- Email: [email protected]
W15.398 The influence of long-term glycemic control on the fibrinolytic system in type-1 diabetic patients
92
W15
Zabena
Workshops Thrombotic risk factors in atherosclerosis
Results: LDL levels decreased with 48.9% and HDL levels increased with 13.3% during two year treatment with simvastatin o1" atorvastatin treatment. High PON-1 levels significantly predicted a more pronounced LDL reduction during the first 8 weeks and a less steep HDL increment during the whole treatment period. Conclusions: These results indicate that pat'aoxonase modifies the process of lipid lowering with statins.
~
IS THE PRO12ALA POLYMORPHISM OF PPARy GENE ASSOCIATED W I T H INSULIN RESISTANCE AND METABOLIC COMPLICATIONS IN HIV PATIENTS W I T H / W I T H O U T LIPODYSTROPHY?
C. Zabena, V. Estrada, J. Gonz lez-S nchez, M. Mat't nez-Lan'ad, M. Mat't nez-CalaU'ava, N.G.E de Villar, M. Sen'ano. Hospital Cl nico San
Carlos, Madrid, Spain Aims: 1-To estimate the fi'equency of IS"ol2Ala polymorphism of PPARy gene in treated HIV subjects with/without lipodystrophy (LD), naive patients and controls. 2-To investigate the role of this polymoqohism in the susceptibility to IR and its metabolic complications. Methods: 92 HIV + males (Group A: 48 treated patients with LD-, Group B: 23 treated subjects without LD, Group C: 21 naive patients) 71 healthy control subjects age/BMI matched. 34.8% of patients had AIDS. Antha'opometric measurements, fasting and 2 hrs Glucose (FG, G2 ha's), Lipid profile, Insulin (FI), Proinsulin (FP), Leptin (FL) and Adiponectin (FAMP). IR was defined as the upper percentile of the control group. Genotyping of IS"ol2Ala PPARy by PCR-RFLE Results: Prol2Ala genotype distribution: Control group: Prol2Pro: 81.7%; Prol2Ala: 16.9%, Alal2Ala: 1.4%; Group A: Prol2Pro: 81.2%, Prol2Ala: 18.8%; Group B: Prol2Pro: 87.0%, Prol2Ala: 13.0%, Group C: Prol2Pro: 90.5%; Prol2Ala: 9.5% (p=0.82). Significant differences in SBP, FG, FI, FP, HOMA, lipid profile, FL, and FAMP were found between four groups. Frequency of IR was: Control Group 24.6%, Group A 43.1%, Group B 24.6%, Group C 7.7% (p< 0.001). In a multiple logistic legression analysis, after adjustment for age, waist circumference, triglycerides, HDL-cholesterol and Prol2Ala polymorphism, IR was more fi'equent in groups A and B compared with control group (ORadj: 5.59/8.60, CI 95% 1.80-17.33/2.25-32.88, p=0.003/0.002; respectively). Conclusions: Our results suggest that the IR is associated with anth'eU'ovh'al treatment independently of the Prol2Ala PPARy polymorphism and the presence or absence of lipodystrophy.
tertiles of the HbAlc, the group with the highest tertile (above o1" equal to 8.4%) had, compared with the two lower, significantly higher levels of PAI-1 activity (10.0 vs 6.3 U/mL), tPAag (6.7 vs 5.3 ng/mL) and TNFc~ (2.45 vs 1.79 pg/mL) and significantly lower levels of tPA activity (0.82 vs 1.60 IU/mL) and serum D-dimer (0.56 vs 1.53 I~g/mL). Conclusion: Long-term glycemic conU'ol (assessed as mean HbAlc over time) was highly associated with atherotha'ombotic markers, especially reduced fibrinolysis.
I wl
I
5.399 iI INHIBITION OF ANNEXIN V-BINDING TO
E N D O T H E L I A L CELLS- A NOVEL M E C H A N I S M IN ATHEROTHROMBOSIS
A. Cederholm, E. Svenungsson, G. Fei, J. Frosteg rd. Department of Medicine, Karolinska University Hospital, Huddinge, Sweden Background: Patients with systemic lupus erythematosus (SLE) at'e at high risk of cat'diovasculat" disease (CVD). SLE-related CVD could therefore be an important "human disease model" for inflammation and atherosclerosis in addition to being a clinical problem. Annexin V is a potent anticoagulant, forming an antithrombotic shield by binding to exposed phosphatidylserine (PS). This binding of Annexin V is crucial for the mainteneance of placental blood flow and consequently fetal survival. Method: Twenty-six women (52-4-8.2 yrs) with SLE and a history of CVD (SLE cases) were compared with 26 age matched women with SLE but no CVD (SLE controls) and 26 age-matched healthy women (population controls). Annexin V and propidium iodide binding were assessed by flow cytometry after 24 hrs plasma cultivation with HUVECs. For analysis of cell survival and apoptosis, MTT assay was performed and cytoplasmic DNA and oligonuleosomes fi'action were determined by ELISA. Results: Thele was no effect on HUVEC viability o1"apoptosis detectable by employed methods. Binding of annexin V, determined as percentage of positive cells, was significantly lower after 24 hrs when plasma fi'om SLE cases was used as compared to SLE controls and controls (p<0.05). Depletion of total IgG fi'om sera with a high capacity to inhibit binding of Annexin V restored this binding completely. Conclusions: Inhibition of Annexin V-binding to EC may represent a novel mechanism for CVD, by causing a procoagulant state. Studies to identify antibody specificity ate under way. I
IN THE SEASONAL VARIATION OF IW l 5.400 I DIFFERENCES PLASMA FIBRINOGEN B E T W E E N DIPPER AND i
N O N D I P P E R HYPERTENSIVE PATIENTS
W15
~
THROMBOTIC RISK FACTORS IN ATHEROSCLEROSIS
THE INFLUENCE OF L O N G - T E R M GLYCEMIC C O N T R O L ON THE FIBRINOLYTIC SYSTEM IN TYPE-1 DIABETIC PATIENTS
I. Seljeflot, J. Lat'sen, K. Dahl-JCrgensen, K. Hanssen, H. Arnesen. Ullev 1
University Hospital and Aker University Hospital, Oslo, Norway Disturbances in the haemostatic system at'e well-known risk factors for atherotha'ombosis. Diabetic individuals at'e known to be prone to atherotha'ombosis and coronat'y heat't disease (CDH). Objective: In the present study we have evaluated the relation between long-term glycemic control in insulin dependent diabetes mellitus (IDDM) patients and some fibrinolytic and inflammatory variables. The population consists of 38 type-1 diabetic patients (35-56 yeat's, 40% women) who pat'ticipated in the Oslo study fi'om 1982. They were all regulat'ily followed during 18 years with HbAlc measurements 3-4 times yeat'ly. Results: Mean HbAlc levels during 18 yeat's were 8.2% and cola'elated significantly with PAI-1 activity (r=0.497, p=0.002) and tPAag (r=0.450, p=0.005) and inversely with tPA activity (r=-0.497, p=0.004) and serum D-dimer (global test of fibrinolysis) (r=-0.371, p=0.022), all remaining statistically significant after adjustments for BMI and serum lipids which also colrelated significantly with HbA1 c (BMI p=0.002; triglycerides p< 0.0001; HDL-C (inversely) p=0.004). HbAlc was also significantly cola'elated with TNFc~ (1"=0.430, p=0.007), however not after adjustments for the highly interconelated vat'iables serum lipids and BMI. No cola'elation with high sensitivity CRP was found. When analyzing the vatiables according to the
R. Hermida, D. Ayala, C. Calvo, M. Dominguez, M. Covelo, A. Mojon, J. Fernandez, M. Fontao, R. Soler, J. Lopez. Bioengineering &
Chronobiology Labs., Univ. Vigo, Vigo, Hypertension and Vascular Risk Unit, Hospital CI nico Universitario, Santiago, Spain A seasonal variation with highest values in winter has been previously reported for plasma fibrinogen, a recognized marker of the potential risk of myocardial infarction and stroke. The lack of nocturnal decline in blood pressure (BP) has also been associated with an increase in cardiovascular events, although results at'e still controversial partly due to the inability to properly reproduce over time the classification of patients into dippers and non-dippers. Accordingly, we have quantified and compat'ed the yeat'ly vat'iation of plasma fibrinogen in dipper and non-dipper hypertensive patients. We studied 1666 mild-to-moderate hypertensive patients (784 men), 52.6-4-13.6 years of age. BP was measured by ambulatory monitoring at 20-min intervals fi'om 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours. Physical activity was simultaneously monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. A complete blood test was performed on the same day before stat'ting BP monitoring. The ch'cannual variation of plasma fibrinogen was established for all patients as well as for subgroups of dippers (n=830) and non-dippers (n=836; nocturnal BP decline < 10%) by multiple-component analysis. For the whole group of patients, plasma fibrinogen is chat'acterized by a highly significant seasonal vat'iation (P<0.001) with a mean value of 313 mg/dL, double ch'cannual amplitude (extent of predictable change along the year) of 42 mg/dL, and time of peak value on Februat'y. A similat" pattern of seasonal vat'iation also chat'acterized dippers and non-dippers analyzed sepat'ately. Tha'oughout the yeat" the nondippers showed higher plasma fibrinogen levels than did the dippers (P<0.001). The ch'cannual variation in fibrinogen hele demonstrated is timely colrelated with the reported yearly
74th EAS Congress, 17-20 April 2004, Seville, Spain
W15
Zabena
Workshops Thrombotic risk factors in atherosclerosis
Results: LDL levels decreased with 48.9% and HDL levels increased with 13.3% during two year treatment with simvastatin o1" atorvastatin treatment. High PON-1 levels significantly predicted a more pronounced LDL reduction during the first 8 weeks and a less steep HDL increment during the whole treatment period. Conclusions: These results indicate that pat'aoxonase modifies the process of lipid lowering with statins.
~
IS THE PRO12ALA POLYMORPHISM OF PPARy GENE ASSOCIATED W I T H INSULIN RESISTANCE AND METABOLIC COMPLICATIONS IN HIV PATIENTS W I T H / W I T H O U T LIPODYSTROPHY?
C. Zabena, V. Estrada, J. Gonz lez-S nchez, M. Mat't nez-Lan'ad, M. Mat't nez-CalaU'ava, N.G.E de Villar, M. Sen'ano. Hospital Cl nico San
Carlos, Madrid, Spain Aims: 1-To estimate the fi'equency of IS"ol2Ala polymorphism of PPARy gene in treated HIV subjects with/without lipodystrophy (LD), naive patients and controls. 2-To investigate the role of this polymoqohism in the susceptibility to IR and its metabolic complications. Methods: 92 HIV + males (Group A: 48 treated patients with LD-, Group B: 23 treated subjects without LD, Group C: 21 naive patients) 71 healthy control subjects age/BMI matched. 34.8% of patients had AIDS. Antha'opometric measurements, fasting and 2 hrs Glucose (FG, G2 ha's), Lipid profile, Insulin (FI), Proinsulin (FP), Leptin (FL) and Adiponectin (FAMP). IR was defined as the upper percentile of the control group. Genotyping of IS"ol2Ala PPARy by PCR-RFLE Results: Prol2Ala genotype distribution: Control group: Prol2Pro: 81.7%; Prol2Ala: 16.9%, Alal2Ala: 1.4%; Group A: Prol2Pro: 81.2%, Prol2Ala: 18.8%; Group B: Prol2Pro: 87.0%, Prol2Ala: 13.0%, Group C: Prol2Pro: 90.5%; Prol2Ala: 9.5% (p=0.82). Significant differences in SBP, FG, FI, FP, HOMA, lipid profile, FL, and FAMP were found between four groups. Frequency of IR was: Control Group 24.6%, Group A 43.1%, Group B 24.6%, Group C 7.7% (p< 0.001). In a multiple logistic legression analysis, after adjustment for age, waist circumference, triglycerides, HDL-cholesterol and Prol2Ala polymorphism, IR was more fi'equent in groups A and B compared with control group (ORadj: 5.59/8.60, CI 95% 1.80-17.33/2.25-32.88, p=0.003/0.002; respectively). Conclusions: Our results suggest that the IR is associated with anth'eU'ovh'al treatment independently of the Prol2Ala PPARy polymorphism and the presence or absence of lipodystrophy.
tertiles of the HbAlc, the group with the highest tertile (above o1" equal to 8.4%) had, compared with the two lower, significantly higher levels of PAI-1 activity (10.0 vs 6.3 U/mL), tPAag (6.7 vs 5.3 ng/mL) and TNFc~ (2.45 vs 1.79 pg/mL) and significantly lower levels of tPA activity (0.82 vs 1.60 IU/mL) and serum D-dimer (0.56 vs 1.53 I~g/mL). Conclusion: Long-term glycemic conU'ol (assessed as mean HbAlc over time) was highly associated with atherotha'ombotic markers, especially reduced fibrinolysis.
I wl
I
5.399 iI INHIBITION OF ANNEXIN V-BINDING TO
E N D O T H E L I A L CELLS- A NOVEL M E C H A N I S M IN ATHEROTHROMBOSIS
A. Cederholm, E. Svenungsson, G. Fei, J. Frosteg rd. Department of Medicine, Karolinska University Hospital, Huddinge, Sweden Background: Patients with systemic lupus erythematosus (SLE) at'e at high risk of cat'diovasculat" disease (CVD). SLE-related CVD could therefore be an important "human disease model" for inflammation and atherosclerosis in addition to being a clinical problem. Annexin V is a potent anticoagulant, forming an antithrombotic shield by binding to exposed phosphatidylserine (PS). This binding of Annexin V is crucial for the mainteneance of placental blood flow and consequently fetal survival. Method: Twenty-six women (52-4-8.2 yrs) with SLE and a history of CVD (SLE cases) were compared with 26 age matched women with SLE but no CVD (SLE controls) and 26 age-matched healthy women (population controls). Annexin V and propidium iodide binding were assessed by flow cytometry after 24 hrs plasma cultivation with HUVECs. For analysis of cell survival and apoptosis, MTT assay was performed and cytoplasmic DNA and oligonuleosomes fi'action were determined by ELISA. Results: Thele was no effect on HUVEC viability o1"apoptosis detectable by employed methods. Binding of annexin V, determined as percentage of positive cells, was significantly lower after 24 hrs when plasma fi'om SLE cases was used as compared to SLE controls and controls (p<0.05). Depletion of total IgG fi'om sera with a high capacity to inhibit binding of Annexin V restored this binding completely. Conclusions: Inhibition of Annexin V-binding to EC may represent a novel mechanism for CVD, by causing a procoagulant state. Studies to identify antibody specificity ate under way. I
IN THE SEASONAL VARIATION OF IW l 5.400 I DIFFERENCES PLASMA FIBRINOGEN B E T W E E N DIPPER AND i
N O N D I P P E R HYPERTENSIVE PATIENTS
W15
~
THROMBOTIC RISK FACTORS IN ATHEROSCLEROSIS
THE INFLUENCE OF L O N G - T E R M GLYCEMIC C O N T R O L ON THE FIBRINOLYTIC SYSTEM IN TYPE-1 DIABETIC PATIENTS
I. Seljeflot, J. Lat'sen, K. Dahl-JCrgensen, K. Hanssen, H. Arnesen. Ullev 1
University Hospital and Aker University Hospital, Oslo, Norway Disturbances in the haemostatic system at'e well-known risk factors for atherotha'ombosis. Diabetic individuals at'e known to be prone to atherotha'ombosis and coronat'y heat't disease (CDH). Objective: In the present study we have evaluated the relation between long-term glycemic control in insulin dependent diabetes mellitus (IDDM) patients and some fibrinolytic and inflammatory variables. The population consists of 38 type-1 diabetic patients (35-56 yeat's, 40% women) who pat'ticipated in the Oslo study fi'om 1982. They were all regulat'ily followed during 18 years with HbAlc measurements 3-4 times yeat'ly. Results: Mean HbAlc levels during 18 yeat's were 8.2% and cola'elated significantly with PAI-1 activity (r=0.497, p=0.002) and tPAag (r=0.450, p=0.005) and inversely with tPA activity (r=-0.497, p=0.004) and serum D-dimer (global test of fibrinolysis) (r=-0.371, p=0.022), all remaining statistically significant after adjustments for BMI and serum lipids which also colrelated significantly with HbA1 c (BMI p=0.002; triglycerides p< 0.0001; HDL-C (inversely) p=0.004). HbAlc was also significantly cola'elated with TNFc~ (1"=0.430, p=0.007), however not after adjustments for the highly interconelated vat'iables serum lipids and BMI. No cola'elation with high sensitivity CRP was found. When analyzing the vatiables according to the
R. Hermida, D. Ayala, C. Calvo, M. Dominguez, M. Covelo, A. Mojon, J. Fernandez, M. Fontao, R. Soler, J. Lopez. Bioengineering &
Chronobiology Labs., Univ. Vigo, Vigo, Hypertension and Vascular Risk Unit, Hospital CI nico Universitario, Santiago, Spain A seasonal variation with highest values in winter has been previously reported for plasma fibrinogen, a recognized marker of the potential risk of myocardial infarction and stroke. The lack of nocturnal decline in blood pressure (BP) has also been associated with an increase in cardiovascular events, although results at'e still controversial partly due to the inability to properly reproduce over time the classification of patients into dippers and non-dippers. Accordingly, we have quantified and compat'ed the yeat'ly vat'iation of plasma fibrinogen in dipper and non-dipper hypertensive patients. We studied 1666 mild-to-moderate hypertensive patients (784 men), 52.6-4-13.6 years of age. BP was measured by ambulatory monitoring at 20-min intervals fi'om 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours. Physical activity was simultaneously monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. A complete blood test was performed on the same day before stat'ting BP monitoring. The ch'cannual variation of plasma fibrinogen was established for all patients as well as for subgroups of dippers (n=830) and non-dippers (n=836; nocturnal BP decline < 10%) by multiple-component analysis. For the whole group of patients, plasma fibrinogen is chat'acterized by a highly significant seasonal vat'iation (P<0.001) with a mean value of 313 mg/dL, double ch'cannual amplitude (extent of predictable change along the year) of 42 mg/dL, and time of peak value on Februat'y. A similat" pattern of seasonal vat'iation also chat'acterized dippers and non-dippers analyzed sepat'ately. Tha'oughout the yeat" the nondippers showed higher plasma fibrinogen levels than did the dippers (P<0.001). The ch'cannual variation in fibrinogen hele demonstrated is timely colrelated with the reported yearly
74th EAS Congress, 17-20 April 2004, Seville, Spain