522A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC March 3, 2004 Vascular Disease, Hypertension, and Prevention tively). The SHRSP group had 12-fold higher levels of total aortic reactive oxygen species (ROS) assessed by 8-iso-PGF 2 α, and 4-fold increase in superoxide content assessed by hydroethidine staining of the aortic media. Both drugs significantly reduced ROS and NAD(P)H oxidase essential subunit p22 phox and its activity (P<0.05), whereas p-Akt, eNOS, and the contractile-type smooth muscle myosin heavy chain SM2 were signifi- cantly increased in SHRSP aorta (P<0.01). In addition, E4177 was more effective at inducing VSMC differentiation by a 43% reduction of ROS through the downregulation of NAD(P)H oxidase activity, and the upregulation of p-Akt by 27%, eNOS by 32%, and SM2 by 34% compared with cilazapril respectively (P<0.05). Conclusions- An ACE inhibitor and an AT1 receptor antagonist inhibited VSMC dedifferentiation through the reduction of ROS by inhibiting NAD(P)H oxidase, and the upregulation of eNOS and Akt in SHRSP aorta; suggesting that, in contrast to the results from in vitro experiments, eNOS and Akt activation through the inhibition of AT1 receptor might be crucial determi- nants for VSMC differentiation in hypertension in vivo. 1161-173 Stromelysin-1 (MMP-3) Gene 5A/6A Promoter Polymorphism Is Associated With Blood Pressure in a Community Population John Beilby, Joseph Hung , Caroline Chapman, Brendan McQuillan, Peter Thompson, Sir Charles Gairdner Hospital, Perth, Australia, PathCentre QEII Medical Center, Perth, Australia Background: Vascular remodelling of large and small arteries contributes to the devel- opment of hypertension. Stromelysin-1, a member of the matrix metalloproteinase (MMP) family may contribute to arterial remodelling. The expression of stromelysin-1 gene is partly regulated by a common polymorphism in the promoter region of either five or six consecutive adenosine bases (5A/6A) that alter transcription factor binding. Methods: A cross-sectional study of 1,111 randomly selected community subjects (553 males and 558 females), age 27-77 years, who were assessed for conventional cardio- vascular risk factors and the stromelysin-1 5A-1171/6A genotype. Mean common carotid intima-medial wall thickness (IMT) and presence of plaque was determined by carotid ultrasound. Results: The frequency of the stromelysin-1 -1171/5A allele was 0.45. Univariate analy- sis demonstrated an association between the stromelysin-1 5A-1171/6A genotype and blood pressure in the whole population. Multivariate analysis showed an independent association between the stromelysin-1 genotype and systolic and diastolic blood pres- sure (both P<0.005) in the whole sample. When the population was split by smoking sta- tus, an independent association with systolic blood pressure (P<0.0001) and diastolic blood pressure (P=0.006) was present only in smokers. Subjects who smoked and car- ried the 5A/5A genotype had a higher mean systolic (+6.0 mmHg) and diastolic (+2.5 mmHg) blood pressure compared to 5A/6A and 6A/6A carriers. The association between the stromelysin-1 genotypes and blood pressure was recessive with the effect only seen with the 5A/5A genotype. Multivariate analysis in the whole population showed there was no association with mean IMT (P=0.42) or the likelihood of carotid plaque formation (P=0.08). Conclusions: In this large randomly selected, cross-sectional population, the 5A/5A variant in the stromelysin-1 gene promoter was independently associated with increased blood pressure in the whole population and in smokers but was not associated with either increased carotid IMT or plaque formation. 1161-174 Pulse Pressure and Interactions Between Polymorphisms in the Angiotensin II Type 1 Receptor and Uncoupling Protein 1 Genes in Hypertensive Hong Kong Chinese Yu-Jing Fang , Cai-Xia Li, Ji-Qian Fang, G Neil Thomas, Brian Tomlinson, Chinese University of Hong Kong, Hong Kong, People's Republic of China, Sun Yat-Sen University, Guangzhou, People's Republic of China Background: Hypertension and obesity are strongly inter-related and have multifactorial genetic and environmental components. The angiotensin II type 1 receptor (AT1R) is involved in the regulation of blood pressure and polymorphisms in this gene have been implicated in the development of hypertension. The uncoupling protein 1 (UCP1) is solely expressed in brown adipose tissue and genetic polymorphisms affecting this may be associated with obesity. The present study was performed to assess the contribution of polymorphisms of these two genes on blood pressure or obesity parameters in a family study. Methods: We studied members of 96 families with a hypertensive proband, including 282 siblings, of which 133 were hypertensive and 144 were obese. Blood pressure, pulse pressure, body mass index (BMI) and waist:hip ratio (WHR) were recorded for each sib- ling. The AT1R gene A1166C polymorphism and the UCP1 gene A-3826G polymorphism were identified with polymerase chain reaction based RFLP protocols. A multi-level mixed linear model for quantitative trait locus (QTL) analysis was applied to identify whether these genetic polymorphism loci were related to blood pressure, pulse pressure or body weight. Results: No significant association was found between the AT1R and UCP1 gene poly- morphisms and systolic or diastolic blood pressure. Age and the BMI/WHR ratio were strongly related to the systolic blood pressure (p<0.0001), diastolic blood pressure (p<0.0001) and pulse pressure (p=0.0003). Gender was only related to pulse pressure (p=0.0003). For the AT1R and UCP1 gene polymorphisms, the QTL analysis showed that the AT1R gene A1166C polymorphism was related to pulse pressure after adjustment for age, gender and BMI/WHR ratio (p=0.038). A significant gene-gene interaction for pulse pressure was found between the two gene polymorphisms after adjustment for age, gen- der and BMI/WHR ratio (p=0.031). Conclusions: Genetic variation at the AT1R gene locus may modify the risk for developing abnormal pulse pressure. An interaction between the AT1R genotype and UCP1 geno- type suggests these loci may be important in determining abnormal blood pressures in relation to obesity. 1161-175 Platelet-Derived Vascular Endothelial Growth Factor in Patients With Hypertension: Relationship to Platelet Activation and Plasma Indices of Angiogenesis Sunil K. Nadar , Graham J. Caine, Andrew D. Blann, Gregory YH Lip, City Hospital, Birmingham, United Kingdom Aims: Platelet activation is an important part of the pathogenesis of complications in hypertension (HT). Hypertension is also associated with abnormal angiogenesis. We hypothesise a relationship of platelet derived Vascular Endothelial Growth Factor (VEGF) to plasma markers of angiogenesis (VEGF, Angiopoietin (Ang)-1 and 2, and Ang receptor Tie-2) and platelet activation (soluble P-selectin) in hypertension. Methods: We studied 199 (151 male, mean age 67+ 9 years) patients with HT and 59 normotensive controls( 41 male; mean age 68+ 11 years). Plasma levels of angiogenesis such as VEGF, Ang-1, and Ang2, and Tie-2 were determined by ELISA. Platelet derived VEGF was measured by lysing a fixed number of platelets, and measuring the levels in the lysate so obtained. Results: Plasma indices were abnormal in HT versus controls [Table1]. Platelet derived VEGF did not vary with the use of aspirin or antihypertensive agents. Platelet derived VEGF correlated with plasma levels of VEGF( Spearmans r=0.257, p=0.001), Ang 1 (r=0.307, p=0.001) and Tie 2 (r=0.19 p=0.007), but not with soluble p-selectin. Conclusions: Hypertensive patients have raised platelet derived VEGF which correlates with the plasma levels of VEGF and Ang-1. This suggests a role for platelets in the abnor- mal angiogenesis that is seen in hypertension 1161-176 Carvedilol Reduces Serum Concentration of DNA- Damage Biomarker 8-Hydroxydeoxyguanosine in Human Hypertension Juyong Lee , Mejeong Lee, Jung-Wook Kim, Jin-Geun Jang, Yoon-Suck Choi, Sang-Sig Cheong, Gangneung Asan Hospital, Gangneung-si, South Korea Background: Oxidative DNA damage due to reactive oxygen species(ROS) has been implicated in cardiovascular diseases. Deoxyguanosine is one of the constituents of DNA and when it is oxidized, it is altered into 8-OHdG. The serum concentration of the DNA repair product 8-OHdG has been proposed as a noninvasive biomarker of oxidative DNA damage in human in vivo. Carvedilol has shown to have antioxidant actions in patients by reduction of anti-oxidized LDL antibodies and to reduce ROS in normal human subjects. However, there has been no data that carvedilol reduce DNA damage in human hyper- tension. Methods: Seventeen newly diagnosed hypertension patients (mean age =51±11, male/female=11/6) who have not taken antihypertensive medication previously volunteered for the study. Fasting blood sample were collected at baseline in tubes with EDTA as an anticoagulant. The subjects were given 12.5 or 25 mg of carvedilol PO once a day for 2 months. Two months later, another blood sample was collected as above. Age and sex matched control subjects (n=22, mean age =45±12, male/female=14/8), not given any drugs, also had 2 samples taken 2 months apart. None of the subjects were on any medications, including NSAIDs, Vitamin E, or other antioxidants. Serum 8-OHdG was measured with ELISA method. High sensitivity C-reactive protein (hs-CRP) was also checked two times. There were no statistical differences in smoking, diabetes, and total cholesterol level between hypertension and control group. Results: In the hypertension group, DNA damage biomarker 8-OHdG at baseline was 9.07±4.23 ng/ml (mean±SD). After carvedilol administration, it fell to 5.74±3.89 ng/ml (p=0.002). In the control group, the 8-OHdG concentrations were 3.41±2.03, 3.01±2.65 ng/ml at baseline and 2 months later, respectively (p=NS). The baseline 8-OHdG was higher in the group of hypertension than in control(p=0.001). hs-CRP had no significant difference before and after carvedilol treatment in the hypertension group( 0.21±0.51, 0.19±0.37 mg/dl). Conclusion: DNA damage due to ROS occurs more in hypertension patients than in normal blood pressure people. Carvedilol may significantly reduce DNA damage in hypertension patients. 1161-177 Modulatory Effect of Inflammation on Blood Pressure Reduction Following Therapeutic Lifestyle Change via Cardiac Rehabilitation and Exercise Training Richard V. Milani , Carl J. Lavie, Ochsner Clinic Foundation, New Orleans, LA Background: Inflammation promotes the development and progression of atherosclerosis and is associated with several traditional CV risk factors including hypertension, diabe- tes, and dyslipidemia. We evaluated the impact of inflammation on improvement in risk factors following 12 weeks (36 sessions) of therapeutic lifestyle change (TLC) via cardiac rehabilitation and exercise training (CRET) in 635 patients (mean age 64.6 ±10.7 years) 4-6 weeks following a major CHD event. Methods: Patients were dichotomized based upon baseline median hs-CRP (median = 3.2 mg/L) values. At baseline there were no differences in age, gender, systolic and dias- Controls (n=59) Hypertensive (n=199) p-value SBP (mmHg) 130(9) 147(22) 0.001 DBP (mmHg) 80 (9) 80(11) 0.9 s P-selectin (ng/ml) 77(38-110) 150(106-213) <0.001 VEGF (ng/ml) 500(42-7750) 1500(30-100000) <0.001 Ang-1 (ng/ml) 10(6-60) 700(250-1300) <0.001 Ang-2 (ng/ml) 1.8(0.5-3.0) 1.8(1.1-3.5) 0.01 Platelet VEGF (ng/ml) 30 (10-200) 600(50-3000) <0.001 Downloaded From: http://content.onlinejacc.org/ on 01/30/2013