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How can a single gene defect present with a varied phenotype- Cited2 gene deletion in the mouse results in pleiotropic, penetrant and variable cardiovascula malformations, laterality defects, adrenal agenesis, neural tube defects and fused cranial ganglia. CITED2 acts as a transcriptional co-activator, and as transcriptional repressor of PHFIA. Loss of Cited2 has been shown to be associated with increased levels of Vegf-a, a HIFIA target, and reduced levels of the key left-right patteming genes Nodal, Pitxlc, Leftyl in the left lateral piate mesoderm, and Pitx2c in the heart.

The global demographic, socio-economic and technological changes linked with lifestyle modifications are widely considered to be the underlying cause of the increased prevalence of CVD and other non-communicable disease worldwide. Understanding the role of the lifestyle factors in associations with these problems is important for treatment and prevention. The aims of the present thesis were: 1) To evaluate the associations between some lifestyle factors, body weight and shape, and CVD risk factors. 2) To determine the combination association between lifestyle factors and body weight and CVD risk factors. 3) To evaluate the effects of a smoking cessation program on energy balance. To achieve these aims a secondary analysis of Scottish Health Survey (SHS) 1998 and an observational study have been carried out. The relationships between smoking status and body size and shape have been examined using the SHS data from those aged 16-74 years. After adjustment for some confounding factors, BMI was lower in current smokers and higher in ex-smokers (p<0.001) when compared to non-smokers in the survey population as a whole. Smoking was associated with a lower BMI in the sample as a whole, but not for the youngest age group. Smoking cessation was associated with weight gain. Smoking and obesity were the two major risk factors, which showed the strongest associations with the CVD risk factors, and their combination exaggerated CVD risk factors. Achievement of currently recommended physical activity levels were associated with lower BMI and prevalence of obesity, and a smaller WC and WHR. However, approximately 50% of active subjects were overweight and obese. These levels of activity were associated with lower CVD risk factors, however the joint associations of physical activity and BMI showed that obese active people still had higher CVD risk factors than inactive people with BMI < 25 kg/m2. Smoking and inactivity were two major modifiable behaviours that showed the strongest associations with unhealthy dietary habits. Smoking cessation was associated with increased body weight and WC within weeks of cessation, particularly in females with NRT. Attrition rates were high and effective weight maintenance strategies may improve this.

Dietary long chain n-3 fatty acids in fish-oil have proven efficacy in reducing cardiovascular risk associated with an atherogenic lipoprotein phenotype (ALP) and in reducing CHD mortality. However, the acquisition of these health benefits is seriously limited by low habitual intakes of oily fish. Since the shorter chain fatty acid alpha-linolenic acid (ALA) can be converted, to a variable extent, in vivo to its longer chain counterparts, in theory, it should have the capacity to exert fish oil like effects on cardiovascular risk. To test this hypothesis, a pilot study was designed to assess the practical issues of delivering 16g of ALA per day to a group of normal healthy (n=9) volunteers. Outcomes were used in a larger study designed to examine the relative effects of diets enriched with ALA in flaxseed oil, and fish oil on plasma lipids, lipoproteins and selected haemostatic variables in subjects with an ALP. Normal, healthy male subjects (n=57) with an ALP were randomly assigned to one of three diets for 12 weeks; a diet enriched with flaxseed oil (high ALA n=21), a "control" diet enriched with sunflower oil (high linolenic acid n-17) and the "control" diet supplemented with fish oil capsules (3g EPA+DHA n=19). Evidence for dietary compliance was provided by 7-day records of food intakes and increases in the concentration of n-3 PUFA in erythrocyte membrane phospholipids. The pilot study provided valuable information on the delivery of ALA into the study diet, which improved accuracy of dietary dose, portability and stability of the oil and aided dietary compliance in the principal study. The flaxseed, fish oil and "control" diets achieved intake ratios of n-6:n-3 of 0.4, 5.2 and 30.0 respectively. There was no overall difference in any measured variable between the 3 diets (6 & 12 week post diet) or between the flaxseed and fish-oil groups compared to control. Total plasma cholesterol decreased relative to baseline values, within all 3 test diets (pre versus post-diet). Plasma TAG was significantly decreased after the fish oil diet, relative to baseline (-23%. P < 0.001). The change in plasma TAG was inversely associated with the level of DHA (C22:6 n-3) in erythrocyte membrane fatty acids at 12 weeks (r2 = 48% p=0.001). LDL subclasses showed a significant reduction towards larger, lighter particles after fish-oil (small, dense LDL-3 -22% p=0.003). There was no change in the concentrations of plasma fibrinogen, factor VII, or in the plasma activity of PAI-1 on any diet or endothelial function as measured by flow-mediated dilatation on a subset on each diet. In conclusion, the fish-oil diet induced predictable changes in plasma lipids and lipoproteins that are associated with lower CHD risk. The flaxseed-oil diet did not reproduce these effects even in the presence of low intakes of dietary n-6 fatty acids.

Nitric Oxide (NO) is an important mediator of cardiovascular function and its impaired synthesis is a feature of many cardiovascular diseases. Raised concentrations of an endogenous inhibitor of NO synthesis, asymmetric dimethylarginine (ADMA), are associated with renal failure, hypertension, heart failure and impaired angiogenesis. ADMA is generated during protein turnover and metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The significance of this pathway in vivo is unknown. This series of studies demonstrates that the metabolism of ADMA by DDAH influences NO synthesis in vitro and in vivo and that this pathway is likely to be important in man. An important regulator of tissue development and remodelling, all-trans-retinoic acid (atRA), has been shown to upregulate an isoform of DDAH, DDAH2, and regulate NO synthesis in vitro. Using a novel transgenic mouse model, it has been shown that the overexpression of DDAH in vivo can increase NOS activity and lower blood pressure. A mouse model of unilateral hindlimb ischaemia has been used to demonstrate that ischaemia can increase ADMA formation and also upregulate DDAH expression in order to restore ADMA levels to baseline and potentiate NO synthesis. Finally, a randomised, double-blind, placebo-controlled study demonstrates that an acute systemic increase in ADMA produces adverse cardiovascular effects in humans, both at rest and during exercise. These results support a causal role relationship between raised ADMA levels and cardiovascular dysfunction. The data also indicates that ADMA is metabolised by DDAHs extensively in humans in vivo; humans generate approximately 300 mol of ADMA per day, of which approximately 250 mol is metabolised by DDAHs.