training, and consequent prevention and control of BP

A doença arterial coronária (DAC) tem sido a maior causa de morte por doenças nos paises ocidentais. Existem vários fatores responsáveis pela iniciação e progressão desta doença - fatores ambiental ou genético. Muitos fatores de risco para a DAC estão relacionados a alterações do metabolismo lipídico, como acúmulo de lipoproteína de baixa densidade (LDL) no plasma seguida da deposição da lipoproteína na parede arterial. Recentemente, foi demonstrado que uma emulsão rica em colesterol que se assemelha a composição lipídica da LDL liga-se aos receptores que captam a lipopoteína da circulação e internalizam-na no citoplasma. A emulsão, denominada LDE, é feita sem proteína mas quando injetada na circulação sangüínea adquire várias apolipoproteínas (apo) como apo E que pode ser reconhecida pelo receptor de LDL. A apo E tem mais afinidade pelo receptor do que a apo B, a apo que liga a LDL nativa ao receptor. No presente estudo, para esclarecer o processo metabólico que a LDL enfrenta no plasma e o processo de captação da lipoproteína pelos vasos, a LDE marcada com colesterol livre-3H (CL) e oleato de colesterol-14C (CE) foi injetada em 10 pacientes portadores de DAC (57 ± 2,2 anos) submetidos à cirurgia de revascularização miocárdica. Amostras de sangue foram coletadas em intervalos de tempo pré-determinados. A radioatividade presente nas alíquotas de plasma foi determinada por cintilação líquida e a taxa fracionai de remoção (TFR) calculada por análise compartimental. Os fragmentos dos enxertos de aorta, artérias radial e torácica interna, veia safena e pericárdio removidos durante o procedimento cirúrgico foram coletados para extração lipídica, separação por cromatografia de camada delgada e quantificação radioativa. A remoção plasmática do CE da LDE foi similar a do CL da LDE (0,0617 ± 0,0087 vs 0,0528 ± 0,0123, p = 0,5635, respectivamente). A captação do CL da LDE foi maior do que a do CE da LDE na aorta (21% vs 3,1%, p = 0,0049), artéria torácica interna (10,3% vs 2%, p = 0,0007) e veia safena (8% vs 2%, p = 0,0326). Nos fragmentos de artéria radial (14,4% vs 4,3%) e de pericardio (2,2% vs 0,3%), a captação do CL tendeu ser maior do que a captação do CE, porém não foi estatisticamente confirmado. A taxa de esterificação foi maior nos fragmentos de aorta, de toráxica interna e de pericárdio do que nos fragmentos de veia safena (p < 0,001). Concluindo, a LDE foi captada pelos vasos e pericardio em quantidades concideráveis e a captação do CL pelos tecidos foi maior do que a do CE. Ainda, a taxa de esterificação do colesterol livre foi mais intensa nos fragmentos de aorta e torácica interna do que nos fragments de veia safena. / Coronary artery disease (CAD) is the main mortality cause in western countries. There are many factors responsible for the onset and progression of the disease - either environmental or genetic. Many risk factors in CAD are related with disorders of lipid metabolism, such as accumulation of low-density lipoprotein (LDL) in the plasma with deposition of the lipoprotein in the arterial wall. Recently, it was shown that a cholesterol-rich emulsion that mimics the lipid composition of LDL binds to the receptors that take-up the lipoprotein from the circulation and internalizes it into the cytoplasm. The emulsion, denominated LDE, is made without protein but when injected into the bloodstream it picks-up several apolipoproteins (apo) such as apo E that can be recognized by the LDL receptor. Apo E has even more affinity for the receptor than apo B, the apo that binds native LDL to the receptors. In the current study, aiming to clarity the metabolic processes that LDL undergoes in the plasma and the process of lipoprotein uptake by the vessels, LDE labeled with 3H- Cholesterol (CL) and 14C-Cholesteryl Oleate (CE) was injected into 10 CAD patients (57 ± 2,2 yr.) scheduled to be submitted to myocardial revascularization surgery. Blood samples were collected over 24 hour at pre-established intervals. Radioactivity present in plasma aliquots was determined in a scintillation solution and the fractional clearance rate (FCR) was calculated by compartimental analysis. The gratt\'s fragments of aortic, radial, internal thoracic arteries, safenous vein and pericardium discarded during the surgical procedure were collected for lipid extraction, separation by thin layer chromatography and radioactive counting. The removal from plasma of the LDE CE was similar to that of the LDE CL (0,0617 ± 0,0087 vs 0,0528 ± 0,0123, p = 0,5635, respectively). The uptake of LDE CL was greater than that of LDE CE in aorta (21% vs 3,1%, p = 0,0049), internal toracic artery (10,3% vs 2%, p = 0,0007) and safenous vein (8% vs 2%, p = 0,0326). In the radial artery (14,4% vs 4,3%) and pericardium (2,2% vs 0,3%) fragments, the CL uptake also tended to be greater than that of CE, but this was not statistically confirmed. The esterification rate was greater in the aorta, internal thoracic artery and pericardium fragments than in safenous vein fragments (p < 0,001). In conclusion, LDE was taken-up by vessels and pericardium at considerable amounts and LDE CL uptake by those tissues was greater than that of CE. In addition, the cholesterol esterification rate was more intense in the aorta and internal thoracic artery than in venous fragments.

Submitted by Samira Ramos (samira.ramos@unifenas.br) on 2019-02-26T18:07:29Z No. of bitstreams: 1 Tese_Ariane_Borges.pdf: 1192468 bytes, checksum: 14a5f0b78794c95edf17ef4ee983572f (MD5) / Made available in DSpace on 2019-02-26T18:07:29Z (GMT). No. of bitstreams: 1 Tese_Ariane_Borges.pdf: 1192468 bytes, checksum: 14a5f0b78794c95edf17ef4ee983572f (MD5) Previous issue date: 2018-06-29 / Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Variations in lipids and lipoproteins are considered a risk factor for cardiovascular diseases, such as atherosclerosis. This study evaluated the effect of genetic and alimentary dyslipidemia on testicular morphofunctional characteristics and whether its relation with the cardiovascular diseases developed by hyperlipidic diets in genetically modified mice, absent LDL receptor (Ldlr-/-) and wild type mice. In addition to evaluating the replacement of testosterone in the protection of the cardiovascular system of Ldlr-/- mice fed or not with a hyperlipidic diet. In the first study, Ldlr-/- mice were selected, divided into four groups (n = 10): S: animals fed standard diet (Nuvital®) for rodents and without testosterone application; ST: animals fed standard diet (Nuvital®) for rodents and with testosterone application (0.01 ml per week); HL: animals fed a hyperlipid diet (20% total fat, 1.25% cholesterol and 0.5% cholic acid) and without testosterone application; HLT: animals fed a hyperlipid diet (20% total fat, 1.25% cholesterol and 0.5% colic) and with testosterone application (0.01 ml per week). In the analysis of the lipid profile, the mice that received hyperlipidic diets (HL and HLT) presented severe mixed dyslipidemia with increased serum levels of total cholesterol, LDL, VLDL and triglycerides, when compared to the mice of the S and ST groups. However, the HLT group showed an increase in serum HDL levels when compared to the mice in the HL group. The mice from the S and ST groups had increased serum HDL levels in relation to the other groups studied. In the second study, it was observed that the dyslipidemia generated by the LDL receptor deficiency (Ldlr-/-) has a positive relation with the increase in the production of vascular superoxide anions, increased expression of CD40 and FasL in the testis. Genetic deletion of the LDL receptor (Ldlr-/-) in mice associated with a hyperlipidic diet increased both systemic and testicular damage. In conclusion, the metabolic disorders of the lipids generated by the deletion of the LDL gene induced testicular dysfunction, by mechanisms involving oxidative stress, inflammation and apoptosis, impairing spermatogenesis and testicular steroidogenesis. It is also suggested that testosterone may indirectly cause hypertrophy of cardiomyocytes / As variações nos lipídeos e lipoproteínas são consideradas um fator de risco para doenças cardiovasculares, como a aterosclerose. Este estudo avaliou o efeito da dislipidemia genética e alimentar nas características morfofuncionais testiculares e se sua relação com as doenças cardiovasculares desenvolvidas por dietas hiperlipídicas em camundongos geneticamente modificados, ausente do receptor do LDL (Ldlr-/-) e em camundongos selvagens (wild type). Além de avaliar a reposição da testosterona na proteção do sistema cardiovascular de camundongos Ldlr-/- alimentados ou não com dieta hiperlipídica. No primeiro trabalho, foram selecionados camundongos Ldlr-/-, divididos em quatro grupos (n=10): S: animais alimentados com dieta padrão (Nuvital®) para roedores e sem aplicação de testosterona; ST: animais alimentados com dieta padrão (Nuvital®) para roedores e com aplicação de testosterona (0,01ml por semana); HL: animais alimentados com dieta hiperlipídica (20% de gordura total, 1,25% de colesterol e 0,5% de ácido cólico) e sem aplicação de testosterona; HLT: animais alimentados com dieta hiperlipídica (20% de gordura total, 1,25% de colesterol e 0,5% de ácido cólico) e com aplicação de testosterona (0,01ml por semana). Na análise do perfil lipídico, os camundongos que receberam dietas hiperlipídicas (HL e HLT) apresentaram dislipidemia mista severa com aumento dos níveis séricos do colesterol total, LDL, VLDL e triglicérides, quando comparados com os camundongos dos grupos S e ST. Contudo os camundongos dos grupos HLT apresentaram aumento nos níveis séricos de HDL quando comparados com os camundongos do grupo HL. Os camundongos do grupo S e ST apresentaram níveis séricos de HDL aumentados em relação aos demais grupos estudados. No segundo trabalho, observou-se que a dislipidemia gerada pela deficiência do receptor de LDL (Ldlr-/-) tem uma relação positiva com o aumento da produção de ânions de superóxido vascular, aumento da expressão de CD40 e FasL no testículo. A deleção genética do receptor de LDL (Ldlr-/-) em camundongos associados a uma dieta hiperlipídica aumentou o dano sistêmico e testicular. Em conclusão, os distúrbios metabólicos dos lipídeos gerados pela deleção do gene LDL induziram a disfunção testicular, por mecanismos envolvendo estresse oxidativo, inflamação e apoptose, prejudicando a espermatogênese e a esteroidogênese testicular. Sugere-se também que a testosterona possa causar indiretamente a hipertrofia de cardiomiócitos.

A cohort of 87 SLE female patients underwent non-invasive assessments (e.g., vascular ultrasound, pulse wave analysis with applanation tonometry and echocardiography with TDI). In addition, disease activity, organ damage and SLE-related lab markers were also evaluated. Forty female healthy subjects were included as normal control. / In summary, pulse wave analysis and tissue Doppler imaging are sensitive and accurate to detect premature atherosclerosis and subclinical myocardial dysfunction. The current study demonstrated a close correlation of inflammatory burden (disease activity and organ damage) to premature atherosclerosis and subclinical myocardial dysfunction, which may implicate the importance of routinely monitoring and early treatment to attenuate cardiovascular involvement. / Systemic lupus erythematosus (SLE), an autoimmune-inflammatory disease, results in multi-organ damage of the body. Compared to Caucasian, Chinese in Hong Kong have high prevalence of SLE. Cardiovascular diseases are common manifestations of SLE, which have emerged to be one of main causes of mortality. Detection of premature atherosclerosis, arterial stiffening and subclinical myocardial impairment early in the course of the disease is important as there may be a role of early therapeutic intervention in these patients that might translate into better clinical outcomes. In this regard, newer non-invasive methods, such as, pulse wave analysis and tissue Doppler imaging (TDI), have gained clinical popularity due to their accurate, reliable and reproducible measurements for the early detection of subclinical cardiovascular complications. / The main findings were as follows: (1) Increased arterial stiffness and premature atherosclerosis were demonstrated in SLE patients with mild disease and a low prevalence of end-organ damage and SLE itself was an independent risk factor of early atherosclerosis; (2) The abnormal vascular parameters correlated with disease activity; (3) SLE patients without overt cardiovascular involvement still have abnormal diastolic function with or without elevated LV filling pressure identified by a ratio of mitral Doppler inflow velocity to lateral annulus velocity (lateral E/E'>10) on pulse-wave and tissue Doppler echocardiography; (4) Both pulmonary artery hypertension and organ-damage were the independent predictors of elevated LV filling pressure alter adjustment of traditional risk factors, with the former adding incremental predictive value to the latter; (5) There was evidence of subclinical LV systolic dysfunction in patients with SLE even when LV ejection fraction appeared to be normal; (6) The independent determinants of subclinical LV systolic dysfunction included long disease duration of >10 years, active disease, reduced total arterial compliance as well as abnormal mid-wall fractional shortening, and the assessment of these factors provided incremental predictive value. / This thesis applied the above non-invasive methods to SLE subjects with the following aims: (1) To ascertain whether there is evidence of preclinical atherosclerosis (as indicated by carotid intima-media thickness), and/or increased arterial stiffeness (as reflected by direct and indirect surrogate parameters, including pulse wave velocity, augmentation index and ankle-brachial index) in SLE; (2) To investigate the relationships of these noninvasive vascular parameters to inflammatory disease burden in terms of SLE disease activity and organ damage; (3) To assess whether there is evidence of subclinical myocardial diastolic dysfunction; (4) To determine the associations between various clinical and echocardiographic parameters, including presence of pulmonary arterial hypertension, SLE-related clinical data, and elevated LV filling pressure; (5) To detect whether there is evidence of subclinical myocardial systolic dysfunction by tissue Doppler echocardiography; (6) To determine various clinical and echocardiographic parameters in predicting subclinical LV longitudinal-axis systolic function. / Shang, Qing. / Advisers: Yu Cheuk-man; Tam Lai-Shan; Yip Wai-Kwok. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3421. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 166-201). / 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.