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W15.435 Relationship between major hemostasis and lipid profile parameters and coronary artery disease severity in men with arterial hypertension and dyslipidemia
100
Stanger
W15
Workshops Thrombotic risk factors in atherosclerosis
TF procoagulant activity (PCA) was inhibited by FFR-rFVIIa (p<0.01), while thele was no effect on plasma. ProtIu'ombin time (PT) was prolonged with treatrnent (p=0.0001) and PT values were positively COla'elated with FFR-rFVIIa plasma levels (r2=0.82; p=0.0001). Conclusion: TF pathway inhibition by systemic administration of FFRrFVIIa reduces thrombosis on severely damaged normal and atherosclerotic vessels by blocking blood-borne and vasculm" TF. This study was supported by SAF-2000/0174, Novo-Nordisk (Denmaa'k) and Fundaci n MAPFRE Medicina.
~ O R A L F O L I C ACID DOES NOT R E D U C E P L A S M A CONCENTRATIONS OF ENDOGENOUS NOS I N H I B I T O R A D M A IN H Y P E R H O M O C Y S T E I N E M I C SUBJECTS O. Stanger, M. St hlinger, B. Paulweber, J. Schirnhofer, O. Pachinger. Unic. Clinic of Cardiac Surgery, PMU Salzburg, Endocrinology, Univ. Clinic of lnternal Medicine, Salzburg; Cardiology, Univ. Clinic of lnternal Medicine, Innsbruck, Austria Objective: Endothelial function is impafl'ed in hyperhomocysteinemia (HHcy), the mechanism remains unclear. Homocysteine (Hcy) inhibits NO production by accumulating asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase (NOS), in endothelial cells. A randomized, placebo-controlled, double-blind study design was chosen to investigate the effect of oral folic acid on ADMA plasma concentrations in relation to Hcy-lowering capacity. Methods: 29 subjects (16m/14f; 57-4-4y; Hcy> 12raM) were randomized into 4 groups: each individual was treated with either 0.4rag (n=7), ling (n=7) o1" 5mg of folic acid (n=8), or placebo (n=7) for 8 weeks. Hcy and ADMA plasma concentrations were measmed every 2 weeks, among other functional and biochemical parameters. Five healthy subjects with normal Hcy concentrations were included as controls. Results: At baseline Hcy (13.36-4-0.40 vs. 6.91-4-1.27mM, p<0.001) as well as ADMA (1.67-4-0.86mM vs. 0.55-4-0.03mM, p<0.001) plasma concentrations were significantly higher in hyperhomocysteinemic subjects. All doses of oral folate significantly reduced Hcy after 8 weeks of treatrnent, but not placebo. ADMA was not affected by placebo (fi'om 1.66-t-0.19 to 1.61-t-0.17; p--n.s.) or folate at any dose: with 5mg fi'om 1.59-t-0.10 to 1.77-t-0.16, with l m g fi'om 1.86-t-0.21 to 1.98-t-0.30 and with 0.4mg fi'om 1.58-4-0.22 to 1.56-4-0.20 (all p--ms.). Conclusion: Significant decline of Hcy tIu'ough oral folate within 8 weeks of treatrnent is not accompanied with decrements of plasma ADMA concentrations. Out" results suggest that the beneficial effects of folate on endothelial function and the NOS pathway are not mediated by ADMA.
•
EFFECTS OF A NOVEL NITRIC OXIDE -DONOR, C L O P I D O G R E L AND COMBINED T H E R A P Y IN INHIBITING THROMBOSIS AND M O N O C Y T E CHEMOATTRACTANT PROTEIN-1
G. Vilahur, P. Catalina, T. Padro, L. Badimon. Cardiovascular Research Center, CSIC-ICCC, Hospital Sta. Creu i S. Pau, Barcelona, Spain Recent evidence shows that blockade of the ADP-receptor by clopidogrel is effective in the prevention of arterial thrombosis. Objective and methods: Evaluate whether a novel anti-ischemic nitric oxide (NO)-donor (LA419) can protect against thrombosis triggered by damaged vessel wall when administered alone o1" combined with clopidogrel. Thrombogenicity was measured in the previously validated ex vivo Badimon pelfusion chamber and assessed by radioisotopic quantization of deposited platelets on damaged arteries. Pigs were randomly assigned to one of four" groups: I) control; II)LA419; III)Clopidoglel; IV)Clopidogrel+LA419. LA419 was administered for ten days (0.9mg/kg, dose selected because in preliminary experiments gave a submaximal anti thrombotic activity) and clopidogrel treatment started 3 days before intervention (10mg/kg). Blood pressure, heart rate and in vitro platelet aggregation were evaluated. Additionally, by western blot we measut'ed effects of treatment on MCP-1 expression in the vascular wall. Results: Under low shear rate conditions, thrombosis triggered by mildly o1"sevelely damaged vessel wall was significantly reduced by LA419 (30%) o1" clopidogrel (63%) (P<0.05 vs. control). Interestingly, combination of LA419+clopidogrel produced a synergistic further reduction in platelet deposition triggered by severely damaged vessel (78% vs controls; P < 0.0001 ). LA419 did not modify systemic blood pressure nor heart rate. Clopidogrel
blocked ADP-induced platelet aggregation. Vascular MCP-1 expression was significantly reduced by any treatrnent (p<0.001). Conclusion: Combination of an anti-ischemic NO-donor and an antagonist of the PY12 receptor provide additional benefits since they synergy in inhibiting thrombosis while reducing vasculaa" inflammation (MCP-1 protein expression). (This study was funded by Lacer, S.A, SAF-2000/0174, BEFI) I
IW15.4341 I DIET AND SERUM H O M O C Y S T E I N E LEVELS IN PATIENTS W I T H I S C H A E M I C H E A R T DISEASE F R O M A M E D I T E R R A N E A N COUNTRY G. Vrentzos, J. Papadakis, N. Malliaraki, E. Zacharis, E. Potolidis, E. Ganotakis. University Hospital of Heraklion, Heraklion, Greece Homocysteine (Hcy) is recognized as a risk factor for ischaemic heart disease (IHD). Serum Hcy is negatively COlTelated with serum folate levels, which the main sources are fl'uits, vegetables and legumes. This case-control study was designed to examine the relationship between serum Hcy levels and IHD and to assess the role of dietm'y factors in the southern Mediten'anean population of Crete, Greece. Methods: Serum Hcy, folate, vitamin B12 (B12), creatinine and glucose levels and a full lipid profile were measut'ed in 152 patients with established IHD, median age 64 (33-77) yeaa's, and 152 healthy control subjects, age and sex matched. Dietary data was assessed using a 3-day food intake record. Results: Compared with controls, patients with IHD had significantly higher daily intakes of B12 and monounsaturated fatty acids and significantly lower intakes of cm'bohydrates, fibres, folate, cholesterol, omega 3 fatty acids and total trans unsatut'ated, fatty acids. Moreover patients had significantly higher serum Hcy, B12 and creatinine levels, but significantly lower folate. Serum folate concenU'ations in both groups had a significant positive COlrelation with dietary fibres consumption and a significant reverse COlVelation with B12 intake. Conclusion: IHD patients should be encouraged to inoease daily dietary intakes of fibre, folate and omega-3 fatty acids, which are significant components of the traditional Cretan Mediten'anean diet. Where dietary folate intake is inadequate, folate supplements are recommended to reduce elevated Hcy.
IW15.4351
RELATIONSHIP B E T W E E N M A J O R HEMOSTASIS AND LIPID P R O F I L E P A R A M E T E R S AND CORONARY ARTERY DISEASE SEVERITY IN MEN W I T H A R T E R I A L HYPERTENSION AND DYSLIPIDEMIA
M. Zhuk, V. Metelskaya, N. Zhidko, D. Aronov, N. Perova. National Research Center for Preventive Medicine, Moscow, Russia This study aimed to reveal the relationship, if any, between hemostasis parameters and blood lipid levels, fi'om one hand, and the severity of coronm'y m'tery disease (CAD), verified by coronm'y angiography, fl'om another, in men having CAD risk factors (m'terial hypertension, AH, and/or dyslipidemia, DLP). TIu'ee groups of patients aged 45-60 (n=70) were compared: no stenoses (group 1, n=25); stenoses <50% (32,8-t-1,8%; n=26, group 2); and stenoses >50% (69,2-t-3,4%; group 3, n=19) with maximal number of damaged vessels 1,4-4-0,1 in group 2 and 2,7-4-0,3 in group 3, respectively; p< 0,05. Among CAD-fi'ee patients AH and DLP combination was registered in 40%, in patients with moderate CAD in 73% (c2=5,7; p<0,02), and in patients with severe CAD in 89,5% (c2=13,1; p<0,001). Patients with CAD independently of its severity (groups 2 and 3) had higher SBP and DBP, as well as elevated total cholesterol (C), LDL C and triglycerides levels, and decreased HDL C concentration as compaa'ed to patients without coronary arteries stenoses (group 1). Significantly higher apolipoprotein (apo) B level in both CAD groups resulted in higher apo B/AI ratio: 0,90-t-0,03 and 0,93-t-0,04 vs 0,78-t-0,04 in CAD fi'ee patients. Fibrinogen level was significantly higher in groups 2 (2,91-4-0,12 g/l) and 3 (2,82-4-0,12 g/l) as compared to group 1 (2,55-4-0,09 g/l); p<0,05. No diffelences in ECLT between tIu'ee groups were found. However, plasminogen activity was higher in both groups of CAD pts (148,7-4-2,5 and 145,2-4-2,7%, respectively) than in patients flee of CAD (135,8-t-3,0%; p<0,05), and a2-antiplasmin was significantly higher only in patients with moderate CAD (group 2): 119,1-4-1,3 vs 112,4-4-1,7 % in patients without stenoses (group 1); p< 0,05. Maximal spontaneous platelet aggregation registeled dut'ing 10 min was the lowest in CAD-fi'ee patients. In conclusion, in men with AH and/or DLP more pronounced athero-thrombogenic abnormalities were associated with the presence of CAD per se, and were nor dependent on its severity.
74th EAS Congress, 17-20 April 2004, Seville, Spain
Stanger
W15
Workshops Thrombotic risk factors in atherosclerosis
TF procoagulant activity (PCA) was inhibited by FFR-rFVIIa (p<0.01), while thele was no effect on plasma. ProtIu'ombin time (PT) was prolonged with treatrnent (p=0.0001) and PT values were positively COla'elated with FFR-rFVIIa plasma levels (r2=0.82; p=0.0001). Conclusion: TF pathway inhibition by systemic administration of FFRrFVIIa reduces thrombosis on severely damaged normal and atherosclerotic vessels by blocking blood-borne and vasculm" TF. This study was supported by SAF-2000/0174, Novo-Nordisk (Denmaa'k) and Fundaci n MAPFRE Medicina.
~ O R A L F O L I C ACID DOES NOT R E D U C E P L A S M A CONCENTRATIONS OF ENDOGENOUS NOS I N H I B I T O R A D M A IN H Y P E R H O M O C Y S T E I N E M I C SUBJECTS O. Stanger, M. St hlinger, B. Paulweber, J. Schirnhofer, O. Pachinger. Unic. Clinic of Cardiac Surgery, PMU Salzburg, Endocrinology, Univ. Clinic of lnternal Medicine, Salzburg; Cardiology, Univ. Clinic of lnternal Medicine, Innsbruck, Austria Objective: Endothelial function is impafl'ed in hyperhomocysteinemia (HHcy), the mechanism remains unclear. Homocysteine (Hcy) inhibits NO production by accumulating asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase (NOS), in endothelial cells. A randomized, placebo-controlled, double-blind study design was chosen to investigate the effect of oral folic acid on ADMA plasma concentrations in relation to Hcy-lowering capacity. Methods: 29 subjects (16m/14f; 57-4-4y; Hcy> 12raM) were randomized into 4 groups: each individual was treated with either 0.4rag (n=7), ling (n=7) o1" 5mg of folic acid (n=8), or placebo (n=7) for 8 weeks. Hcy and ADMA plasma concentrations were measmed every 2 weeks, among other functional and biochemical parameters. Five healthy subjects with normal Hcy concentrations were included as controls. Results: At baseline Hcy (13.36-4-0.40 vs. 6.91-4-1.27mM, p<0.001) as well as ADMA (1.67-4-0.86mM vs. 0.55-4-0.03mM, p<0.001) plasma concentrations were significantly higher in hyperhomocysteinemic subjects. All doses of oral folate significantly reduced Hcy after 8 weeks of treatrnent, but not placebo. ADMA was not affected by placebo (fi'om 1.66-t-0.19 to 1.61-t-0.17; p--n.s.) or folate at any dose: with 5mg fi'om 1.59-t-0.10 to 1.77-t-0.16, with l m g fi'om 1.86-t-0.21 to 1.98-t-0.30 and with 0.4mg fi'om 1.58-4-0.22 to 1.56-4-0.20 (all p--ms.). Conclusion: Significant decline of Hcy tIu'ough oral folate within 8 weeks of treatrnent is not accompanied with decrements of plasma ADMA concentrations. Out" results suggest that the beneficial effects of folate on endothelial function and the NOS pathway are not mediated by ADMA.
•
EFFECTS OF A NOVEL NITRIC OXIDE -DONOR, C L O P I D O G R E L AND COMBINED T H E R A P Y IN INHIBITING THROMBOSIS AND M O N O C Y T E CHEMOATTRACTANT PROTEIN-1
G. Vilahur, P. Catalina, T. Padro, L. Badimon. Cardiovascular Research Center, CSIC-ICCC, Hospital Sta. Creu i S. Pau, Barcelona, Spain Recent evidence shows that blockade of the ADP-receptor by clopidogrel is effective in the prevention of arterial thrombosis. Objective and methods: Evaluate whether a novel anti-ischemic nitric oxide (NO)-donor (LA419) can protect against thrombosis triggered by damaged vessel wall when administered alone o1" combined with clopidogrel. Thrombogenicity was measured in the previously validated ex vivo Badimon pelfusion chamber and assessed by radioisotopic quantization of deposited platelets on damaged arteries. Pigs were randomly assigned to one of four" groups: I) control; II)LA419; III)Clopidoglel; IV)Clopidogrel+LA419. LA419 was administered for ten days (0.9mg/kg, dose selected because in preliminary experiments gave a submaximal anti thrombotic activity) and clopidogrel treatment started 3 days before intervention (10mg/kg). Blood pressure, heart rate and in vitro platelet aggregation were evaluated. Additionally, by western blot we measut'ed effects of treatment on MCP-1 expression in the vascular wall. Results: Under low shear rate conditions, thrombosis triggered by mildly o1"sevelely damaged vessel wall was significantly reduced by LA419 (30%) o1" clopidogrel (63%) (P<0.05 vs. control). Interestingly, combination of LA419+clopidogrel produced a synergistic further reduction in platelet deposition triggered by severely damaged vessel (78% vs controls; P < 0.0001 ). LA419 did not modify systemic blood pressure nor heart rate. Clopidogrel
blocked ADP-induced platelet aggregation. Vascular MCP-1 expression was significantly reduced by any treatrnent (p<0.001). Conclusion: Combination of an anti-ischemic NO-donor and an antagonist of the PY12 receptor provide additional benefits since they synergy in inhibiting thrombosis while reducing vasculaa" inflammation (MCP-1 protein expression). (This study was funded by Lacer, S.A, SAF-2000/0174, BEFI) I
IW15.4341 I DIET AND SERUM H O M O C Y S T E I N E LEVELS IN PATIENTS W I T H I S C H A E M I C H E A R T DISEASE F R O M A M E D I T E R R A N E A N COUNTRY G. Vrentzos, J. Papadakis, N. Malliaraki, E. Zacharis, E. Potolidis, E. Ganotakis. University Hospital of Heraklion, Heraklion, Greece Homocysteine (Hcy) is recognized as a risk factor for ischaemic heart disease (IHD). Serum Hcy is negatively COlTelated with serum folate levels, which the main sources are fl'uits, vegetables and legumes. This case-control study was designed to examine the relationship between serum Hcy levels and IHD and to assess the role of dietm'y factors in the southern Mediten'anean population of Crete, Greece. Methods: Serum Hcy, folate, vitamin B12 (B12), creatinine and glucose levels and a full lipid profile were measut'ed in 152 patients with established IHD, median age 64 (33-77) yeaa's, and 152 healthy control subjects, age and sex matched. Dietary data was assessed using a 3-day food intake record. Results: Compared with controls, patients with IHD had significantly higher daily intakes of B12 and monounsaturated fatty acids and significantly lower intakes of cm'bohydrates, fibres, folate, cholesterol, omega 3 fatty acids and total trans unsatut'ated, fatty acids. Moreover patients had significantly higher serum Hcy, B12 and creatinine levels, but significantly lower folate. Serum folate concenU'ations in both groups had a significant positive COlrelation with dietary fibres consumption and a significant reverse COlVelation with B12 intake. Conclusion: IHD patients should be encouraged to inoease daily dietary intakes of fibre, folate and omega-3 fatty acids, which are significant components of the traditional Cretan Mediten'anean diet. Where dietary folate intake is inadequate, folate supplements are recommended to reduce elevated Hcy.
IW15.4351
RELATIONSHIP B E T W E E N M A J O R HEMOSTASIS AND LIPID P R O F I L E P A R A M E T E R S AND CORONARY ARTERY DISEASE SEVERITY IN MEN W I T H A R T E R I A L HYPERTENSION AND DYSLIPIDEMIA
M. Zhuk, V. Metelskaya, N. Zhidko, D. Aronov, N. Perova. National Research Center for Preventive Medicine, Moscow, Russia This study aimed to reveal the relationship, if any, between hemostasis parameters and blood lipid levels, fi'om one hand, and the severity of coronm'y m'tery disease (CAD), verified by coronm'y angiography, fl'om another, in men having CAD risk factors (m'terial hypertension, AH, and/or dyslipidemia, DLP). TIu'ee groups of patients aged 45-60 (n=70) were compared: no stenoses (group 1, n=25); stenoses <50% (32,8-t-1,8%; n=26, group 2); and stenoses >50% (69,2-t-3,4%; group 3, n=19) with maximal number of damaged vessels 1,4-4-0,1 in group 2 and 2,7-4-0,3 in group 3, respectively; p< 0,05. Among CAD-fi'ee patients AH and DLP combination was registered in 40%, in patients with moderate CAD in 73% (c2=5,7; p<0,02), and in patients with severe CAD in 89,5% (c2=13,1; p<0,001). Patients with CAD independently of its severity (groups 2 and 3) had higher SBP and DBP, as well as elevated total cholesterol (C), LDL C and triglycerides levels, and decreased HDL C concentration as compaa'ed to patients without coronary arteries stenoses (group 1). Significantly higher apolipoprotein (apo) B level in both CAD groups resulted in higher apo B/AI ratio: 0,90-t-0,03 and 0,93-t-0,04 vs 0,78-t-0,04 in CAD fi'ee patients. Fibrinogen level was significantly higher in groups 2 (2,91-4-0,12 g/l) and 3 (2,82-4-0,12 g/l) as compared to group 1 (2,55-4-0,09 g/l); p<0,05. No diffelences in ECLT between tIu'ee groups were found. However, plasminogen activity was higher in both groups of CAD pts (148,7-4-2,5 and 145,2-4-2,7%, respectively) than in patients flee of CAD (135,8-t-3,0%; p<0,05), and a2-antiplasmin was significantly higher only in patients with moderate CAD (group 2): 119,1-4-1,3 vs 112,4-4-1,7 % in patients without stenoses (group 1); p< 0,05. Maximal spontaneous platelet aggregation registeled dut'ing 10 min was the lowest in CAD-fi'ee patients. In conclusion, in men with AH and/or DLP more pronounced athero-thrombogenic abnormalities were associated with the presence of CAD per se, and were nor dependent on its severity.
74th EAS Congress, 17-20 April 2004, Seville, Spain