Background: Childhood overweight and obesity remains high, contributing to cardiometabolic risk factors at younger ages. It is unclear which measures of adiposity serve as the best proxies for identifying children at metabolic risk. This study assessed whether DXA-derived direct measures of adiposity are more strongly related to cardiometabolic risk factors in children than indirect measures. Methods: Anthropometric and DXA measures of adiposity and a comprehensive assessment of cardiometabolic risk factors were obtained in 288, 9-12 year old girls, most being of Hispanic ethnicity. Multiple regression models for each metabolic parameter were run against each adiposity measure while controlling for maturation and ethnicity. In addition, regression models including both indirect and direct measures were developed to assess whether using direct measures of adiposity could provide a better prediction of the cardiometabolic risk factors beyond that of using indirect measures alone. Results: Measures of adiposity were significantly correlated with cardiometabolic risk factors (p < 0.05) except fasting glucose. After adjusting for maturation and ethnicity, indirect measures of adiposity accounted for 29-34% in HOMA-IR, 10-13% in TG, 14-17% in HDL-C, and 5-8% in LDL-C while direct measures accounted for 29-34% in HOMA-IR, 10-12% in TG, 13-16% in HDL-C, and 5-6% in LDL-C. The addition of direct measures of adiposity to indirect measures added significantly to the variance explained for HOMA-IR (p = 0.04). Conclusion: Anthropometric measures may perform as well as the more precise direct DXA-derived measures of adiposity for assessing most CVD risk factors in preadolescent girls. The use of DXA-derived adiposity measures together with indirect measures may be advantageous for predicting insulin resistance risk.

Cyclic-3',5'-guanosine monophosphate (cGMP) is a fundamental intracellular signalling molecule that regulates vascular homeostasis through the tight control of vascular smooth muscle cell (VSMC) reactivity (i.e. vasoconstriction/relaxation) and proliferation. Aberrant VSMC growth and sustained vasoconstriction are hallmarks of cardiovascular disease, exemplified by pulmonary hypertension (PH). Multidrug resistance proteins (MRPs) are membrane bound transporters that facilitate cGMP cellular export thereby representing a potential mechanism that regulates intracellular cGMP-driven signalling. C-type natriuretic peptide (CNP) is an important vasoactive peptide released from the endothelium that maintains vascular homeostasis. CNP binds to natriuretic peptide receptor-B (NPR-B), generating cGMP, and NPR-C, which acts as a clearance receptor removing CNP from the circulation and a signalling pathway regulating vascular function via a cGMP-independent mechanism. Herein, I investigated two separate hypotheses: that MRPs play an important role in maintaining vascular homeostasis, and that endothelium-derived CNP and its cognate receptor, NPR-C, protects against the development of PH. The role of MRPs in regulating vascular homeostasis was investigated using organ bath pharmacology, human VSMC (hVSMC) proliferation and measuring mean arterial blood pressure (MABP) in conscious and anaesthetised mice. To investigate the role of endothelium-derived CNP and NPR-C in PH, male and female CNP and NPR-C knockout (KO) mice were used in two experimental models of PH: hypoxia plus Sugen5416 (SU5416) and bleomycin-induced. The severity of PH was measured using right ventricular systolic pressure (RVSP), MABP, right ventricular hypertrophy (RVH) and pulmonary vascular remodelling. MRP inhibition resulted in concentration-dependent vasorelaxation of mouse aorta per se and increased the potency of cGMP-dependent vessel relaxation in response to activation of both particulate and soluble guanylate cyclases (pGC and sGC). MRP inhibition alone also caused concentration-dependent attenuation of hVSMC proliferation, and enhanced cGMP-mediated attenuation of hVSMC growth via pGC and sGC activation. MRP inhibition per se did not decrease MABP in either anaesthetised or telemeterised mice. However, MRP inhibition did dose-dependently enhance reductions in MABP due to pGC activation in anaesthetised mice. Deletion of endothelial cell-derived CNP (ecCNP KO) in male and female mice did not result in any significant differences in RVSP, RVH or pulmonary vascular remodelling between WT and KO in the hypoxia plus SU5416 model of PH. However, global deletion of NPR-C in both male and female mice caused a significant increase in RVH but not RVSP or vascular remodelling when compared to WT. Both male and female NPR-C KO mice developed significantly increased RVSP compared to WT in the bleomycin-induced model of PH. However, only females exhibited a significant increase in RVH and lung weight in addition to RVSP. In conclusion, MRP inhibition demonstrates potential therapeutic utility to treat cardiovascular diseases by potentiating the vasodilatory and VSMC antiproliferative actions of natriuretic peptides and nitric oxide. Endothelial cellderived CNP is not essential to host protection against PH, whereas its cognate receptor NPR-C demonstrates a cardioprotective capacity. NPR-C attenuates bleomycin-induced PH in both males and females, with a greater effect observed in females. Overall, NPR-C agonism could potentially be used to ameliorate the cardiac and vascular pathology associated with PH.

Cardiovascular disease and cancer are the two most common causes of death worldwide. Angiogenesis plays a critical role tumourigenesis and atherogenesis. As a member of the basic region-leucine zipper protein family, c-Jun, has been linked with cell proliferation, migration and cell survival. However, the relationship between c-Jun and angiogenesis has not been firmly established. In this thesis, strategies targeting c-Jun mRNA such as DNAzyme and siRNA have been designed and evaluated for their ability to inhibit the c-Jun mRNA and c-Jun protein expression in vitro and in vivo. These agents block c-Jun expression and inhibit DNA binding activity of c-Jun. Luciferase assay showed that c-Jun siRNA suppressed c-Jun/AP-1-dependent reporter activity. The processes of cell proliferation, migration, invasion and tube formation were all down-regulated after treatment with c-Jun targeting agents. In vivo, c-Jun DNAzymes and siRNA inhibit angiogenesis in multiple models of angiogenesis in multiple models of angiogenesis, including tumour angiogenesis and growth, matrix angiogenesis, corneal angiogenesis and retinal neovascularization. This is mediated, at least in part, by c-Jun siRNA or DNAzyme inhibition of MMP-2 expression. These findings demonstrate the critical role played by c-Jun in the involvement of neovascularization and suggest that DNAzymes or siRNAs are efficient gene-silencing agents. The ability to identify and control key genes in angiogenesis provides opportunities for developing therapeutic molecular tools to treat cancer or other angiogenesis related diseases.

About half of all deaths in developed countries are caused by cardiovascular disease. It is well known that cardiovascular disease (CVD) risk can be influenced by diet, but optimal dietary content of fatty acids continues to be debated. The effect of fatty acid composition of ground beef on selected cardiovascular disease risk indicators was evaluated with two primary goals. The first goal was to document effects of ground beef fatty acid composition on plasma lipoprotein concentrations, whereas the second goal was to determine the effects of ground beef fatty acid composition on gene expression in peripheral blood mononuclear cells (PBMC). In both studies the results were compared between men and women. Twelve men and women over age of 45 out of initially 15 completed a two-way crossover design. Subjects consumed five, 114-g ground beef patties per week for 5-wk periods separated by a 3-wk washout period. Patties contained on average 20% fat and monounsaturated fatty acid (MUFA): saturated fatty acid (SFA) of 0.8 and 1.1 for low- MUFA (conventional) ground beef high-MUFA (premium) ground beef patties, respectively. Blood was collected from each subject before and at the end of each diet period. Overall, the ground beef interventions decreased total plasma cholesterol, triacylglycerol, and very low density lipoprotein (VLDL) cholesterol. Plasma concentrations of high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol decreased and increased, respectively with premium ground beef consumption. The change in HDL cholesterol was significant in women but not in men suggesting that premium ground beef consumption had a greater impact on women than in men. For the second goal PBMC were isolated and the expression of selected genes was quantified by real-time PCR. ATP-binding cassette A1, ATP-binding cassette G1, and low-density lipoprotein receptor relative expression was increased with premium ground beef consumption. A significant increase was seen in stearoyl-Coenzyme-A desaturase 1 expression after premium ground beef treatment. With the exception of stearoyl-Coenzyme-A desaturase 1, all these genes were down-regulated with conventional ground beef consumption. Both sterol regulatory element binding transcription factor 1 and mediator complex subunit 1 were down-regulated after each beef patty treatment, but the effect was significant after consuming conventional ground beef. This suggests that genes involved in cholesterol metabolism were down-regulated with conventional ground beef consumption; whereas genes related to lipogenesis were up-regulated with premium ground beef consumption. From these data we concluded that different ground beef dietary interventions have different impacts on the PBMC gene expression that is related to cholesterol metabolism, inflammation and liver X receptor pathways.

<p>Background: There is limited information available about the prevalence of Metabolic Syndrome (MetS), its trend over time and its predisposing risk factors according to different definitions in Canadian adults. No studies have compared the ability of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) and the International Diabetes Federation (IDF) definitions to predict Cardiovascular Disease (CVD) mortality among Canadian adults.</p> <p>Objectives: a) To examine the age and sex specific prevalence of the Metabolic Syndrome in Canadian adults by using the ATP III and the IDF definitions. b) To examine the risk factors for Metabolic Syndrome in Canadian adults by using the ATP III and the IDF definitions. c) To examine the association between Metabolic Syndrome and cardiovascular disease mortality in Canadian adults by using the ATP III and the IDF definitions.</p> <p>Methods: The Canadian Heart Health Survey was a cross-sectional probability sample survey conducted in all 10 Canadian provinces between 1986 and 1992.The first two studies in this thesis were based on individuals for whom full anthropometric measurements were obtained and for whom data on all components of MetS were available (provinces of Alberta, Manitoba, Ontario, Quebec and Saskatchewan). Statistics Canada linked the CHHS data set to Canadian Mortality Database. The third study was based on three provinces (Alberta, Manitoba, and Saskatchewan) for whom full anthropometric measurements, mortality data, and data on all components of MetS were available. MetS was defined according to ATP III and IDF definitions. A weighted analysis using SPSS PASW Complex Samples (version18) was used to conduct stepwise logistic regression analysis to identify risk factors significantly associated with MetS (p < 0.05). Cox-regression analyses using the STATA (version11) was conducted to predict CVD mortality.</p> <p>Results: According to ATP III, 17.9% and 15.3% of men and women have MetS, while according to IDF, 23.8% and 17.3% of men and women have MetS, respectively. Kappa agreement between the definitions is 72 % for men and 80% for women (pâ¤0.05). Older age and low level of physical activity are significant risk factors for the MetS regardless of gender and definition. Higher level of education and alcohol consumption are additional significant protective factors for women, whereas retirement and being unemployed are additional significant risk factors for men. The hazards of death due to CVD events in women with the syndrome according to the ATP III and the IDF definitions are 3.96(1.30-12.09) and 2.56 (1.32-4.97), respectively. The comparable numbers for men are 2.21(1.16-4.02) and 2.50(1.50-4.17). Conclusion: In Canadian adults the prevalence of MetS is higher when the IDF definition is applied but the metabolic derangement of individuals identified is less severe. Demographic, socio economic factors, and lifestyle habits are significantly associated with MetS among the Canadian adults. The ATP III definition predicts CVD mortality better in women, while the IDF definition predicts CVD mortality better in men.</p>

<p>Background: There is limited information available about the prevalence of Metabolic Syndrome (MetS), its trend over time and its predisposing risk factors according to different definitions in Canadian adults. No studies have compared the ability of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) and the International Diabetes Federation (IDF) definitions to predict Cardiovascular Disease (CVD) mortality among Canadian adults.</p> <p>Objectives: a) To examine the age and sex specific prevalence of the Metabolic Syndrome in Canadian adults by using the ATP III and the IDF definitions. b) To examine the risk factors for Metabolic Syndrome in Canadian adults by using the ATP III and the IDF definitions. c) To examine the association between Metabolic Syndrome and cardiovascular disease mortality in Canadian adults by using the ATP III and the IDF definitions.</p> <p>Methods: The Canadian Heart Health Survey was a cross-sectional probability sample survey conducted in all 10 Canadian provinces between 1986 and 1992.The first two studies in this thesis were based on individuals for whom full anthropometric measurements were obtained and for whom data on all components of MetS were available (provinces of Alberta, Manitoba, Ontario, Quebec and Saskatchewan). Statistics Canada linked the CHHS data set to Canadian Mortality Database. The third study was based on three provinces (Alberta, Manitoba, and Saskatchewan) for whom full anthropometric measurements, mortality data, and data on all components of MetS were available. MetS was defined according to ATP III and IDF definitions. A weighted analysis using SPSS PASW Complex Samples (version18) was used to conduct stepwise logistic regression analysis to identify risk factors significantly associated with MetS (p < 0.05). Cox-regression analyses using the STATA (version11) was conducted to predict CVD mortality.</p> <p>Results: According to ATP III, 17.9% and 15.3% of men and women have MetS, while according to IDF, 23.8% and 17.3% of men and women have MetS, respectively. Kappa agreement between the definitions is 72 % for men and 80% for women (pâ¤0.05). Older age and low level of physical activity are significant risk factors for the MetS regardless of gender and definition. Higher level of education and alcohol consumption are additional significant protective factors for women, whereas retirement and being unemployed are additional significant risk factors for men. The hazards of death due to CVD events in women with the syndrome according to the ATP III and the IDF definitions are 3.96(1.30-12.09) and 2.56 (1.32-4.97), respectively. The comparable numbers for men are 2.21(1.16-4.02) and 2.50(1.50-4.17). Conclusion: In Canadian adults the prevalence of MetS is higher when the IDF definition is applied but the metabolic derangement of individuals identified is less severe. Demographic, socio economic factors, and lifestyle habits are significantly associated with MetS among the Canadian adults. The ATP III definition predicts CVD mortality better in women, while the IDF definition predicts CVD mortality better in men.</p>

Abstract It has widely been shown that exercise, particularly aerobic exercise, has extensive cardioprotective benefits and is an important tool in the prevention of coronary heart disease (CHD). The present investigation aimed to determine the multivariate impact of strength training, designed to prevent the development of CHD, on the Framingham Risk Assessment (FRA) score. Twenty-eight healthy untrained men with low CHD risk (mean age 28 years and 7 months) participated in an eight-week (3- d/wk) strength training programme. Self-administered smoking records, resting blood pressures, total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), FRA scores and absolute 10-year risks for CHD were determined at the pre-test and post-test. After the eight-week period, no significant (p > 0.05) differences were found in number of cigarettes smoked daily, systolic blood pressure, TC, HDLC, FRA scores and absolute 10-year risks for CHD in both the strength-trained (n = 13) and non-exercising control (n = 15) groups. The data indicate that strength training did not reduce the risk of developing CHD and absolute 10-year risk for CHD as assessed by the FRA score.

Ischemic heart disease is the largest cause of death due to cardiovascular origins. A better understanding of the mechanisms responsible for ischemic heart disease increases the potential for therapies. This will lead to decreased mortalities in Canada and around the world. Nutritional interventions have gained increasing attention as causes or treatments for cardiovascular disease. For example, trans fats (TFAs) have both beneficial and deleterious effects on cardiovascular disease [1]. In this study, we would like to examine this phenomenon. We contrast the effects of two different TFAs on cardiomyocyte viability. We compare the industrially produced trans-fat elaidic acid (EA) and the ruminant trans-fat vaccenic acid (VA) on apoptotic and autophagic markers during non-ischemic (control), ischemic (ISCH) and ischemia/reperfusion (IR) conditions. Rat cardiomyocytes are exposed to medium containing fatty acids conjugated with bovine serum albumin for 24 hours. VA and EA have no significant effect on biomarkers of apoptosis or cell death. Interestingly, a similar effect is observed with autophagic and apoptotic markers of LDLr-/- mice whose diets were supplemented with VA or EA. Cells pre-treated with EA prior to 60 minutes of simulated ISCH and 120 minutes of IR increased cell death compared to control through augmented apoptosis. VA decreases the number of dead cells during ISCH and IR. However, the apoptotic parameters remain unchanged. We also observe that VA decreases oxidized phospholipid content in non-ischemic conditions. We conclude that not all TFAs are deleterious to the heart. EA is toxic to cardiomyocytes with or without ISCH or IR whereas VA is cardioprotective during IR and ISCH conditions. We believe VA decreases oxidized phospholipid content to produce this cardioprotective effect. For the purposes of comparison, we examined the effects of α-linolenic acid (ALA), an essential polyunsaturated fatty acid found in foods like flaxseed. Omega-3 fatty acids have been associated with improved cardiovascular outcomes. Here, isolated adult rat cardiomyocytes from male Sprague Dawley rats were exposed to medium containing ALA for 24 hours and then exposed control, ISCH or IR conditions. Cell death increases during ISCH and IR. An increase in DNA fragmentation and caspase-3 activity was observed in both the ISCH and IR conditions. Pre-treatment of the cells with ALA subsequently inhibits cell death during ISCH and IR challenge and significantly reduced both DNA fragmentation and caspase-3 cleavage during ISCH and IR. Cardiomyocyte resting Ca2+ increased and Ca2+ transients decreased during ISCH or I/R but ALA pre-treatment did not improve either parameter significantly. We hypothesize that apoptosis is initiated through phosphatidylcholine oxidation within the cardiomyocytes. Pre-treatment of cells with ALA resulted in a significant incorporation of ALA within cardiomyocyte phosphatidylcholine. Two pro-apoptotic oxidized phosphatidylcholine (OxPC) species, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) were significantly increased during both ISCH and IR. ALA pre-treatment significantly decreased the production of POVPC and PGPC during ISCH and I/R. It is concluded that ALA protects the cardiomyocyte from apoptotic cell death during simulated ISCH and IR by inhibiting the production of specific pro-apoptotic OxPC species. In summary, we observe a differential effect of ALA, VA and EA on parameters of cardiomyocyte viability during ISCH or IR.

No description available.

Cardiovascular disease and cancer are the two most common causes of death worldwide. Angiogenesis plays a critical role tumourigenesis and atherogenesis. As a member of the basic region-leucine zipper protein family, c-Jun, has been linked with cell proliferation, migration and cell survival. However, the relationship between c-Jun and angiogenesis has not been firmly established. In this thesis, strategies targeting c-Jun mRNA such as DNAzyme and siRNA have been designed and evaluated for their ability to inhibit the c-Jun mRNA and c-Jun protein expression in vitro and in vivo. These agents block c-Jun expression and inhibit DNA binding activity of c-Jun. Luciferase assay showed that c-Jun siRNA suppressed c-Jun/AP-1-dependent reporter activity. The processes of cell proliferation, migration, invasion and tube formation were all down-regulated after treatment with c-Jun targeting agents. In vivo, c-Jun DNAzymes and siRNA inhibit angiogenesis in multiple models of angiogenesis in multiple models of angiogenesis, including tumour angiogenesis and growth, matrix angiogenesis, corneal angiogenesis and retinal neovascularization. This is mediated, at least in part, by c-Jun siRNA or DNAzyme inhibition of MMP-2 expression. These findings demonstrate the critical role played by c-Jun in the involvement of neovascularization and suggest that DNAzymes or siRNAs are efficient gene-silencing agents. The ability to identify and control key genes in angiogenesis provides opportunities for developing therapeutic molecular tools to treat cancer or other angiogenesis related diseases.