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Nitrated tyrosine in porcine stented and unstented vein grafts
Tuesday June 27, 2000: Poster Abstracts P: Wl l Restenosis
108 P:Wll
JTuP12Wl1
RESTENOSIS
] Inhibitory effect of TS-962, an acat inhibitor, on intimal
thickening of carotid artery in a rabbit balloon injury model H. Tomoike, Y. Asami, I. Yamagishi, K. Akiyoshi, K. Fukushima. Taisho
Pharmaceutical Co., Ltd., Omiya, Saitama, Japan Objective: To determine the inhibitory effect of TS-962 on intimal thickening caused by ballooning in hyperlipidemic and norrnolipidemic rabbits. Methods: Ballooning of the right common carotid artery of 2-month-old male WHHL and NZW rabbits was performed. TS-962 was added to the diet of WHHL rabbits (n = 4 in each group) for 4 weeks and to the diet of NZW rabbits (n = 9-10 in each group) for 2 weeks after ballooning. For NZW rabbits, pre-medication was given for one week before ballooning. The effects of probucol on WHHL rabbits and tranilast on NZW rabbits were also evaluated. Intimal thickening was evaluated as the intimal/medial area (I/M) ratio. Results: Smooth muscle cell rich-intima featured lipid accumulation in the WHHL rabbits, and TS-962 (0.0003 and 0.003% in the diet) reduced the I/M ratio below that in the control group (0.45 4- 0.19 and 0.38 4- 0.05 vs 1.00 40.23 in the control). The I/M ratio with probucol administration (0.35%) was 0.43 + 0.06. In the normolipidemic NZW rabbits as well, TS-962 (0.0001, 0.0003 and 0.003%) reduced the I/M ratio below that in the control group (0.230 4- 0.055, 0.126 4- 0.028 and 0.145 -4- 0.032 vs 0.279 + 0.039 in the control). The I/M ratio with tranilast administration (0.167%) was 0.184 -40.050. TS-962 induced no change in serum cholesterol level at the end of the study in both WHHL and NZW rabbits. Conclusions: TS-962 inhibited intimal thickening induced by ballooning, in both hyperlipidemic and normolipidemic rabbits. TS-962 may influence cell migration or proliferation associated with intirnal formation independent of its effect on lipid metabolism, and may be effective in preventing arterial restenosis.
TuP3:W11 J Nitrated tyrosine in porcine stented an d unstented vein grafts E Gadsdon, A. Yim, S. Wan, A.C. Newby, G.D. Angelini, J.Y. Jeremy.
Liverpool John Moores University, Liverpool; Division of Cardiothoracic Surgery, The Chinese University of Hong Kong, Department of Cardiac Surgery, University of Bristol, UK Objectives: Peroxynitrite (ONTO) formed by the reaction of nitric oxide (NO) with superoxide (02) may play a role in the aetiology of vein graft failure due to neointima formation. We therefore investigated the distribution and content of nitrated tyrosine (NT: an index of O N t O formation) in porcine vein grafts, with and without external stents (reduces neointima formation). Methods: Saphenous vein-carotid artery interposition grafting was performed in Large White pigs (22-36 kg, n = 8), one graft being externally supported with an oversized Dacron stent. After four weeks the grafts were removed and the distribution of NT and nitric oxide synthase (NOS) established using immunocytochemistry and tissue levels of NT measured with an ELISA. Results: NT was found to be present in large amounts in the adventitia of vein grafts but was mainly concentrated around microvessels which also expressed high levels of both eNOS and iNOS. Absolute NT levels were greater in all regions of stented grafts compared to unstented grafts. Candusinn: Since external stents prevent neointima formation and stented grafts contain greater levels of NT than unstented grafts, these data mitigate against NT as playing a role in vein graft failure. On the contrary, the dense localisation of NT around microvessels points to a role for O N t O in angiogenesis, a mechanism proposed to be axiomatic in mediating the beneficial effect of the external stent.
TuP4:W11 I Elevated C-reactive protein (CRP)after percutaneons transluminal
coronary angioplasty (PTCA) is a predictor
of restenosis S. Morimoto, Y. Fujioka, S. Tsuboi, T. Okumum, M. Masai, J. Tateishi, M. Masutani, T. Iwasaki. Hyogo College of Medicine, Nishinomiya, Japan
I TuP2:W11 ] Genetic risk factors in coronary heart disease (CHD) and reslenosis L. Previato, F. Sandrelli, S. Stefanato, A. Codemo, R. Razzolini I , I. Cortella, S. Martini, C. Gabelli, G. Crepaldi. Clinica Medica 1; 1Dept. of Cardiology,
University of Padua, Italy Introduction: Many different genetic polymorphisms of proteins involved in lipoprotein metabolism, platelet aggregation and coagulation have been pro-posed as risk factors for atherosclerosis. The relevance of these polymorphisms in restenosis after percutaneous coronary interventions remains controversial. Methods: In order to study their role in CHD and restenosis we have analyzed the genetic polymorphisms of platelet glycoprotein fib/Ilia (GplIbfllIa), Angiotensin Converting Enzyme (ACE), MethylenTetraHydrofolate Reductase (MTHRF), coagulation Factor VII (intron 7) and apolipoprotein E (apoE) in an Italian population of 115 CHD subjects (P) with single vessel disease and successful coronary angioplasty; clinical follow-up of this group, including stress test and/or myocardial nuclear scintigraphy and/or coronary angiography, detected restenosis in 51 patients. A group of 117 subjects, randomly selected among the workers of a local factory was also studied as control (C). Results: Frequency distribution of the Gpllb/I/Ia genotype showed a significant difference between C and P (p = 0.0178) and between patients with (R) and without restenosis (NR) (p = 0.0118), with an higher frequency of the PIA2 allele in P and R subjects. ApoE4 had an higher prevalence in P compared with C (p = 0.038), while no difference was observed between R and NR. Difference in the distribution of the Factor VII polimorphysm approached statistical significan-ce (p = 0.067) in comparison between R and NR only. We observed no difference in ACE and MTHFR polymorphism distribution in any of the groups analyzed. Conclusions: These results confirm the suggested role of Gpllb/llIa and apoE genetic variations as risk factors in CHD while only GplIb/IIIa polymorphism shows a relationship with the restenosis process.
Objective: Recent evidences support that C-reactive protein (CRP) might be a candidate of risk factors of coronary artery disease. CRP and fibrinogen are acute-phase reactants induced by inflammatory processes, which is associated with cell proliferation. We studied if elevation of CRP in intervention of acute myocardial infarction or unstable angina can be related to restenosis after PTCA. Methods: We selected 25 patients with restenosis (R) and 25 patients without restenosis (NR) found at six months after the urgent PTCA. In all patients, Serum CRP and fibrinogen levels were measured everyday in a week after the urgent PTCA. Results: Summation of CRP values of initial 7 days (ECRP) in R was significantly higher that in NR (p < 0.05). Taking 20 mg/dl as a cutoff point, the risk ratio for restenosis of ECRP >__20 mg/dl was 8.07 (95%CI 1.04-62.49, p < 0.05). On the other hand, there was no difference in ,UFib between NR and R. Peak values of CRP and fibrinogen were observed at 3rd or 4th day after intervention. Taking 10 mg/dl for peakCRP or 450 mg/dl for peakFib as a cutoff point, the risk ratio of peakCRP > 10 mg/dl for restenosis was 3.50 (95%CI 1.02-11.96, p < 0.05) or that of peakFib > 450 mg/dl was 4.71 (95%CI 1.05-21.27, p < 0.05). The ratio of peakCRP > 10 mg/dl combined with peakFib > 450 mg/dl was 3.94 (95%CI 1.08-14.32, p < 0.05). Conclusions: Persistent elevation of CRP and fibrinogen levels in acute phase could be powerful predictors of late restenosis after the urgent PTCA.
TuP5:W11 J Homocysteine, copper and caeruloplnsmin in patients undergoing coronary artery bypass graft surgery J.Y. Jeremy, A. Lotto, A. Day, N. Shalda, R. Ascione, I. Wan, D. Stansbie, G.D. Angelini. Departments of Cardiac Surgery and Chemical Pathology,
Bristol Royal Infirmary, Bristol, UK Objective: Copper (Cu) and the Cu-binding protein, caemloplasmin (CP) augment the generation of superoxide (02) from homocysteine (HC). O 2 is proatherogenic through several mechanisms, including the negation of NO bioactivity via formation of peroxynitrite. In turn, impaired NO formation has been implicated in graft failure following coronary artery bypass graft surgery (CABG). The plasma concentrations of HC, Cu and CP were therefore measured in patients undergoing CABG. Methods: Blood was taken from 12 patients undergoing CABG before and after surgery and plasma levels of Cu, CP and HC measured.
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000
108 P:Wll
JTuP12Wl1
RESTENOSIS
] Inhibitory effect of TS-962, an acat inhibitor, on intimal
thickening of carotid artery in a rabbit balloon injury model H. Tomoike, Y. Asami, I. Yamagishi, K. Akiyoshi, K. Fukushima. Taisho
Pharmaceutical Co., Ltd., Omiya, Saitama, Japan Objective: To determine the inhibitory effect of TS-962 on intimal thickening caused by ballooning in hyperlipidemic and norrnolipidemic rabbits. Methods: Ballooning of the right common carotid artery of 2-month-old male WHHL and NZW rabbits was performed. TS-962 was added to the diet of WHHL rabbits (n = 4 in each group) for 4 weeks and to the diet of NZW rabbits (n = 9-10 in each group) for 2 weeks after ballooning. For NZW rabbits, pre-medication was given for one week before ballooning. The effects of probucol on WHHL rabbits and tranilast on NZW rabbits were also evaluated. Intimal thickening was evaluated as the intimal/medial area (I/M) ratio. Results: Smooth muscle cell rich-intima featured lipid accumulation in the WHHL rabbits, and TS-962 (0.0003 and 0.003% in the diet) reduced the I/M ratio below that in the control group (0.45 4- 0.19 and 0.38 4- 0.05 vs 1.00 40.23 in the control). The I/M ratio with probucol administration (0.35%) was 0.43 + 0.06. In the normolipidemic NZW rabbits as well, TS-962 (0.0001, 0.0003 and 0.003%) reduced the I/M ratio below that in the control group (0.230 4- 0.055, 0.126 4- 0.028 and 0.145 -4- 0.032 vs 0.279 + 0.039 in the control). The I/M ratio with tranilast administration (0.167%) was 0.184 -40.050. TS-962 induced no change in serum cholesterol level at the end of the study in both WHHL and NZW rabbits. Conclusions: TS-962 inhibited intimal thickening induced by ballooning, in both hyperlipidemic and normolipidemic rabbits. TS-962 may influence cell migration or proliferation associated with intirnal formation independent of its effect on lipid metabolism, and may be effective in preventing arterial restenosis.
TuP3:W11 J Nitrated tyrosine in porcine stented an d unstented vein grafts E Gadsdon, A. Yim, S. Wan, A.C. Newby, G.D. Angelini, J.Y. Jeremy.
Liverpool John Moores University, Liverpool; Division of Cardiothoracic Surgery, The Chinese University of Hong Kong, Department of Cardiac Surgery, University of Bristol, UK Objectives: Peroxynitrite (ONTO) formed by the reaction of nitric oxide (NO) with superoxide (02) may play a role in the aetiology of vein graft failure due to neointima formation. We therefore investigated the distribution and content of nitrated tyrosine (NT: an index of O N t O formation) in porcine vein grafts, with and without external stents (reduces neointima formation). Methods: Saphenous vein-carotid artery interposition grafting was performed in Large White pigs (22-36 kg, n = 8), one graft being externally supported with an oversized Dacron stent. After four weeks the grafts were removed and the distribution of NT and nitric oxide synthase (NOS) established using immunocytochemistry and tissue levels of NT measured with an ELISA. Results: NT was found to be present in large amounts in the adventitia of vein grafts but was mainly concentrated around microvessels which also expressed high levels of both eNOS and iNOS. Absolute NT levels were greater in all regions of stented grafts compared to unstented grafts. Candusinn: Since external stents prevent neointima formation and stented grafts contain greater levels of NT than unstented grafts, these data mitigate against NT as playing a role in vein graft failure. On the contrary, the dense localisation of NT around microvessels points to a role for O N t O in angiogenesis, a mechanism proposed to be axiomatic in mediating the beneficial effect of the external stent.
TuP4:W11 I Elevated C-reactive protein (CRP)after percutaneons transluminal
coronary angioplasty (PTCA) is a predictor
of restenosis S. Morimoto, Y. Fujioka, S. Tsuboi, T. Okumum, M. Masai, J. Tateishi, M. Masutani, T. Iwasaki. Hyogo College of Medicine, Nishinomiya, Japan
I TuP2:W11 ] Genetic risk factors in coronary heart disease (CHD) and reslenosis L. Previato, F. Sandrelli, S. Stefanato, A. Codemo, R. Razzolini I , I. Cortella, S. Martini, C. Gabelli, G. Crepaldi. Clinica Medica 1; 1Dept. of Cardiology,
University of Padua, Italy Introduction: Many different genetic polymorphisms of proteins involved in lipoprotein metabolism, platelet aggregation and coagulation have been pro-posed as risk factors for atherosclerosis. The relevance of these polymorphisms in restenosis after percutaneous coronary interventions remains controversial. Methods: In order to study their role in CHD and restenosis we have analyzed the genetic polymorphisms of platelet glycoprotein fib/Ilia (GplIbfllIa), Angiotensin Converting Enzyme (ACE), MethylenTetraHydrofolate Reductase (MTHRF), coagulation Factor VII (intron 7) and apolipoprotein E (apoE) in an Italian population of 115 CHD subjects (P) with single vessel disease and successful coronary angioplasty; clinical follow-up of this group, including stress test and/or myocardial nuclear scintigraphy and/or coronary angiography, detected restenosis in 51 patients. A group of 117 subjects, randomly selected among the workers of a local factory was also studied as control (C). Results: Frequency distribution of the Gpllb/I/Ia genotype showed a significant difference between C and P (p = 0.0178) and between patients with (R) and without restenosis (NR) (p = 0.0118), with an higher frequency of the PIA2 allele in P and R subjects. ApoE4 had an higher prevalence in P compared with C (p = 0.038), while no difference was observed between R and NR. Difference in the distribution of the Factor VII polimorphysm approached statistical significan-ce (p = 0.067) in comparison between R and NR only. We observed no difference in ACE and MTHFR polymorphism distribution in any of the groups analyzed. Conclusions: These results confirm the suggested role of Gpllb/llIa and apoE genetic variations as risk factors in CHD while only GplIb/IIIa polymorphism shows a relationship with the restenosis process.
Objective: Recent evidences support that C-reactive protein (CRP) might be a candidate of risk factors of coronary artery disease. CRP and fibrinogen are acute-phase reactants induced by inflammatory processes, which is associated with cell proliferation. We studied if elevation of CRP in intervention of acute myocardial infarction or unstable angina can be related to restenosis after PTCA. Methods: We selected 25 patients with restenosis (R) and 25 patients without restenosis (NR) found at six months after the urgent PTCA. In all patients, Serum CRP and fibrinogen levels were measured everyday in a week after the urgent PTCA. Results: Summation of CRP values of initial 7 days (ECRP) in R was significantly higher that in NR (p < 0.05). Taking 20 mg/dl as a cutoff point, the risk ratio for restenosis of ECRP >__20 mg/dl was 8.07 (95%CI 1.04-62.49, p < 0.05). On the other hand, there was no difference in ,UFib between NR and R. Peak values of CRP and fibrinogen were observed at 3rd or 4th day after intervention. Taking 10 mg/dl for peakCRP or 450 mg/dl for peakFib as a cutoff point, the risk ratio of peakCRP > 10 mg/dl for restenosis was 3.50 (95%CI 1.02-11.96, p < 0.05) or that of peakFib > 450 mg/dl was 4.71 (95%CI 1.05-21.27, p < 0.05). The ratio of peakCRP > 10 mg/dl combined with peakFib > 450 mg/dl was 3.94 (95%CI 1.08-14.32, p < 0.05). Conclusions: Persistent elevation of CRP and fibrinogen levels in acute phase could be powerful predictors of late restenosis after the urgent PTCA.
TuP5:W11 J Homocysteine, copper and caeruloplnsmin in patients undergoing coronary artery bypass graft surgery J.Y. Jeremy, A. Lotto, A. Day, N. Shalda, R. Ascione, I. Wan, D. Stansbie, G.D. Angelini. Departments of Cardiac Surgery and Chemical Pathology,
Bristol Royal Infirmary, Bristol, UK Objective: Copper (Cu) and the Cu-binding protein, caemloplasmin (CP) augment the generation of superoxide (02) from homocysteine (HC). O 2 is proatherogenic through several mechanisms, including the negation of NO bioactivity via formation of peroxynitrite. In turn, impaired NO formation has been implicated in graft failure following coronary artery bypass graft surgery (CABG). The plasma concentrations of HC, Cu and CP were therefore measured in patients undergoing CABG. Methods: Blood was taken from 12 patients undergoing CABG before and after surgery and plasma levels of Cu, CP and HC measured.
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000