Ng, Mei. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves xvi-xlviii). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT / In English --- p.ii / In Chinese --- p.iv / LIST OF TABLES --- p.vi / LIST OF FIGURE --- p.viii / ABBREVIATIONS / For Units --- p.ix / For Prefixes of the International System of Units --- p.ix / For Terms Commonly Used --- p.X / Chapter CHAPTER 1 --- Overview of Childhood Obstructive Sleep Apnoea Syndrome (OSAS) / Chapter 1.1 --- Prevalence --- p.1 / Chapter 1.2 --- Clinical Features --- p.3 / Chapter 1.3 --- Definitions and Cutoffs --- p.4 / Chapter 1.4 --- Pathophysiology --- p.6 / Chapter 1.5 --- Risk Factors / Chapter 1.5.1 --- Gender --- p.8 / Chapter 1.5.2 --- Obesity --- p.9 / Chapter 1.5.3 --- Adenotonsillar Hypertrophy --- p.10 / Chapter 1.5.4 --- Genetic --- p.11 / Chapter 1.5.5 --- Atopic Diseases --- p.12 / Chapter 1.6 --- Complications / Chapter 1.6.1 --- Neurobehavioural Deficits --- p.13 / Chapter 1.6.2 --- Growth Defects --- p.14 / Chapter 1.6.3 --- Metabolic Disorders --- p.16 / Chapter 1.6.4 --- Systemic inflammation --- p.17 / Chapter 1.6.5 --- Cardiovascular Consequences --- p.19 / Chapter 1.7 --- Diagnosis --- p.20 / Chapter 1.8 --- Treatment / Chapter 1.8.1 --- Surgical Treatment --- p.22 / Chapter 1.8.2 --- Continuous Positive Airway Pressure (CPAP) --- p.24 / Chapter 1.8.3 --- Corticosteroids --- p.24 / Chapter 1.8.4 --- Leukotriene Receptor Antagonist --- p.25 / Chapter 1.8.5 --- Oral Appliances --- p.26 / Chapter 1.8.6 --- Weight Control --- p.27 / Chapter CHAPTER 2 --- OSAS and Cardiovascular Complications in Adults / Chapter 2.1 --- Mechanism / Chapter 2.1.1 --- Acute Cardiovascular Responses --- p.28 / Chapter 2.1.2 --- Chronic Cardiovascular Responses --- p.29 / Chapter 2.2 --- Hypertension / Chapter 2.2.1 --- Epidemiological and Clinical Data --- p.31 / Chapter 2.2.2 --- Characteristics --- p.32 / Chapter 2.2.3 --- Mechanisms --- p.33 / Chapter 2.2.4 --- Treatment --- p.34 / Chapter 2.3 --- Heart Failure --- p.35 / Chapter 2.4 --- Stroke --- p.37 / Chapter 2.5 --- Cardiac Arrhythmias --- p.39 / Chapter 2.6 --- Myocardial Ischemia and Vascular Disease --- p.41 / Chapter 2.7 --- Pulmonary Hypertension --- p.43 / Chapter CHAPTER 3 --- OSAS and cardiovascular complication in children / Chapter 3.1 --- Blood Pressure --- p.45 / Chapter 3.2 --- Ventricular Hypertrophy and Dysfunctions --- p.48 / Chapter 3.3 --- Heart Rate Variability --- p.50 / Chapter 3.4 --- Arterial Tone --- p.51 / Chapter 3.5 --- Endothelial Function --- p.51 / Chapter CHAPTER 4 --- Longitudinal follow-up study of children with OSAS - a cardiovascular perspective / Chapter 4.1 --- Introduction --- p.53 / Chapter 4.2 --- Methods / Chapter 4.2.1 --- Subjects and Study Design --- p.57 / Chapter 4.2.2 --- Polysomnography --- p.59 / Chapter 4.2.3 --- Ambulatory Blood Pressure Measurement --- p.61 / Chapter 4.2.4 --- Statistical Analysis --- p.62 / Chapter 4.3 --- Results / Chapter 4.3.1 --- Subject Characteristics --- p.64 / Chapter 4.3.2 --- Blood Pressure During Wakefulness --- p.71 / Chapter 4.3.3 --- Blood Pressure During Sleep --- p.76 / Chapter 4.3.4 --- Nocturnal Blood Pressure Dipping --- p.83 / Chapter 4.3.5 --- Blood Profile --- p.86 / Chapter 4.4 --- Discussion --- p.87 / Chapter 4.5 --- Conclusion --- p.99 / Reference List --- p.xvi

Au, Chun Ting. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves xxvii-lv). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT / In English --- p.ii / In Chinese --- p.v / LIST OF TABLES --- p.vii / ABBREVIATIONS / For Units --- p.ix / For Prefixes of the international system of units --- p.ix / For Terms commonly used in the report --- p.x / STATEMENT OF WORK DONE --- p.xvi / Chapter CHAPTER 1 --- Overview of Childhood Obstructive Sleep Apnea Syndrome (OSAS) / Chapter 1.1. --- Clinical Features of Childhood OSAS --- p.1 / Chapter 1.2. --- Definition of Childhood OSAS --- p.2 / Chapter 1.3. --- Prevalence of Childhood OSAS --- p.3 / Chapter 1.4. --- Pathophysiology --- p.4 / Chapter 1.5. --- Risk Factors --- p.6 / Chapter 1.6. --- Diagnosis --- p.10 / Chapter 1.7. --- Treatment / Chapter 1.7.1. --- Tonsillectomy and Adenoidectomy (T&A) --- p.12 / Chapter 1.7.2. --- Continuous Positive Airway Pressure (CPAP) --- p.14 / Chapter 1.7.3. --- Corticosteroids --- p.15 / Chapter 1.7.4. --- Leukotriene Receptor Antagonist --- p.16 / Chapter 1.8. --- Complications of Childhood OSAS / Chapter 1.8.1. --- Growth Failure --- p.17 / Chapter 1.8.2. --- Neurocognitive Abnormalities --- p.19 / Chapter 1.8.3. --- Cardiovascular Abnormalities --- p.20 / Chapter CHAPTER 2 --- Cardiovascular Complications of OSAS in Adults (Literature Review) / Chapter 2.1. --- Acute Effects of OSAS on Cardiovascular System --- p.21 / Chapter 2.2. --- Chronic Effects of OSAS on Cardiovascular System --- p.23 / Chapter 2.3. --- Hypertension --- p.24 / Chapter 2.4. --- Heart Failure --- p.28 / Chapter 2.5. --- Pulmonary Hypertension --- p.30 / Chapter 2.6. --- Arrhythmias --- p.31 / Chapter 2.7. --- Cardiac Ischemia and Vascular Disease --- p.33 / Chapter 2.8. --- Stroke --- p.34 / Chapter CHAPTER 3 --- Cardiovascular Complications of Childhood OSAS (Literature Review) / Chapter 3.1. --- Blood Pressure --- p.37 / Chapter 3.2. --- Ventricular Structure and Function --- p.40 / Chapter 3.3. --- Arterial Distensibility --- p.42 / Chapter 3.4. --- Heart Rate Variability --- p.42 / Chapter CHAPTER 4 --- Ambulatory Blood Pressure in Children with OSAS / Chapter 4.1. --- Introduction --- p.44 / Chapter 4.2. --- Methods / Chapter 4.2.1. --- Subjects and Study Design --- p.46 / Chapter 4.2.2. --- Polysomnography (PSG) --- p.47 / Chapter 4.2.3. --- Ambulatory Blood Pressure Measurement (ABPM) --- p.49 / Chapter 4.2.4. --- Statistical Analysis --- p.50 / Chapter 4.3. --- Results / Chapter 4.3.1. --- Subject Characteristics --- p.52 / Chapter 4.3.2. --- Blood Pressure during Wakefulness --- p.55 / Chapter 4.3.3. --- Blood Pressure during Sleep --- p.57 / Chapter 4.4. --- Discussion --- p.62 / Chapter 4.5. --- Conclusion --- p.70 / Chapter CHAPTER 5 --- Cardiac Remodeling and Dysfunction in Children with OSAS / Chapter 5.1. --- Introduction --- p.71 / Chapter 5.2. --- Methods / Chapter 5.2.1. --- Subjects and Study Design --- p.72 / Chapter 5.2.2. --- Polysomnography (PSG) --- p.74 / Chapter 5.2.3. --- Conventional Echocardiography --- p.75 / Chapter 5.2.4. --- Tissue Doppler Imaging --- p.76 / Chapter 5.2.5. --- Statistical Analysis --- p.77 / Chapter 5.3. --- Results / Chapter 5.3.1. --- Study Population --- p.79 / Chapter 5.3.2. --- Polysomnographic Findings --- p.79 / Chapter 5.3.3. --- Echocardiographic Findings / Chapter 5.3.3.1. --- Right Ventricle --- p.81 / Chapter 5.3.3.2. --- Left Ventricle --- p.83 / Chapter 5.3.4. --- Treatment Effect --- p.86 / Chapter 5.4. --- Discussion --- p.90 / Chapter 5.5. --- Conclusion --- p.95 / Chapter CHAPTER 6 --- Conclusion --- p.96 / APPENDIX I Hong Kong Children Sleep Questionnaire (Chinese) --- p.xvii / APPENDIX II Hong Kong Children Sleep Questionnaire (English) --- p.xxii / REFERENCES --- p.xxvii

目的：針對心血管初級預防，世界各國均推薦某一年齡段人群全部測量膽固醇以估算心血管病發病風險。此舉耗費高且非必須，本研究旨在建立並驗證一個新型的选择性膽固醇篩查模型，用以篩查需藥物治療之高危人群，并在成本效益方面與其它篩查模型相比較。 / 方法：本模型具體采用兩步法：首先利用一個足夠高的假設膽固醇值代入心血管病風險預測方程，用以系統性的高估絶大多數人的心血管病風險；其次只有假設心血管病風險高於推薦治療閾值時，該個體才需要測量膽固醇，並進行實際心血管病風險分析。 / 英国健康调查和中国营养与健康调查是本次研究的合适数据。我們首先探索最優的假設膽固醇值，尋找到最後膽固醇值之後，我們將繼續測試我們的新型膽固醇篩查模型，在不同的治療閾值下，表現是否穩定。我們以靈敏度，特異度和徐篩查人群為指標，比較我們模型與全民篩查模型和英國NICE 選擇篩查模型相比較。之後我們估算在中英人群中應用該篩查模型，所需耗費的成本和可預防心血管事件數。 / 结果：與全名篩查模型相比，我們的模型靈敏度相若但可以節省80%左右的篩查費用。模型的靈敏度主要取決於所採用的假設膽固醇值，與所用風險預測方程，治療閾值和人群心血管風險分佈無關。當以均數加2 倍標準差作為假設膽固醇值時，靈敏度可達到97.5%左右，特異度可以達到90%左右，符合預期。模型應用於中國人群得到的結果類似。值得註意的是，在中國人群中，即使不測量膽固醇，模型靈敏度亦接近95%。此外，將膽固醇篩查項目限制于男性50-84歲，女性60-84 歲年齡段可以進一步減少篩檢費用。在人群影響方面，我們模型可預防心血管事件數比全名篩查模型略少，但成本大大降低。英國NICE 模型適用於某些特定情況，但並非全部。 / 結論：我們的新型篩查模型靈敏度與全民篩查模型相若，但可以節省大量篩查費用。在资源匮乏地区，可考虑在某一特定年龄段运用我们的模型已达到进一步减少费用的效果。如果本研究结果得到进一步数据证实，對於中國人群而言，膽固醇測量可能並非心血管風險評估所必須。 / Objectives / Since the mid 1990s, most guidelines on primary prevention of cardiovascular disease (CVD) have recommended regular cholesterol measurement for all adults or those above a certain age (which is known as mass screening). Cholesterol measurement comprises a large cost of CVD prevention and is not necessarily required in those who do not need drug intervention. In order to reduce this cost, we have developed a new selective cholesterol screening model in order to determine whose cholesterol should be measured for drug prevention. The model was evaluated and compared with other widely adopted models in basic model performance as well as cost effectiveness. / Methods / The new model has two steps. In the first step, we purposely over-estimated the majority of respondents’ CVD risk by substituting a sufficiently high hypothetical cholesterol value in the risk estimation. We then recommend cholesterol measurement only to those with the estimated CVD risk above a predetermined risk threshold for drug treatment. In the second step, the CVD risk is re-estimated based on the individual’s real cholesterol consentration. Those with a risk above the treatment threshold are recommended for drug treatment. / We evaluated the performance of our two-step model with data from the Health Survey for England and re-evaluated it with data from the China Nutrition and Health Survey 2002. By varying the hypothetical cholesterol values and treatment thresholds in CVD risk, we assessed the sensitivity, specificity and proportion of the population who need to measure cholesterol and compared it with the US mass screening model and the UK NICE selective screening model. We further compared the costs and CVD events avoided in the compared screening programmes. We also examined how the age restriction should be set in cholesterol screening programmes. / Results / As compared to mass screening, our new model can achieve a high sensitivity and save some 80% the cost of cholesterol measurements. The sensitivity depends mainly on the hypothetical cholesterol level used and seems independent of population’s CVD risk, treatment cut-off values and risk prediction model. The model performed well in almost all the conditions tested. When the hypothetical cholesterol was set at MEAN+2SD, the resulting sensitivity of our selective screening model was almost always above 95% and close to the expected 97.5%. The sensitivity was only compromised slightly if cholesterol is not measured at all for the Chinese population. Furthermore, in order to save more costs, cholesterol measurement could be better restricted to men aged 50-84 and women 60-84 years regardless of the screening model used. In CVD events prevented, mass screening is always the best but our model can prevent almost as many. In costs, mass screening is always the most expensive but our model can save all or most of the cost. The NICE selective model can perform as well as our model only when it is used in an appropriate manner and in certain circumstances. / Conclusion / Our new cholesterol screening model has a high sensitivity which is comparable to that of universal screening programs but can save most of the cost on cholesterol measurements. In where resources are particular sparse, our model can also perform well by applying it only to certain age groups, which will further save cholesterol measurement costs. Cholesterol measurement could even be completely avoided for the Chinese population if our findings can be re-confirmed correct with more updated data. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Hu, Xuefeng. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 114-121). / Abstract also in Chinese. / Abstract (in English) --- p.i / Abstract (in Chinese) --- p.iv / Acknowledgements --- p.vi / Abbreviations used in the thesis --- p.viii / List of Tables --- p.xvi / List of Figures --- p.xviii / List of Boxes --- p.xix / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- The burden of cardiovascular disease --- p.1 / Chapter 1.2 --- Primary prevention of CVD --- p.2 / Chapter 1.3 --- The high-risk individual strategy for CVD primary prevention --- p.3 / Chapter 1.3.1 --- The high risk individual strategy is effective --- p.4 / Chapter 1.3.2 --- The high risk individual strategy is cost-effective --- p.4 / Chapter 1.4 --- Who should be treated with drugs? --- p.5 / Chapter 1.4.1 --- The single risk factor strategy --- p.5 / Chapter 1.4.2 --- The overall CVD risk strategy --- p.7 / Chapter 1.4.3 --- Scope of CVD primary prevention --- p.8 / Chapter 1.5 --- Methods for assessing the CVD risk --- p.9 / Chapter 1.6 --- Current strategies for cholesterol measurements --- p.10 / Chapter 1.6.1 --- United States National Cholesterol Education Program --- p.13 / Chapter 1.6.2 --- American Heart Association CVD and Stroke prevention guideline --- p.14 / Chapter 1.6.3 --- The U.S. Preventive Services Task Force guideline --- p.15 / Chapter 1.6.4 --- New Zealand guideline 2003 --- p.16 / Chapter 1.6.5 --- Australian guideline 2009 --- p.17 / Chapter 1.6.6 --- The Joint British Society guideline-2 --- p.17 / Chapter 1.6.7 --- UK Department of Health guideline on vascular check --- p.18 / Chapter 1.6.8 --- China Blood Lipid Modification Guideline 2007 --- p.18 / Chapter 1.6.9 --- Summary of the reviewed guidelines --- p.19 / Chapter 1.7 --- Rationale for a selective screening model --- p.20 / Chapter 1.8 --- The UK NICE model --- p.22 / Chapter 1.9 --- Objectives of this study --- p.24 / Chapter 2 --- Methods --- p.25 / Chapter 2.1 --- The new cholesterol screening model --- p.25 / Chapter 2.2 --- Framework for evaluating the new screening model --- p.27 / Chapter 2.3 --- Indexes for evaluating the basic performance of screening models --- p.28 / Chapter 2.3.1 --- Sensitivity, specificity and % need cholesterol measurement --- p.28 / Chapter 2.3.2 --- Sensitivity analysis for model performance --- p.29 / Chapter 2.3.2.1 --- Using different hypothetical cholesterol values --- p.29 / Chapter 2.3.2.2 --- Using different treatment cut-off thresholds --- p.30 / Chapter 2.3.2.3 --- Using different populations --- p.30 / Chapter 2.3.2.4 --- Using different risk equations --- p.31 / Chapter 2.4 --- Data --- p.31 / Chapter 2.4.1 --- The Health Survey for England --- p.31 / Chapter 2.4.1.1 --- Background and aim of the survey --- p.31 / Chapter 2.4.1.2 --- Survey design --- p.32 / Chapter 2.4.1.2.1 --- Sampling Frame --- p.32 / Chapter 2.4.1.2.2 --- Weighting variables --- p.33 / Chapter 2.4.1.3 --- Data collection --- p.33 / Chapter 2.4.1.3.1 --- Blood cholesterol --- p.34 / Chapter 2.4.1.3.2 --- Blood pressure --- p.34 / Chapter 2.4.1.3.3 --- Smoking --- p.34 / Chapter 2.4.1.3.4 --- History of CVD and diabetes --- p.34 / Chapter 2.4.1.3.5 --- Treatment history --- p.35 / Chapter 2.4.2 --- The 2002 China National Nutrition and Health Survey --- p.35 / Chapter 2.4.2.1 --- Survey design --- p.36 / Chapter 2.4.2.2 --- Data collection --- p.36 / Chapter 2.4.2.2.1 --- Blood pressure --- p.36 / Chapter 2.4.2.2.2 --- Blood cholesterol --- p.38 / Chapter 2.4.2.2.3 --- Smoking --- p.38 / Chapter 2.4.2.2.4 --- History of CVD, diabetes and drug treatment --- p.38 / Chapter 2.4.3 --- Subjects eligible for analysis in this study --- p.38 / Chapter 2.5 --- CVD risk prediction --- p.43 / Chapter 2.5.1 --- The Framingham risk equation for the UK population --- p.43 / Chapter 2.5.2 --- The Asian equation for the Chinese population --- p.44 / Chapter 2.5.3 --- Adjusting for cholesterol and blood pressure --- p.45 / Chapter 2.5.4 --- Deriving the hypothetical cholesterol --- p.46 / Chapter 2.6 --- Identifying the appropriate age ranges for cholesterol measurement --- p.47 / Chapter 2.7 --- Comparing various screening models and options --- p.47 / Chapter 2.7.1 --- Compared screening models and options --- p.47 / Chapter 2.7.1 --- Indices for the performance of the screening options --- p.49 / Chapter 2.7.2 --- Costs of different screening options --- p.50 / Chapter 2.7.2.1 --- Components of screening cost from societal perspective --- p.50 / Chapter 2.7.2.1.1 --- Cost for inviting people for data collection --- p.50 / Chapter 2.7.2.1.2 --- Cost for the full risk assessment --- p.51 / Chapter 2.7.2.1.3 --- Treatment cost --- p.51 / Chapter 2.7.2.1.4 --- Cost saved for avoided CVD events --- p.52 / Chapter 2.7.2.2 --- Components of screening cost from health system’s perspective --- p.52 / Chapter 2.7.3 --- Number of CVD events avoidable --- p.53 / Chapter 2.8 --- Statistical analysis --- p.54 / Chapter 2.8.1 --- Descriptive analysis --- p.54 / Chapter 2.8.2 --- Cross-tabulation analysis --- p.54 / Chapter 2.8.3 --- Survey data analysis --- p.54 / Chapter 3 --- Results --- p.57 / Chapter 3.1 --- Description of data --- p.57 / Chapter 3.1.1 --- The UK population --- p.57 / Chapter 3.1.1.1 --- Sumamry of CVD risk and risk factors --- p.57 / Chapter 3.1.1.2 --- Distribution of age --- p.57 / Chapter 3.1.1.3 --- Distribution of blood pressure and blood cholesterol --- p.58 / Chapter 3.1.1.4 --- Distribution of the predicted 10-year CVD risk --- p.62 / Chapter 3.1.1.5 --- Relation between the risk threshold and age --- p.63 / Chapter 3.1.2 --- The Chinese population --- p.65 / Chapter 3.1.2.1 --- Summary of CVD risk and risk factors --- p.65 / Chapter 3.1.2.2 --- Distribution of age --- p.65 / Chapter 3.1.2.3 --- Distribution of blood pressure and blood cholesterol --- p.66 / Chapter 3.1.2.4 --- Distribution of the predicted 10-year CVD risk --- p.69 / Chapter 3.1.2.5 --- Relation between the risk threshold and age --- p.70 / Chapter 3.2 --- Performance of our new screening model --- p.72 / Chapter 3.2.1 --- Performance according to cholesterol values in the UK population --- p.72 / Chapter 3.2.2 --- Performance according to treatment cut-offs in the UK population --- p.73 / Chapter 3.2.3 --- Performance according to cholesterol values in the Chinese population --- p.73 / Chapter 3.2.4 --- Performance according to the risk cut-offs in the Chinese population --- p.74 / Chapter 3.2.4 --- Performance using different risk equations --- p.76 / Chapter 3.3 --- Comparison with other existing screening models --- p.77 / Chapter 3.3.1 --- Performance of the 3 models within an age-restricted UK population --- p.79 / Chapter 3.3.2 --- Performance of the 3 models within an age-restricted Chinese population --- p.81 / Chapter 3.3.3 --- Performance of the 3 models in the entire UK population --- p.83 / Chapter 3.3.4 --- Performance of the 3 models in the entire Chinese population --- p.84 / Chapter 3.3.5 --- Costs of various screening options --- p.87 / Chapter 3.3.6 --- Number of CVD events avoidable of the screening programmes --- p.92 / Chapter 4 --- Discussion --- p.96 / Chapter 4.1.1 --- Performance at different hypothetical cholesterol values --- p.96 / Chapter 4.1.2 --- Performance at various treatment cut-off thresholds --- p.97 / Chapter 4.1.3 --- Performance with different risk equations --- p.98 / Chapter 4.1.4 --- Performance in different populations --- p.99 / Chapter 4.1.5 --- Performance with different survival functions --- p.99 / Chapter 4.2 --- Further modifications of the model --- p.100 / Chapter 4.2.1 --- A model without any cholesterol measurement --- p.100 / Chapter 4.2.2 --- Age restriction for selective models --- p.102 / Chapter 4.2.3 --- Our model with potential personalized treatment cut-off --- p.103 / Chapter 4.2.4 --- Three key things to ensure model performance in other population --- p.104 / Chapter 4.3 --- CVD events preventable --- p.105 / Chapter 4.3.1 --- Importance of age restriction --- p.105 / Chapter 4.3.2 --- Limitations of the NICE model --- p.106 / Chapter 4.4 --- Costs of different screening models --- p.107 / Chapter 4.4.1 --- Cost from different perspectives --- p.107 / Chapter 4.4.2 --- Cholesterol measurement cost and routine data collection --- p.108 / Chapter 4.4.3 --- Cost components --- p.109 / Chapter 4.4.4 --- Ways to reduce cholesterol measurement costs --- p.109 / Chapter 4.4.5 --- Costs and gain of the missing 2.5% high risk individuals --- p.109 / Chapter 4.5 --- Strengths and limitations of this study --- p.110 / Chapter 4.6 --- Recommendations --- p.113 / References --- p.114

As doenças cardiovasculares são as principais causas de morte no Brasil e no mundo e constituem problema de saúde médico-social, de grande impacto econômico. As alterações no perfil lipídico e hematológico são fundamentais na formação da aterosclerose, considerando que o LDL (do inglês Low-Density Lipoprotein) e a agregação plaquetária estão envolvidos na formação dos trombos e, consequentemente, em eventos vaso-oclusivos. Entre os fármacos utilizados, encontram-se as estatinas. A rosuvastatina, um dos fármacos utilizados, é inibidora da hidroximetilglutaril coenzima A (HMG CoA) redutase e possui melhor perfil farmacodinâmico entre as estatinas, com maior potência e seletividade. O ácido acetilsalicílico, anti-inflamatório não-esteroide com atividade antiplaquetária mais difundido na terapia, é utilizado, por esse efeito, em associação com estatinas. Fatores limitantes para o uso da rosuvastatina e o ácido acetilsalicílico são: a baixa permeabilidade da rosuvastatina cálcica, e consequente baixa biodisponibilidade (biodisponibilidade absoluta 20%), e tempo de meia-vida do ácido acetilsalicílico de 6-7 h, o que leva à necessidade de elevadas doses e maior frequência de administração de ambos os fármacos. Visto que a associação das estatinas e do ácido acetilsalicílico promove melhor eficácia na prevenção e tratamento de doenças cardiovasculares, o objetivo foi aumentar a solubilidade da estatina e, consequentemente, a sua biodisponibilidade, e a meia-vida do ácido acetilsalicílico, juntamente com a diminuição da toxicidade desse último.. Por outro lado, considerando-se a importância dos dendrímeros como transportadores de fármacos na latenciação, propôs-se o planejamento e a síntese de pró-fármacos dendriméricos, potencialmente cardiovasculares, derivados da associação de rosuvastatina e ácido acetilsalicílico, utilizando etilenoglicol e pentaeritritol como núcleos e ácido L(-)-málico, ácido 2,2-bis(hidroximetil)propiônico e etilenoglicol, como espaçantes.. Obtiveram-se dois pró-fármacos, que se constituem em dendrons como parte dos dendrímeros planejados. O primeiro foi sintetizado pelo método convergente em duplo estágio e faz parte do bloco da camada externa do dendrímero I e o segundo, pela abordagem convergente clássica, sendo este o dendron do dendrímero II. Parte limitante na obtenção desses dendrímeros, além das etapas de purificação, são as etapas de desproteção. / Cardiovascular diseases have been the main causes of death in Brazil and in the world and are medical-social health problem with great economic impact. Alterations in the lipid hematological profiles are essentials in atherosclerosis, as LDL (Low-Density Lipoprotein) and the platelet aggregation are involved in the thrombus formation and, consequently, in occlusive vessel events. Among the drugs used to overcome those alterations are the statins. Rosuvastatin, one of the drugs used, is a hydroxymethylglutaryl coenzine A (HMG CoA) reductase inhibitor and it has the best pharmacodynamics profile among the statins, with higher potency and selectivity. Acetylsalicylic acid, a non-steroid anti-inflammatory agent with antiplatelet activity most disseminated in therapeutics, has been used in combination with statins due to this effect. Limited factors for the use of rosuvastatin and acetylsalycilic acid are the low permeability of the former, and consequently a low bioavailability (20% absolute bioavailability), and a 6 to 7 h half-life time of acetylsalycilic acid. Those factors lead to the need of high doses and higher frequency of administration of both drugs. Considering the combination of statins and acetylsalycilic acid promotes a better efficacy in either prevention or in the treatment of cardiovascular diseases, the objective of this work was to increase the rosuvastatin solubility and, consequently, its bioavailability, and the half-life time of acetylsalicylic acid, together with the decrease of its toxicity. On the other hand, considering the importance of dendrimers as drug carriers in prodrug approach, the design and synthesis of potentially cardiovascular dendrimer prodrugs derived from de combination of rosuvastatin and acetylsalicylic acid was proposed. With this goal, ethylene glycol and pentaerytritol were used as core and L(-)malic acid, 2,2-bis(hydroxymethyl)propionic acid and ethylene glycol were used as spacer groups. Two prodrug dendrons were obtained as part of the designed dendrimers. The first one was synthesized by two-step convergent method and it is part of the external layer block of dendrimer I. The second was obtained through classical convergent synthesis as the dendron of dendrimer II. The purification and deprotection steps showed to be the greatest obstacles for obtaining the proposed compounds.

INTRODUÇÃO: O elevado número de fatores de risco para doença cardiovascular (DCV) é evidente em portadores de doença renal crônica (DRC). Parece que estes fatores de risco estão intrinsicamente ligados à progressão da DRC. O objetivo deste estudo foi determinar os fatores de risco para DCV independentemente associados à progressão da DRC. MÉTODOS: Através da análise prospectiva, avaliamos os fatores de risco tradicionais, não-tradicionais e os relacionados à DRC em 112 pacientes consecutivos portadores de DRC (clearance de creatinina entre 15 - 89 ml/min),. A progressão da DRC foi avaliada pela variação do clearance de creatinina (DClCr) durante o seguimento, sendo os pacientes estratificados em dois grupos: não-progressores e progressores. RESULTADOS: A frequência dos fatores de risco para DCV foi muito alta e a mediana do DClCr foi de 2,445 ml/min/ano, durante o seguimento. No início do seguimento, não havia diferença significante entre os grupos, quanto ao sexo, raça, clearance de creatinina, IMC, pressão arterial sistólica (PAS) e diastólica (PAD), índice cintura-quadril (ICQ), colesterol total, HDL-colesterol, triglicérides, marcadores inflamatórios, hemoglobina, hematócrito, paratormônio (PTHi), cálcio sérico e ácido úrico. Enquanto, a média do peso corporal, fibrinogênio sérico, LDL-colesterol, fósforo sérico, ingestão de sal e proteinúria foram significativamente maiores no grupo progressores; a média de idade e albumina sérica foi menor. Em adição, os fatores de risco para DCV, idade avançada (p= 0,0140) e história prévia de DCV (p= 0,0063) foram mais freqëntes no grupo não-progressores; ao passo que a anemia (p< 0,0001), hiperfibrinogenemia (p= 0,0112), hipoalbuminemia (p= 0,0019) e proteinúria elevada (p<0,0001) foram mais freqüentes no grupo progressores. Durante o seguimento, o grupo progressores apresentou média de PAS e PAD, LDL-colesterol e proteinúria maiores, no entanto, a albumina sérica foi menor. Os fatores de risco para DCV, durante o seguimento, anemia (p< 0,0001), hiperfosforemia (p< 0,0001), proteinúria elevada (p< 0,0001), hiperparatiroidismo (p= 0,0050) e hipoalbuminemia (p= 0,0019) foram mais freqüentes no grupo progressores. Na análise de regressão múltipla, somente o fator proteinúria, tanto no início como durante o seguimento, foi um preditor significante para a progressão da DRC. CONCLUSÃO: Os fatores de risco para DCV são muito prevalentes entre os pacientes com DRC em tratamento conservador. Embora, este estudo não possa mostrar evidências, sugerindo associação entre a maioria destes fatores de risco para DCV e a taxa de progressão da DRC, apenas a proteinúria predisse uma pior evolução da função renal / Background. The increased risk factors of cardiovascular disease (CVD) is evident in patients with chronic kidney disease (CKD). It has been hypothesized that a number of these risk factors is inextricably linked to the progression of CKD. The purpose of this study was to determine the CVD risk factors independently associated with progression of CKD. Methods. Through prospective analysis, we evaluated traditional, non-traditional, and uremia-related CVD risk factors in 112 consecutive patients with CKD (creatinine clearance between 15 89 ml/min). Progression of kidney disease was evaluated by rate of decline of creatinine clearance during follow-up period, and patients were stratified into two groups: progressor and nonprogressor. Results. The frequency of CVD risk factors was very high, and the median decline of creatinine clearance was 2,445 ml/min/yr, during follow-up period. At baseline, there were no significant differences between progressor and nonprogressor groups in terms of gender, race, creatinine clearance, body mass index, systolic and diastolic blood pressure, and waistrip ratio; cholesterol, HDL-cholesterol, triglycerides, inflammatory markers, hemoglobin, hematocrit, serum calcium, iPTH, and uric acid concentrations While, the mean body weight , serum fibrinogen, LDL-cholesterol, serum phosphate concentrations, salt ingest and proteinuria were significantly higher in the progressor group, the mean age and serum albumin concentrations were lower. In addition, CVD risk factors such as older age (p= 0,0140) and history of previous CVD (p= 0,0063) were more frequent in the nonprogressor group, whereas the hyperfibrinogenemia (p= 0.0112), anemia (p< 0.0001), proteinuria (p< 0.0001) and hypoalbuminemia (p= 0,0019) were more frequent in the progressor group. During follow-up period, the patients in the progressor group had higher systolic and diastolic blood pressure, LDL cholesterol and proteinuria, however serum albumin concentrations were lower. The CVD risk factors, during follow-up period, such as anemia (p< 0,0001), hyperphosphatemia (p< 0,0001), proteinuria (p< 0,0001) were more frequent in the progressor group. In multiple regression analysis, only the factor proteinuria at baseline and during follow-up period was a significant predictor for progression of CKD. Conclusions. CVD risk factors were very prevalent among patients with CKD not requiring dialysis. Although, this study may not show evidences suggesting association between most of these factors and the rate of progression of CKD; only proteinuria predicts an worsening of evolution of kidney function

Submitted by Rosina Valeria Lanzellotti Mattiussi Teixeira (rosina.teixeira@unisantos.br) on 2018-03-08T19:08:23Z No. of bitstreams: 1 Dennise Pimentel Claro.pdf: 637790 bytes, checksum: c4ed000204776db603ecf343f477a919 (MD5) / Made available in DSpace on 2018-03-08T19:08:23Z (GMT). No. of bitstreams: 1 Dennise Pimentel Claro.pdf: 637790 bytes, checksum: c4ed000204776db603ecf343f477a919 (MD5) Previous issue date: 2010-06-10 / Introduction - In 2001, it was reported the presence of toxic sources in areas located in the estuary of Santos and Sao Vicente, such as heavy metals, organochlorine, polychlorinated biphenyls, dioxins and furans. The exposure to these contaminants produces several adverse effects on the cardiovascular system of humans by damaging the endothelial cells of blood. To understand the impact of health conditions in these contaminated areas it is important to explore the risk of developing cardiovascular disease in the exposed population. Objective - To analyze the mortality of cardiovascular diseases in areas exposed to the referred environmental contaminants. Methods ¿ A cross-sectional study with analysis of historical series allowed an investigation of the mortality from cardiovascular disease, as provided by Fundação SEADE in five areas determined by a previous study entitled "Epidemiological Study in the Baixada Santista - Santos Estuary: Assessment of predictors of effects and exposure to environmental contaminants.", which investigated the health effects associated with exposure to environmental contaminants among residents of areas alongside Santos estuary. In this study the deaths of the five areas were subjected to descriptive analysis based on the period from 2003 through 2007 of the national census (IBGE) of 2000. The mortality rates were calculated by the direct method to standardize them with the population of São Paulo city. In addition to standardized mortality rates were estimated and the average mortality ratios. The resulting estimates allowed a comparison between the contaminated areas and the area that is contaminated free. The comparison between two proportion and Kruskal-Wallis tests was used with a significance level of 0.05. Results - observed the highest mortality coefficient in Area 1, with 24.66 per 1000 of male population, with statistically significant difference (p<0.005), but other areas with environmental contaminants their average coefficient ranged between 1.47 per 1000 to 3.96 per 1000 in both gender. Also, in both gender and all periods, there was significant statistical difference between the contaminated area 1 and Bertioga. The other areas sometimes presented lower coefficient ranged than the area without exposure to environmental contaminats (p<0.05).The mortality also showed high ratios in Area 1 (Pilões) compared to all other areas of the sample. And up to 32 times higher among females in 2003 compared with the control area (area 5, located in Bertioga). Conclusion ¿ for the analysis, higher mortality rates in Pilões and Água Fria was found, although it needs further studies to investigate a causal relationship between exposure and outcome studied. / Introdução - Em 2001 foi relatada a presença de fontes tóxicas em áreas localizadas na região estuarina de Santos e São Vicente, como os metais pesados, organoclorados, bifenilas policloradas, dioxinas e furanos. A exposição a esses contaminantes, a longo prazo, produzem diversos efeitos deletérios à saúde do ser humano, sendo uma delas o aparecimento de doenças cardiovasculares, através do dano nas células endoteliais dos vasos sanguíneos. Explorar o perfil das doenças cardiovasculares na população exposta permite entender o impacto das condições de saúde nestas áreas contaminadas. Objetivo ¿ analisar o perfil da mortalidade de doenças cardiovasculares nas áreas expostas a contaminantes ambientais. Casuística e Método ¿ estudo transversal com análise de séries históricas. Foram estudados os óbitos por doenças cardiovasculares, fornecidas pela Fundação SEADE, em 5 áreas determinadas por um estudo prévio intitulado ¿Estudo Epidemiológico na População Residente na Baixada Santista ¿ Estuário de Santos: Avaliação dos Indicadores de Efeito e de Exposição à Contaminantes Ambientais.¿, financiado pelo CNPq, no qual investigou os efeitos à saúde associados à exposição aos contaminantes ambientais entre moradores da baixada Santista. No presente trabalho os óbitos das 5 áreas foram submetidos a uma análise descritiva, no período de 2003 a 2007, utilizando as estimativas populacionais do Instituto Brasileiro de Geografia e Estatística no ano 2000. Os cálculos dos coeficientes de mortalidade foram realizados pelo método direto, padronizando-os com a população do município de São Paulo. Além do coeficiente padronizado foram calculados os coeficientes médios e as razões entre os coeficientes de mortalidade por doenças cardiovasculares. Os resultados calculados permitiram uma comparação entre as áreas contaminadas e a área não contaminada, o município respectivo do local, e o município de São Paulo. Foi utilizado o teste de comparação entre duas proporções e o teste Kruskal-Wallis com teste Dunn positivo, adotando um nível de significância menor ou igual a 0,05. Resultados ¿ o coeficiente de mortalidade padronizados por doenças cardiovasculares mais elevado foi de 24,66/1000 habitantes na Área 1 (Pilões e Água Fria) no sexo masculino, com diferença estatisticamente significante com a área não contaminada (p<0,05), Nas outras áreas contaminadas os coeficientes médio de mortalidade variaram entre 1,47/1000 a 3,96/1000 em ambos os sexos, valores inferiores a area 1. Em todos os períodos, observou-se diferença estatisticamente significante entre a área 1 (Pilões) e a área contaminada (Bertioga), em ambos os sexos. Nas áreas 2 (Cubatão Centro), área 3 (São Vicente) e área 4 (Vicente de Carvalho) em alguns períodos da série histórica apresentaram coeficientes de mortalidade inferiores a área contaminada, sendo estatisticamente significante. As razões de mortalidade também se apresentaram elevadas na área 1 (Pilões) com todos os locais de comparação, chegando a 32 vezes maior no sexo feminino no ano de 2003, quando comparado com a área controle (área 5, localizada na região de Bertioga). Conclusão ¿ a análise da mortalidade, através dos coeficientes, revelou-se alta na área contaminada a poluentes ambientais, localizada em Pilões e Água Fria, porém há necessidade de novos estudos para investigar uma relação causal entre a exposição e o desfecho estudado.

Cardiovascular disease (CVD) is the leading cause of death in the United States. Nearly half of the people diagnosed with heart failure (HF) die within 5 years of diagnosis. Brain abnormalities secondary to CVD have been observed in many discrete regions, including the hippocampus. Nearly 25% of patients with CVD also have major depressive disorder (MDD), and hippocampal dysfunction is a characteristic of both diseases. In this study, the hippocampus and an area of the hippocampal formation, the dentate gyrus (DG), were studied in a canine model of HF. Using this canine HF model previously, we have determined that myocardial infarction with mitral valve regurgitation (MI/MR) + spinal cord stimulation (SCS) can preserve cardiac function. The goal of this study was to determine if the SCS can also protect the brain in a similar fashion. Both the entire hippocampus and the DG tissues were dissected from canine brains and analyzed. These findings provide strong evidence that, in addition to the cardioprotective effects observed previously, SCS following MI/MR induces neuroprotective effects in the brain.

In this study, we used a cross-sectional study design to examine the relationship between the calcium intake and risk factors for CVD among obese adults by using continuous waves of National Health and Nutrition Examination Survey (NHANES) data 1999-2010. The association between calcium intake and risk factors of CVD (hypertension, total cholesterol, HDL, glycohemoglobin), CRP, albuminuria) is assessed among obese adults in USA. The incidence of Cardiovascular Disease (CVD) is high among obese people. The potential effects of inadequate calcium intake on CVD are receiving increased epidemiologic attention. Understanding the association between risk factors for CVD and calcium intake among obese adults is important for the advancement of CVD, nutrition and obesity research. Data collected from the National Health and Nutrition Examination Survey from 1999-2010 were examined, utilizing a subset of 14,856 obese subjects. Analysis of Variance statistical tests were conducted to determine associations between calcium intake and CVD risk. Simple and multiple linear and logistic regression analyses were conducted to determine the predicted value of calcium intake with CVD. After adjusting for energy intake and other potential risk factors, systolic blood pressure, diastolic blood pressure, C-reactive protein, glycosylated hemoglobin and albuminuria were negatively associated with calcium intake at &alpha = 0.05 level in both linear and logistic regression analyses. In a comparison of calcium intake by quartiles, results reveal that total cholesterol had a weak negative association with calcium intake at &alpha = 0.1 level. The implications of these study results are important as the importance of adequate calcium intake and its potential to decrease CVD among obese adults has incredible preventive value for populations. Additional research that focuses on dietary intake, calcium thresholds and impacts on total cholesterol levels in the body is warranted.

Aim: To examine the association of cardiovascular disease risk factors with and their cumulative effect on coronary artery calcium in hard-to-reach asymptomatic patients with diabetes. Methods: : A total of 2563 community-dwelling asymptomatic subjects from Central Appalachia participated in coronary artery calcium screening at a heart centre. Binary variable was used to indicate that coronary artery calcium was either present or absent. Independent variables consisted of demographic and modifiable risk factors and medical conditions. Descriptive statistics and multinomial logistic regression analyses were conducted. Results: : In total, 55.8% and 13.7% of study participants had subclinical atherosclerosis (coronary artery calcium ⩾1) and diabetes, respectively. The presence of coronary artery calcium was higher in subjects with diabetes (68.5%) than those without (53.8%). Compared to subjects without diabetes with coronary artery calcium = 0, obesity, hypertension, hypercholesterolaemia and smoking increased the odds of the presence of coronary artery calcium (coronary artery calcium score ⩾1) regardless of diabetes status; however, with larger odds ratios in subjects with diabetes. Compared to subjects without diabetes with coronary artery calcium score = 0, having 3, 4 and ⩾5 risk factors increased the odds of presence of coronary artery calcium in subjects with diabetes by 14.06 (confidence interval = 3.26–62.69), 32.30 (confidence interval = 7.41–140.82) and 47.12 (confidence interval = 10.35–214.66) times, respectively. Conclusion: : There is a need for awareness about subclinical atherosclerosis in patients with diabetes and more research about coronary artery calcium in subpopulations of patients.

Conventional medical treatments fail to address the underlying problems associated with the damage inflicted by a coronary event. Thus, the long-term prognosis of patients admitted for heart failure is disheartening, with reported survival rates of 25 percent. Recent advances in stem cell research highlight the potential benefits of autologous stem cell transplantation for stimulating repair in heart tissue. However, a majority of those suffering from cardiovascular diseases are older adults whose autologous cells no longer possess optimum functional capacity. Additional work is needed to identify the optimal cell types or conditions that will promote cardiovascular regeneration across all age groups. A pretreatment, such as short-term hypoxia, and concurrent implementation of a novel progenitor, such as those that co-express Isl-1 and c-Kit, may enhance the results reported in clinical trials completed to date. However, the effects of short-term hypoxia in this novel cell type are unknown and warrant investigation in vitro. Cloned adult and neonatal Isl-1+ c-Kit+ human cardiovascular progenitor cells were characterized and expanded for study. Populations from both age groups were preconditioned using short-term hypoxia (1% O2 for six hours) and, to identify shifts in gene expression, compared to their respective control (21% O2 at 37 °C) via qRT-PCR. Flow cytometry and western blot analysis was utilized to measure phosphorylation of Akt. Progression through the cell cycle was also analyzed by flow cytometry. Cellular function was evaluated by the use of a TUNEL assay and Transwell® invasion assay. Hypoxia-mediated alterations of a genetic or functional nature in Isl-1+ c-Kit+ human cardiac progenitors are clearly age-dependent. Although both age groups accrued benefit, the neonatal progenitors procured significantly greater improvements. Short-term hypoxia significantly elevated Akt phosphorylation in neonatal Isl-1+ c-Kit+ human cardiac progenitors. Benefits afforded to both age groups by hypoxic pretreatment included significant upregulation of pro-survival transcripts, and enhanced invasion capabilities in vitro. Therefore, prior to transplantation, hypoxic preconditioning may improve the ability of transplanted stem cells to home towards damaged areas of the heart and support cardiac regeneration in vivo.