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The functional state of the hemostasis system in traumatologic and orthopedic patients with atherosclerosis
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Korshunov
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THE FUNCTIONAL STATE OF THE HEMOSTASIS SYSTEM IN TRAUMATOLOGIC AND ORTHOPEDIC PATIENTS W I T H ATHEROSCLEROSIS
G.V. Korshunov, D.M. Puchinyan, A.G. Korshunov, L.O. Khvichiya, I.V. Matasova, S.I. Yaroshevskaya, S.G. Shahmartova. The Scientific
rise of vascular endothelium thromboresistance. The synthesis and secretion of prostacyclin, At-III and Pg activators increased. The fetal therapy effect lasts a year. ~]
Research Institute of Traumatology and Orthopedics, Saratov, Russia 436 patients aged from 45 to 79 with locomotor system pathology and with atherosclerosis in anamnesis were examined in preoperative and postoperative periods for theologic properties comparing different approaches to the following hemostasis system functional state parametrs. The aggregative properties of thrombocytes were investigated using aggregants (ADF, ristomycin) and theological properties of citrated blood (rotational viscosimeter AKR-2, Moscow, Russia) at shift rates from 10 to 300 s-1 with calculation of erythrocyte aggregation index and index of erythrocyte deformity. We identificed the total coagulation activity using automated electrocoagulography (Korshunov G.V. et al., 1999) in citrated blood and plasma. The findings were processed by means of program package 'Statgraphics' (version 2.6) using variational statistic methods, factor correlation and cluster analysis. The outcomes of investigation suggested the adaptive changes were exposed in 10%, disadaptation states in 47%, latent form of DIC syndrome in 33% and acute form DIC syndrome in 10% of patients. The studies show that the presence of atherosclerosis in traumatologic and orthopedic patients increases significantly risk of thromboembolic complications development in postoperative period. ~]
MAPPING OF QUANTITATIVE TRAIT LOCI INVOLVED IN ATHEROSCLEROSIS IN THE MOUSE
R. Korstan[e, R. Li, G. Churchill, B. Paigen. The Jackson Laboratory, Bar
Harbor, ME, USA In the past decade, we identified, mapped, and named five quantitative trait loci (QTL) associated with atherosclerosis in female mice: Athl, Ath2, Ath6, Ath7, and Ath9. We recently mapped Ath8, a locus involved in the difference in atherosclerosis susceptibility between the susceptible SM/J and the resistant NZB/B1NJ strains, to chromosome 4 using a small backcross. To narrow the region we generated an F2 intercross. All 515 F2 progeny (males and females) were phenotyped for a large number of traits including atherosclerotic lesions and genotyped for more than 100 DNA markers across the genome. Using this cross and an additional recombinant strain segregation test (RIST), we confirmed the QTL on chromosome 4 in female mice and narrowed the Ath8 region to 3.8 cM. Furthermore, we identified two new QTL in male mice. The first QTL is on the distal end of chromosome 3 near marker D3Mit147 with a LOD score of 4.0. The second QTL is on the distal end of chromosome 11 near marker D11Mitl 1 with a LOD score of 4.1 and has the gene for angiotensin converting enzyme (Ace) as the most important candidate gene. We are currently performing gene expression analyses (using microarrays and RT-PCR) to study the candidate genes in these regions. ~35-~ FETAL THERAPY EFFECT ON THE HEMOSTASIS CORRECTION L. Koryakina, V. Marchenko, L. Zubareva, A. Runovich. Center of
Reconstructive Surgery, Irkutsk, Russia We present the results of studying the hemostasis potential in different alloand xenogenic tissues, effect of fetal tissue transplantation on hemostasis system of patients with coronary atheroclerosis (CA). Protrombin complex, antithrombin-III (At-III), plasminogen (Pg), fibrinogen (Fg), and factor XIII were detected in cellular suspension of embryonic tissues at 18 20 week gestation and in the tissues of newborn rabbits. It was stated that concentration of blood coagulation factors in human embryonic tissues and newborn rabbits was lower than in the adults. In human embryonic tissues Fg was 0.4-0.6 g/l, At-III, activin 22.502%, Pg - 5.1~.3%. Incubation of various fetal tissue extracts with CA patients plasma the level of Pg was 120%, factor XIII - 85%, proconvertin - 90%. Following the incubation Pg concentration increased to 231%, proconvertin to 250%, factor XIII lowered to 37%. We studied the influence of fetal heart, liver, and placenta tissue transplantation on the hemostasis system in CA patients. The examination was performed dynamycally prior to fetal tissue transplantation and during 1-year follow-up. The examination of hemostasis system included the severity of thrombocyte aggregation disorders, vascular entothelium thromboresistance that is the capability of vessel wall to synthesize prostacyclin, At-III and Pg activators. The study showed that in ischemic patients the transplantation resulted in the
INFLUENCE OF IRBESARTAN ON PLASMA CONCENTRATIONS OF ADHESION MOLECULES AND CHEMOKINES IN CORONARY HEART DISEASE W I T H DOCUMENTED CORONARY ATHEROSCLEROSIS
I.V. Korzh. Kharkov Medical University, Kharkov, Ukraine
Objective: To evaluate the effect of angiotensin II receptor antagonist irbesartan on plasma concentrations of intercellular adhesion molecule-1 (ICAM-1) and monocytes chemoattractant peptide-1 (MCP-1) in patients with coronary heart disease (CItD). Methods: 78 patients with CItD (angiographic luminal narrowing >50% or history of myocardial infarction) were treated with irbesartan (150 mg/day) for 8 weeks. Plasma levels of ICAM-1 and MCP-1 were measured by the ELISA method. The control group included 35 age-matched healthy volunteers. Results: The concentration of ICAM-1 at the onset of the study was higher in patients with CItD than in the control group (389±21 ng/ml; p<0.01). After irbesartan treatment it decreased significantly to level 324±25 ng/ml; p<0.05). MCP-1 was significantly higher in CItD comparing to the control group (p<0.05). MCP-1 level in patients with CItD was 172±13 pg/ml and gained to 134±11 (p<0.05) after treatment with irbesartan. It has been found that change of MCP-1 level in irbesartan treatment was correlated with diastolic blood pressure (r-+0.42; p<0,05). Conclusions: These results show that in patients with coronary atherosclerosis verified angiography the increase the plasma adhesion molecules and chemokines occur. Treatment with irbesartan has a tendency to normalise enhanced levels of ICAM-1 and MCP-1 and that is the further advantage of this drug.
~3ff~ THE INFLUENCE OF LIPID-LOWERING TREATMENT ON NITRIC OXIDE SYNTHESIS IN ENDOTHELIAL CELLS I.V. Korzh. Kharkov Medical University, Kharkov, Ukraine Endothelial-derived nitric oxide (NO) is produced by constitutive NO synthase (cNOS) and inhibits platelet activation via a cGMP-dependent mechanism. Loss of endothelial NO plays an important role in the vascular response to injury with increased platelet adhesion, aggregation, and subsequent mitogen release. The aim of this study was to investigate the effect of simvastatin on calcium-dependent NO production in human umbilical vein endothelial cells (HUVEC). Methods: NO generation after ionomycin stimulation of HUVEC (2 mM, 15 min) was detected as formation of citrulline from labelled L-arginine and as accumulation of intracellular cGMP. In addition, the activity of the cNOS was measured in HUVEC lysates as calcium-dependent citrulline production from L-[3H]-arginine. Results: Basal citrulline production was 0,3±0,37 pmol/mirl/mg protein and cGMP levels in resting cells were 0,54±0,45 pmol/106 cells. Pretreatment of HUVEC with simvastatin (0,1 100 mM, 24 hours) potentiated ionomycin-stimulated citrulline- and cGMP-formation in a dose-dependent manner (100 mM: 3 to 4 fold increase with both parameters). Accordingly, cNOS in lysates from simvastatin-pretreated cells showed up to 4 fold higher activity. Conclusions: The enhancing effect on citrulline formation and cNOS activity indicates that simvastatin restores effective NO release not only by normalization of lipid metabolism but also by an increase of endothelial cNOS activity. The potentiating effect of simvastatin on calcium-induced NO formation might protect endothelial cells from the development of dysfunction and could explain other beneficial effects of the compound. ~-~
ROLE OF PRO-INFLAMMATORY CYTOKINES AND ENDOTHELIAL DYSFUNCTION IN PATIENTS W I T H ANGIOGRAFICALLY PROVED CORONARY ATHEROSCLEROSIS
O.M. Korzh. Ukrainian National Academy of Pharmacy, Kharkov, Ukraine
Objective: To assess role immune mechanisms in the development of endothelial dysfunction in patients with coronary artery disease (CAD) with proven coronary atherosclerosis.
73rd EAS Congress
•
Korshunov
3
]
THE FUNCTIONAL STATE OF THE HEMOSTASIS SYSTEM IN TRAUMATOLOGIC AND ORTHOPEDIC PATIENTS W I T H ATHEROSCLEROSIS
G.V. Korshunov, D.M. Puchinyan, A.G. Korshunov, L.O. Khvichiya, I.V. Matasova, S.I. Yaroshevskaya, S.G. Shahmartova. The Scientific
rise of vascular endothelium thromboresistance. The synthesis and secretion of prostacyclin, At-III and Pg activators increased. The fetal therapy effect lasts a year. ~]
Research Institute of Traumatology and Orthopedics, Saratov, Russia 436 patients aged from 45 to 79 with locomotor system pathology and with atherosclerosis in anamnesis were examined in preoperative and postoperative periods for theologic properties comparing different approaches to the following hemostasis system functional state parametrs. The aggregative properties of thrombocytes were investigated using aggregants (ADF, ristomycin) and theological properties of citrated blood (rotational viscosimeter AKR-2, Moscow, Russia) at shift rates from 10 to 300 s-1 with calculation of erythrocyte aggregation index and index of erythrocyte deformity. We identificed the total coagulation activity using automated electrocoagulography (Korshunov G.V. et al., 1999) in citrated blood and plasma. The findings were processed by means of program package 'Statgraphics' (version 2.6) using variational statistic methods, factor correlation and cluster analysis. The outcomes of investigation suggested the adaptive changes were exposed in 10%, disadaptation states in 47%, latent form of DIC syndrome in 33% and acute form DIC syndrome in 10% of patients. The studies show that the presence of atherosclerosis in traumatologic and orthopedic patients increases significantly risk of thromboembolic complications development in postoperative period. ~]
MAPPING OF QUANTITATIVE TRAIT LOCI INVOLVED IN ATHEROSCLEROSIS IN THE MOUSE
R. Korstan[e, R. Li, G. Churchill, B. Paigen. The Jackson Laboratory, Bar
Harbor, ME, USA In the past decade, we identified, mapped, and named five quantitative trait loci (QTL) associated with atherosclerosis in female mice: Athl, Ath2, Ath6, Ath7, and Ath9. We recently mapped Ath8, a locus involved in the difference in atherosclerosis susceptibility between the susceptible SM/J and the resistant NZB/B1NJ strains, to chromosome 4 using a small backcross. To narrow the region we generated an F2 intercross. All 515 F2 progeny (males and females) were phenotyped for a large number of traits including atherosclerotic lesions and genotyped for more than 100 DNA markers across the genome. Using this cross and an additional recombinant strain segregation test (RIST), we confirmed the QTL on chromosome 4 in female mice and narrowed the Ath8 region to 3.8 cM. Furthermore, we identified two new QTL in male mice. The first QTL is on the distal end of chromosome 3 near marker D3Mit147 with a LOD score of 4.0. The second QTL is on the distal end of chromosome 11 near marker D11Mitl 1 with a LOD score of 4.1 and has the gene for angiotensin converting enzyme (Ace) as the most important candidate gene. We are currently performing gene expression analyses (using microarrays and RT-PCR) to study the candidate genes in these regions. ~35-~ FETAL THERAPY EFFECT ON THE HEMOSTASIS CORRECTION L. Koryakina, V. Marchenko, L. Zubareva, A. Runovich. Center of
Reconstructive Surgery, Irkutsk, Russia We present the results of studying the hemostasis potential in different alloand xenogenic tissues, effect of fetal tissue transplantation on hemostasis system of patients with coronary atheroclerosis (CA). Protrombin complex, antithrombin-III (At-III), plasminogen (Pg), fibrinogen (Fg), and factor XIII were detected in cellular suspension of embryonic tissues at 18 20 week gestation and in the tissues of newborn rabbits. It was stated that concentration of blood coagulation factors in human embryonic tissues and newborn rabbits was lower than in the adults. In human embryonic tissues Fg was 0.4-0.6 g/l, At-III, activin 22.502%, Pg - 5.1~.3%. Incubation of various fetal tissue extracts with CA patients plasma the level of Pg was 120%, factor XIII - 85%, proconvertin - 90%. Following the incubation Pg concentration increased to 231%, proconvertin to 250%, factor XIII lowered to 37%. We studied the influence of fetal heart, liver, and placenta tissue transplantation on the hemostasis system in CA patients. The examination was performed dynamycally prior to fetal tissue transplantation and during 1-year follow-up. The examination of hemostasis system included the severity of thrombocyte aggregation disorders, vascular entothelium thromboresistance that is the capability of vessel wall to synthesize prostacyclin, At-III and Pg activators. The study showed that in ischemic patients the transplantation resulted in the
INFLUENCE OF IRBESARTAN ON PLASMA CONCENTRATIONS OF ADHESION MOLECULES AND CHEMOKINES IN CORONARY HEART DISEASE W I T H DOCUMENTED CORONARY ATHEROSCLEROSIS
I.V. Korzh. Kharkov Medical University, Kharkov, Ukraine
Objective: To evaluate the effect of angiotensin II receptor antagonist irbesartan on plasma concentrations of intercellular adhesion molecule-1 (ICAM-1) and monocytes chemoattractant peptide-1 (MCP-1) in patients with coronary heart disease (CItD). Methods: 78 patients with CItD (angiographic luminal narrowing >50% or history of myocardial infarction) were treated with irbesartan (150 mg/day) for 8 weeks. Plasma levels of ICAM-1 and MCP-1 were measured by the ELISA method. The control group included 35 age-matched healthy volunteers. Results: The concentration of ICAM-1 at the onset of the study was higher in patients with CItD than in the control group (389±21 ng/ml; p<0.01). After irbesartan treatment it decreased significantly to level 324±25 ng/ml; p<0.05). MCP-1 was significantly higher in CItD comparing to the control group (p<0.05). MCP-1 level in patients with CItD was 172±13 pg/ml and gained to 134±11 (p<0.05) after treatment with irbesartan. It has been found that change of MCP-1 level in irbesartan treatment was correlated with diastolic blood pressure (r-+0.42; p<0,05). Conclusions: These results show that in patients with coronary atherosclerosis verified angiography the increase the plasma adhesion molecules and chemokines occur. Treatment with irbesartan has a tendency to normalise enhanced levels of ICAM-1 and MCP-1 and that is the further advantage of this drug.
~3ff~ THE INFLUENCE OF LIPID-LOWERING TREATMENT ON NITRIC OXIDE SYNTHESIS IN ENDOTHELIAL CELLS I.V. Korzh. Kharkov Medical University, Kharkov, Ukraine Endothelial-derived nitric oxide (NO) is produced by constitutive NO synthase (cNOS) and inhibits platelet activation via a cGMP-dependent mechanism. Loss of endothelial NO plays an important role in the vascular response to injury with increased platelet adhesion, aggregation, and subsequent mitogen release. The aim of this study was to investigate the effect of simvastatin on calcium-dependent NO production in human umbilical vein endothelial cells (HUVEC). Methods: NO generation after ionomycin stimulation of HUVEC (2 mM, 15 min) was detected as formation of citrulline from labelled L-arginine and as accumulation of intracellular cGMP. In addition, the activity of the cNOS was measured in HUVEC lysates as calcium-dependent citrulline production from L-[3H]-arginine. Results: Basal citrulline production was 0,3±0,37 pmol/mirl/mg protein and cGMP levels in resting cells were 0,54±0,45 pmol/106 cells. Pretreatment of HUVEC with simvastatin (0,1 100 mM, 24 hours) potentiated ionomycin-stimulated citrulline- and cGMP-formation in a dose-dependent manner (100 mM: 3 to 4 fold increase with both parameters). Accordingly, cNOS in lysates from simvastatin-pretreated cells showed up to 4 fold higher activity. Conclusions: The enhancing effect on citrulline formation and cNOS activity indicates that simvastatin restores effective NO release not only by normalization of lipid metabolism but also by an increase of endothelial cNOS activity. The potentiating effect of simvastatin on calcium-induced NO formation might protect endothelial cells from the development of dysfunction and could explain other beneficial effects of the compound. ~-~
ROLE OF PRO-INFLAMMATORY CYTOKINES AND ENDOTHELIAL DYSFUNCTION IN PATIENTS W I T H ANGIOGRAFICALLY PROVED CORONARY ATHEROSCLEROSIS
O.M. Korzh. Ukrainian National Academy of Pharmacy, Kharkov, Ukraine
Objective: To assess role immune mechanisms in the development of endothelial dysfunction in patients with coronary artery disease (CAD) with proven coronary atherosclerosis.
73rd EAS Congress