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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.

Orientador: Antonio Carlos Cicogna / Banca: Maeli Dal-Pai / Banca: André Soares Leopoldo / Resumo: A remodelação cardíaca (RC) ocorre em resposta a determinadas agressões como, por exemplo, sobrecarga pressórica, e pode manifestar-se por alterações de tamanho, forma e função do coração. No modelo de estenose aórtica supravalvar (EAo) em ratos, estudos ecocardiográficos constataram que, 2 e 6 semanas após indução da EAo, os ratos desenvolvem hipertrofia ventricular esquerda, disfunção diastólica e melhoria da função sistólica. Após 12 semanas há disfunção sistólica e perto da 20ª semana aparecem sinais de insuficiência cardíaca. Diversos fatores poderiam contribuir para a disfunção neste modelo experimental, como modificações na expressão proteica da bomba de cálcio do retículo sarcoplasmático (SERCA2a) e das cadeias pesadas de miosina (MyHC), ambas com alta capacidade ATPásica. Na RC patológica ocorre diminuição na beta oxidação de ácidos graxos, podendo acarretar déficit energético para o músculo cardíaco hipertrofiado. O objetivo deste trabalho foi testar a hipótese de que o aumento da oferta energética, proveniente de dieta hiperlipídica, atenua a disfunção diastólica e preserva a função sistólica no modelo de EAo. Os mecanismos envolvidos na preservação ou melhoria da função estão relacionados com a diminuição na transição da isoforma V1(α) para V3(β) da MyHC e com o aumento da relação SERCA2a/PLB. Foram utilizados ratos Wistar machos, com 21 dias, separados em dois grupos: controle operado (Sham) e estenose aórtica supravalvar (EAo). Seis semanas após cirurgia, os animais foram redistribuídos em quatro grupos (n=12/grupo): tratados com dieta normolipídica (EAo-N e Sham-N) ou hiperlipídica (EAo-H e Sham-H) por 12 semanas. O perfil nutricional foi determinado pelas análises de ingestão alimentar e calórica, eficiência alimentar, peso e gordura corporal, índice de adiposidade, glicemia, triacilglicerol e ácidos graxos livres não-esterificados. A RC foi ... / Abstract: Cardiac remodeling (CR) occurs in response to some cardiac injuries, such as pressure overload, and it may be manifested as changes in size, shape and function of the heart. In the model of supravalvar aortic stenosis (SVAS), echocardiographic studies performed in our laboratory showed that, 2 and 6 weeks post SVAS induction, rats developed left ventricular hypertrophy, diastolic dysfunction and improved systolic function. After 12 weeks there is systolic dysfunction and around the 20th week signs of heart failure appear. Several factors could contribute to the dysfunction in this experimental model, such as changes in protein expression of sarcoplasmic reticulum calcium ATPase (SERCA2a) and myosin heavy chain (MyHC), both with high ATPase capacity. Pathological CR is underscored by a reduction in fatty acid beta oxidation, which may cause energy deficit to the hypertrophied cardiac muscle. The aim of this work was to test the hypothesis that increased energy supply, derived from high-fat diet, attenuates cardiac dysfunction in the SVAS model. The mechanisms involved in the attenuation of dysfunction are related to decreased V1(α) to V3(β) MyHC isoform transition and increased SERCA2a/PLB ratio. Male Wistar rats, aged 21 days, were separated into two groups: operated control (Sham) and supravalvar aortic stenosis (SVAS). Six weeks after surgery, the animals were redistributed into four groups (n=12/group): fed with normolipidic diet (Sham-N and SVAS-N) or high-fat diet (Sham-H and SVAS-H). The nutritional profile was determined by food and calorie intake, feed efficiency, weight and body fat, adiposity index, blood glucose, triacylglycerol and non-esterified free fatty acid. The CR was characterized by analyses of the cardiac structure and function by echocardiogram in the 6th and 18th week, macroscopic study, energy metabolism and SERCA2a/PLB and β/α MyHC cardiac ratios. For comparisons between Sham and SVAS we used Student "t" test ... / Mestre

Gao, Ni. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 133-153). / Abstracts also in Chinese. / ACKNOWLEDGEMENTS / TABLE OF CONTENT --- p.1 / LIST OF FIGURES AND TABLES --- p.4 / List of Figures --- p.4 / List of Tables --- p.5 / ABSTRACT --- p.6 / 中文摘要 --- p.9 / ABBREVIATIONS --- p.11 / Chapter CHAPTER 1 - --- BACKGROUND REVIEW AND HYPOTHESIS --- p.13 / Chapter 1.1 --- Overview of Peritoneal dialysis --- p.13 / Chapter 1.2 --- Peritoneal dialysis in Hong Kong --- p.16 / Chapter 1.3 --- Cardiovasular Disease in PD patients --- p.18 / Chapter 1.3.1 --- Arterial disease --- p.21 / Chapter 1.3.2 --- Left ventricular hypertrophy --- p.23 / Chapter 1.4 --- Malnutrition in PD patients --- p.26 / Chapter 1.5 --- Fluid overload in PD patients: a cause and a result of CVD --- p.28 / Chapter 1.5.1 --- Overview --- p.28 / Chapter 1.5.2 --- Fluid overload and residual renal function --- p.29 / Chapter 1.5.3 --- Fluid overload and hypertension --- p.30 / Chapter 1.5.4 --- Fluid overload and malnutrition --- p.32 / Chapter 1.5.5 --- Assessment of fluid status in PD patient --- p.33 / Chapter 1.6 --- Peritoneal transport as the cause of fluid overload --- p.36 / Chapter 1.6.1 --- Structure of peritoneum --- p.36 / Chapter 1.6.2 --- Structural alteration of peritoneal membrane in PD --- p.37 / Chapter 1.6.3 --- Ultrafiltration dysfunction --- p.38 / Chapter 1.6.4 --- Peritoneal transport and outcome of PD patients --- p.40 / Chapter 1.6.5 --- Fluid overload and peritoneal transport --- p.41 / Chapter 1.6.6 --- Peritoneal transport and malnutrition --- p.42 / Chapter 1.6.7 --- Assessment of peritoneal transport --- p.44 / Chapter 1.7 --- Closing the circle: Arterial stiffness as a cause of high peritoneal transport? --- p.47 / Chapter 1.7.1 --- Vascular function and anatomy --- p.47 / Chapter 1.7.2 --- Atherosclerosis --- p.49 / Chapter 1.7.3 --- Atherosclerosis and Endothelial Dysfunction --- p.50 / Chapter 1.7.4 --- Atherosclerosis and Extracellular Matrix --- p.53 / Chapter 1.7.5 --- Arterial stiffness and renal function --- p.54 / Chapter 1.7.6 --- Arterial stiffness in PD --- p.55 / Chapter 1.7.7 --- Arterial stiffness and clinical outcome --- p.55 / Chapter 1.7.8 --- Assessment of arterial stiffness --- p.57 / Chapter 1.8 --- An overall construct --- p.61 / Chapter 1.9 --- Hypothesis --- p.63 / Chapter CHAPTER 2 - --- GENERAL METHODOLOGY --- p.65 / Chapter 2.1 --- Radiographic Parameters of Intravascular Volume Status --- p.65 / Chapter 2.2 --- Pulse Wave Velocity Study --- p.69 / Chapter 2.3 --- Dialysis adequacy study --- p.72 / Chapter 2.4 --- Peritoneal equilibration test (PET) --- p.73 / Chapter 2.5 --- Assessment of nutritional status --- p.75 / Chapter CHAPTER 3 - --- Radiographic Parameters of Intravascular Volume Status as a Prognostic Marker in Chinese Peritoneal Dialysis Patients --- p.77 / Chapter 3.1 --- Introduction --- p.77 / Chapter 3.2 --- Patients and Methods --- p.78 / Chapter 3.3 --- Results --- p.81 / Chapter 3.4 --- Conclusion --- p.90 / Chapter CHAPTER 4 - --- Longitudinal Changes of Radiographic Parameters as the Prognostic Marker of Chinese Peritoneal Dialysis Patients --- p.91 / Chapter 4.1 --- Introduction --- p.91 / Chapter 4.3 --- Results --- p.95 / Chapter 4.4 --- Conclusions --- p.104 / Chapter CHAPTER 5 - --- "The Relation between Arterial Pulse Wave Velocity, Peritoneal Transport Characteristics, and Radiological Parameters of Intravascular Volume Status in Chinese peritoneal dialysis patients" --- p.105 / Chapter 5.1 --- Introduction --- p.105 / Chapter 5.2 --- Patients and Methods --- p.106 / Chapter 5.3 --- Results --- p.110 / Chapter 5.4 --- Conclusions --- p.119 / Chapter CHAPTER 6 - --- DISCUSSION --- p.120 / Chapter 6.1 --- Methodology --- p.120 / Chapter 6.2 --- Results --- p.123 / Chapter 6.3 --- Further Directions of Research --- p.131 / Chapter 6.4 --- Conclusions --- p.132 / REFERENCE --- p.133 / PUBLICATIONS RELATED TO THIS WORK --- p.154 / Index Publication --- p.154 / Abstract --- p.154

Cardiovascular disease (CVD) claims more lives than any other disease in the world. Although numerous biological pathways share the blame, ventricular tachyarrhythmia (VT) is estimated to account for ~25% of all CVD deaths. A complete understanding of the molecular mechanisms underlying VT is unknown but recent studies have linked VT to improper calcium handling in the heart (canine). The principle calcium regulator in the muscle cell is the calcium ion release channel (aka RyR). Numerous endogenous and exogenous compounds can affect the way the RyR regulates calcium. In particular, abnormal levels of oxidants (reactive oxygen species) can oxidize critical thiol groups on the RyR and modulate its activity. Interestingly, high levels of oxidants are also associated with numerous bodily disease states including cancers, muscle fatigue/failure, and CVD. In this thesis, two important dietary antioxidant compounds, the anthocyanidins pelargonidin and delphinidin, are evaluated for their effects on regulating the transport of calcium through the calcium release channel (RyR1) of the sarcoplasmic reticulum of skeletal muscle. Pelargonidin and delphinidin are structurally similar with delphinidin only differing from pelargonidin by the addition of two hydroxyl groups. Both compounds undergo time dependent structural changes in aqueous solutions at physiological pH and a mixture of more than four structures of each compound can be present in solution simultaneously. Pelargonidin and delphinidin show distinct differences in their calcium flux regulating effect on the RyR1. Delphinidin stimulates calcium flux and RyR1 activity where as pelargonidin can cause both inhibition and stimulation of the RyR1. The strength of stimulation and inhibition of calcium transport through the RyR by delphinidin and pelargonidin may be attributed to the structural and chemical changes in those compounds that occur in solutions near physiological pH and the subsequent chemical characteristics of the diverse set of structures that are simultaneously present in solution.

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Bibliography: leaves 100-113.

In this study, we investigated the role of Ang II in pathological vascular remodeling. We sought to determine whether the humoral or the mechanical effects of Ang II are the dominant factor driving the remodeling process. The following experimental groups were used: control group (untreated mice), mice treated with an angiotensin receptor blocker (Candesartan, 0.5 mg/kg/day,SQ), an ACE inhibitor (Captopril, 6 mg/kg/day), and a calcium-channel blocker (Amlodipine, 7.5 mg/kg/day). All mice (n=6 per experimental group) were from the C57Bl/6 background. The carotid ligation model was implemented to study the differences in vascular remodeling. Additionally, multiple time points (7-, 14-, and 21-days post-surgery) were used to track the progression of remodeling. In Day-7 analysis, all three treatment groups yielded similar remodeling patterns as evidenced by a significant reduction in neointimal area, medial thickening and hypertrophy compared with the control group. Histomorphometric analysis of carotid sections collected 1mm below the ligation demonstrated that the Amlodipine group had 26% reduction in total vessel area, Candesartan a 36% reduction, and Captopril a 28% reduction (p less than 0.05 in all groups compared with Control), as well as a parallel 38-40% drop in medial thickness. In Day-14 analysis, no significant differences between the Controls and treatment groups were observed, although differences were emerging between the treatment groups. Candesartan was found to reduce the extent of negative remodeling observed between the 7- and 14-day Control data, whereas the Captopril group did not exhibit this trend. All treatment groups exhibited less neointimal formation than Controls, similar to Day-7. By the 21-day time point, the Captopril group underwent positive remodeling, resembling the Candesartan and Amlodipine groups. Although total vessel area was analogous among all groups, neointimal areas were significantly decreased in the treatment groups. Blood pressure plays a pivotal role in the modulation of vascular remodeling in response to mechanical injury. Although intermediate timepoint analysis suggests that humoral aspects of ACE inhibition or angiotensin-receptor blockade yielded unique effects on the overall vessel caliber, upon reaching the late, 21-day time point, the mechanical factors became predominant. These data support the importance of blood pressure control in the attenuation of pathological vascular remodeling.

With each heartbeat, major arteries experience circumferential expansion due to internal pressure changes. This pulsatile force is called cyclic strain and has been implicated in playing a pivotal role in the genetic regulation of vascular physiology and pathology. This dissertation investigates the hypothesis that in human umbilical vein endothelial cells (HUVEC), pathological levels of cyclic strain activate the c-Myc promoter, leading to c-Myc transcription and downstream gene induction. To determine expression and time-dependency of c-Myc in HUVEC, mRNA and protein expression of c-Myc under physiological (6-10% cyclic strain) and pathological conditions (20% cyclic strain) were studied. Both c-Myc mRNA and protein expression increased more than three-fold in HUVEC (P4-P5) cyclically-strained at 20%. This expression occurred in a time-dependent manner, peaking in the 1.5-2 hour range and falling to basal levels by 3 hours. Subsequently, the mechanism of c-Myc transcription was investigated by using specific inhibitors to modulate c-Myc transcriptional activation. These compounds, obtained from the University of Arizona Cancer Center, attenuated cyclic-strain-induced c-Myc transcription by about 50%. Having established this reduction in expression, it was investigated how these effects modulate downstream genes that are regulated by c-Myc. The results indicate that direct targeting of the c-Myc promoter may decrease stretch-induced gene expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA) and heat shock protein 60 (HSP60). These findings may help in the development of a novel therapeutic opportunity in vascular diseases.

published_or_final_version / Community Medicine / Master / Master of Philosophy