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80. Influence of serum lipids on platelet aggregation and some fibrinolytic parameters in humans
3rd International Fibrinogen Symposium
oxydized, VLDL-LDL) on PAI-1 synthesis by vascular cells (SMC - endothelial cells), hepatocytes or adipocytes. In addition t-PA antigen plasma levels reflect the inflammatory status (ECAT Study). Modulation of the parameters of fibrinolysis is obtained with prescription of hygieno-dietetic rules (hypocaloric diet, physical exercise), with drugs such as oral antidiabetic drugs (Metformin), lipid lowering agents (Niacin, Gimfibrozil), or ACE inhibitor (Captopril).
80. Influence of serum lipids on platelet aggregation and some fibrinolytic parameters in humans R. Kn6fler I , J. Malyszko 2, Y. T a k a d a 3, A. T a k a d a 3, G. Weiigbach 1
1Department of Pediatrics, Technical University Dresden, Germany, 2Department o_fNephrology, Bialystok Medical School, Poland, ~Department of Physiology, Hamamatsu University, Japan Taking into consideration that serum lipids, platelets and the fibrinolytic system are involved in the development of atherosclerosis and thrombotic events, the aim of the study was to investigate possible relations between serum lipids, platelet aggregation and some fibrinolytic parameters in healthy persons. The circadian rhythm of platelet aggregation was compared with that of serum lipids in seven healthy male persons. Daily variations of remnant lipoproteins (RLP) were related to those of arachidonic acid (AA)-, ADP- and collagen-induced aggregation in PRP and to ADP-induced whole blood aggregation. These results confirmed in part, preliminary experiments in which an enhancement of whole blood but not of PRP aggregation by RLP was found. The time course of total cholesterol and triglycerides correlated to that of AA- and serotonin (5-HT)-induced aggregation in PRP, respectively. In contrast, HDL did not influence platelet aggregation. In a separate set of experiments, blood was obtained about 1 hour after breakfast from 16 healthy persons. Under these conditions LDL and total cholesterol were related to 5-HT- and ADP-induced aggregation in PRP, but not to t-PA, PAI-1 and ECLT. These fibrinolytic parameters were negatively correlated to HDL, but not to the VLDL level. In conclusion, serum lipids are closely related to platelet activation. In this connection the importance of RLP represents a new aspect. High levels of HDL may be protective against thrombosis due to the enhancement of fibrinolysis. 81. A v a r i a n t of the a n g i o t e n s i n - c o n v e r t i n g
enzyme gene in patients with a history of ischemic stroke M. Margaglione, E. Grandone, G. Vecchione, E. Celentano, G. Cappucci, N. Giuliani, D. Colaizzo, S. Panico, G. Di M i n n o
Clinica Medica, Istituto di Medicina Interna e Malatti Dismetaboliche, Universita" di NapolL and Unita" a Trombosi e AterosclerosL LR.C.C.S. "Casa Sollievo dell Sofferenza" S. Giovanni Rotondo, Italy We have evaluated the genotypes of the angiotensin converting enzyme (ACE) gene in 101 subjects with and 10 subjects without a history of ischemic stroke. All were attending © Pearson Professk~nal Ltd 1996
25
a metabolic ward. The two groups were compared for major risk factors for ischemic events. Genotypes were determined by the polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Deletion polymorphism of the ACE gene (DD genotype) resulted to be more common in subjects with a history of stroke than in those without (relative risk: 1.76, confidence intervals: 1.02-3.05). A positive family history for ischemic complications of atherosclerosis was also more common in subjects with documented events (relative risk: 1.99, confidence intervals: 1.10-3.59). DD genotype and familial history were strong, independent discriminators of cerebral ischemia. Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) help identify subjects with a history of cerebral ischemic episodes. When such fibrinolytic variables were included in the analysis, the DD genotype still strongly and independently discriminated subjects with a stroke history, and significantly interacted with t-PA levels > 10 ng/ml in such identification. We conclude that in subjects attending a metabolic ward, homozygousite for a deletion polymorphism of the ACE gene consistently discriminates subjects with a stroke history. Interaction with t-PA improves such identification.
82. Determinants of plasma plasminogen activator inhibitor-1 antigen in subjects attending a metabolic ward M. Margaglione, E. Celentano, E. Grandone, G. Vecchione, G. Cappucci, F. P. Mancini, G. Di M i n n o
Clinica Medica, Istituto di Medicina Interna e Malattie Dismetaboliche, Universita" "Federico II" di NapolL Unita" di Trombosi e AterosclerosL I.R.C.C.S. "Casa SoEievo della Sofferenza; S. Giovanni Rotondo, and Istituto di Gerontologia e Geriatra, Universita di Palermo, Italy Background: Plasminogen activator inhibitor-1 (PAI-1) is a determinant of vascular events. A guanine insertion/deletion polymorphism (4G/5G) modulates plasma levels of PAI-1. Moreover, the renin-angiotensin system has been reported to affect plasma PAI-1 levels in humans. Methods and Results: All the genotyping was carried out by polymerase chain reaction technique. In 208 subjects attending a metabolic ward, 5G/SG homozygous were associated with plasma PAI-1 levels lower than those of 4G/4G homozygous (29.4 vs 39.0 ng/dl, p=0.036). Plasma PAI-1 correlated with the 4G/5G genotype (p<0.022), and with tissue plasminogen activator (t-PA) and triglycerides levels (p always <0.001), and depended on the 4G/5G genotype (p<0.009) as well as on t-PA and triglycerides (p<0.001). Triglycerides interacted significantly with the 4G/4G and with the 4G/5G genotypes (p=0.013 and 0.036 respectively), but not with the 5G/5G genotype in determining plasma PAI-1 levels. For all PAI-1 genotypes, the DD genotype of ACE gene was associated with mean plasma PAI-1 levels not statistically different from those associated with II genotype. Conclusions: In a group of subjects from a metabolic ward, the 4G/5G polymorphism within the PAI-1 gene locus exerts effects on plasma PAI-1 antigen levels comparable to those of t-PA or triglycerides. The effects of triglycerides on plasma PAI-1 levels is genotype-dependent. Fibrinolysis (1996) 10, SuppL 1, 1-58
oxydized, VLDL-LDL) on PAI-1 synthesis by vascular cells (SMC - endothelial cells), hepatocytes or adipocytes. In addition t-PA antigen plasma levels reflect the inflammatory status (ECAT Study). Modulation of the parameters of fibrinolysis is obtained with prescription of hygieno-dietetic rules (hypocaloric diet, physical exercise), with drugs such as oral antidiabetic drugs (Metformin), lipid lowering agents (Niacin, Gimfibrozil), or ACE inhibitor (Captopril).
80. Influence of serum lipids on platelet aggregation and some fibrinolytic parameters in humans R. Kn6fler I , J. Malyszko 2, Y. T a k a d a 3, A. T a k a d a 3, G. Weiigbach 1
1Department of Pediatrics, Technical University Dresden, Germany, 2Department o_fNephrology, Bialystok Medical School, Poland, ~Department of Physiology, Hamamatsu University, Japan Taking into consideration that serum lipids, platelets and the fibrinolytic system are involved in the development of atherosclerosis and thrombotic events, the aim of the study was to investigate possible relations between serum lipids, platelet aggregation and some fibrinolytic parameters in healthy persons. The circadian rhythm of platelet aggregation was compared with that of serum lipids in seven healthy male persons. Daily variations of remnant lipoproteins (RLP) were related to those of arachidonic acid (AA)-, ADP- and collagen-induced aggregation in PRP and to ADP-induced whole blood aggregation. These results confirmed in part, preliminary experiments in which an enhancement of whole blood but not of PRP aggregation by RLP was found. The time course of total cholesterol and triglycerides correlated to that of AA- and serotonin (5-HT)-induced aggregation in PRP, respectively. In contrast, HDL did not influence platelet aggregation. In a separate set of experiments, blood was obtained about 1 hour after breakfast from 16 healthy persons. Under these conditions LDL and total cholesterol were related to 5-HT- and ADP-induced aggregation in PRP, but not to t-PA, PAI-1 and ECLT. These fibrinolytic parameters were negatively correlated to HDL, but not to the VLDL level. In conclusion, serum lipids are closely related to platelet activation. In this connection the importance of RLP represents a new aspect. High levels of HDL may be protective against thrombosis due to the enhancement of fibrinolysis. 81. A v a r i a n t of the a n g i o t e n s i n - c o n v e r t i n g
enzyme gene in patients with a history of ischemic stroke M. Margaglione, E. Grandone, G. Vecchione, E. Celentano, G. Cappucci, N. Giuliani, D. Colaizzo, S. Panico, G. Di M i n n o
Clinica Medica, Istituto di Medicina Interna e Malatti Dismetaboliche, Universita" di NapolL and Unita" a Trombosi e AterosclerosL LR.C.C.S. "Casa Sollievo dell Sofferenza" S. Giovanni Rotondo, Italy We have evaluated the genotypes of the angiotensin converting enzyme (ACE) gene in 101 subjects with and 10 subjects without a history of ischemic stroke. All were attending © Pearson Professk~nal Ltd 1996
25
a metabolic ward. The two groups were compared for major risk factors for ischemic events. Genotypes were determined by the polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Deletion polymorphism of the ACE gene (DD genotype) resulted to be more common in subjects with a history of stroke than in those without (relative risk: 1.76, confidence intervals: 1.02-3.05). A positive family history for ischemic complications of atherosclerosis was also more common in subjects with documented events (relative risk: 1.99, confidence intervals: 1.10-3.59). DD genotype and familial history were strong, independent discriminators of cerebral ischemia. Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) help identify subjects with a history of cerebral ischemic episodes. When such fibrinolytic variables were included in the analysis, the DD genotype still strongly and independently discriminated subjects with a stroke history, and significantly interacted with t-PA levels > 10 ng/ml in such identification. We conclude that in subjects attending a metabolic ward, homozygousite for a deletion polymorphism of the ACE gene consistently discriminates subjects with a stroke history. Interaction with t-PA improves such identification.
82. Determinants of plasma plasminogen activator inhibitor-1 antigen in subjects attending a metabolic ward M. Margaglione, E. Celentano, E. Grandone, G. Vecchione, G. Cappucci, F. P. Mancini, G. Di M i n n o
Clinica Medica, Istituto di Medicina Interna e Malattie Dismetaboliche, Universita" "Federico II" di NapolL Unita" di Trombosi e AterosclerosL I.R.C.C.S. "Casa SoEievo della Sofferenza; S. Giovanni Rotondo, and Istituto di Gerontologia e Geriatra, Universita di Palermo, Italy Background: Plasminogen activator inhibitor-1 (PAI-1) is a determinant of vascular events. A guanine insertion/deletion polymorphism (4G/5G) modulates plasma levels of PAI-1. Moreover, the renin-angiotensin system has been reported to affect plasma PAI-1 levels in humans. Methods and Results: All the genotyping was carried out by polymerase chain reaction technique. In 208 subjects attending a metabolic ward, 5G/SG homozygous were associated with plasma PAI-1 levels lower than those of 4G/4G homozygous (29.4 vs 39.0 ng/dl, p=0.036). Plasma PAI-1 correlated with the 4G/5G genotype (p<0.022), and with tissue plasminogen activator (t-PA) and triglycerides levels (p always <0.001), and depended on the 4G/5G genotype (p<0.009) as well as on t-PA and triglycerides (p<0.001). Triglycerides interacted significantly with the 4G/4G and with the 4G/5G genotypes (p=0.013 and 0.036 respectively), but not with the 5G/5G genotype in determining plasma PAI-1 levels. For all PAI-1 genotypes, the DD genotype of ACE gene was associated with mean plasma PAI-1 levels not statistically different from those associated with II genotype. Conclusions: In a group of subjects from a metabolic ward, the 4G/5G polymorphism within the PAI-1 gene locus exerts effects on plasma PAI-1 antigen levels comparable to those of t-PA or triglycerides. The effects of triglycerides on plasma PAI-1 levels is genotype-dependent. Fibrinolysis (1996) 10, SuppL 1, 1-58