Peptide inhibition of neointimal hyperplasia in vein grafts David Calcagno, M D , J o h n V. Conte, M D , Marcus H. Howell, BS, and Marie L. Foegh, M D , Washington D.C. Angiopeptin, a novel synthetic octapeptide, was evaluated as a new approach toward the inhibition of neointimal hyperplasia in vein grafts. Male New Zealand white rabbits (n = 122)underwent carotid artery interposition bypass grafting with autologous reversed jugular vein. Nine rabbits were in the treatment group, and 13 were in the control group. The l~eatment group received angiopeptin 20 l~g/kg/day by subcutaneous injection beginning 1 day before operation and continuing for 3 weeks until they were killed. At death the vein grafts were fixed in situ with 10% buffered formalyn at 80 mm Hg perfusion pressure. Histologic sections through each vein graft were analyzed by computerized morphometric analysis for area of neointimal hyperplasia (ram2). Neointimal hyperplasia in the control animals was 0.080 + 0.017 lm-n2 (mean + SEM), whereas neointimal hyperplasia in the group treated with angiopeptin was 0.022 + 0.006 mm 2 (mean + SEM) ~ = 0.02). This is the first time that peptide inhibition of neointimal hyperplasia has been demonstrated in vein grafts and may have significant implications for future use in vascular surgery. (J VAse Sl3v,~ 1991;13:475-9.)
Thickening of vein grafts when placed in the arterial system has been noted since the work of Carrel and Guthrie in 1906.1 Although this thickening can be an appropriate adaptive response of the vein to the new arterial environment, it can also be a pathologic process resulting in vein graft failure. 2 Clinical prevention of neointimal hyperplasia in peripheral vein grafts by platelet inhibitors or other interventions has never been demonstrated in a prospective trial. 3 Neointimal hyperplasia in these peripheral vein grafts may occur by a mechanism ~nique to vein grafts or by a process similar to neointimal hyperplasia in arteries. Earlier work in our laboratory with successful inhibition of arterial neointimal hyperplasia with a novel octapeptide, angiopeptin, 4-s prompted us to study the effects of angiopeptin on neointimal hyperplasia in vein grafts. METHODS Twenty-two male New Zealand white rabbits (Hazelton Research, Denver, Pa.) weighing 2.5 to Presented at the Society"for Vascular Surgery,VascularForum II, at the Forty-fourthAnnualMeetingof the Societyfor Vascular Surgery, Los Angeles, Calif.,June 6, 1990. Supported in part by National Heart, Lung, and Blood Institute IP40069 and Henri BeaufourInstitute. Reprint requests: David Calcagno,MD, GeorgetownUniversity, Department of Surgery, 3800 ReservoirRd., Washington,DC 20007-2197. 24/1/26866
2.8 kg were randomized to receive angiopeptin (20 ~g/kg/day) or saline by subcutaneous injection in two divided doses. Injections were begun 1 day before operation and continued until the animals were killed. Rabbits were maintained under 12-hour light schedule and fed regular rabbit lab chow diet (No. 5321; Purina Mills, St. Louis, Mo.). All animals were kept in single cages in an accredited facility. The operative procedure was performed under aseptic conditions with ketamine and xylazine anesthesia. The left carotid artery and jugular vein were exposed through a vertical neck incision. The animals were given 1000 units of heparin intravenously, and the jugular vein was reversed and placed as an end-toend interposition graft in the carotid artcry. Anastomoses were performed with 8-0 Prolene suture (Ethicon, Inc. Somerville, N.J.) by means of x 8 magnification. After the third postoperative week animals were again ancsthetized, and the grafts were examined for patency. The animals were killed and the thoracic aorta canulated for in situ perfusion of the carotid vein grafts at 80 mm H g with 10% buffered formalin. The grafts and the adjacent carotid artery segments were removed for histologic sections. Animal care complied with the "Principles of Laboratory Animal Care" and the "Guide for the Care and Use of Laboratory Animals ( N I H Publication No. 80-23, revised 1985). 475
476
Journal of VASCULAR SURGERY
Calcagno et al.
Fig. 1. Histologic sections of (A) control and (B) experimental vein grafts. The area of neointimal hyperplasia is on the luminal side of the internal elastic lamina, which is highlighted by Gomori's stain. (Original magnification × 125.)
Sections were taken from the proximal and distal carotid artery as well as at five regions of the graft (one near each anastomosis and the remaining three along the midportion). The tissues were stained for elastin (Gomori's aldehyde fuchsin method) to demonstrate the internal elastic lamina. Neointimal hyperplasia was defined as the area on the luminal side of the internal elastic lamina. The area of neointimal hyperplasia for each section was determined by use of a digitizing system (The Morphometer, Woods Hole, Mass.) attached to a light microscope at x 100 magnification. Since no difference in neointimal hyperplasia area was found in the proximal, midsection, and distal sections of individual
grafts, these areas were averaged for each graft, and control and experimental groups were compared by use of Student's unpaired t test. RESULTS The operative procedure was performed in 22 rabbits (9 experimental, 13 controls). Four technical failures occurred leaving 7 experimental and 11 control rabbits available for analysis at 3 weeks. Histologic sections of control and experimental grafts are shown in Fig. 1. Neointimal hyperplasia in the control animals was 0.080 + 0.017 m m 2 (mean + SEM), whereas neointimal hyperplasia in the angiopeptin group was 0.022 + 0.006 m m 2
Volume 13 Number 4 April 1991
Inhibition of neointimal hyperplasia in vein grafts
100
80
477
Vein Graft Neointimal Area (lxlo-%m ~ )
H p-O.02
60
40
20
Control n-ll
Angiopeptin n-7
Fig. 2. The area of neointimal hyperplasia was significantly less in the angiopeptin group,
(mean + SEM) (p = 0.02) (Fig. 2). The neointimal hyperplasia did not show a significant predilection for either the proximal or distal anastomatic sites or midportions of the grafts. N o significant neointimal hyperplasia was noted in the arterial segments in either group. DISCUSSION This study showed that angiopeptin, an octapeptide, inhibits neointimal hyperplasia in rabbit carotid vein grafts. N o difference in neointimal hy-perplasia was noted in the proximal, midsection, or distal portions of individual grafts, although this could be due to the short overall graft length. Very little neointimal hyperplasia was found in the proximal and distal artery sites in both the carotid and experimental groups. Neointim~J hyperplasia is a leading cause of vein graft failure. ~ Neointimal hyperplasia has been extensively studied i[n arteries and occurs as smooth muscle cells from the media migrate through the internal elastic lamina and proliferate. Morphologically the lesion ofneointimal hyperplasia is usually disordered without layered architectural organization.9 Narrowing of the vascular lumen by neointimal hyperplasia may- cause stcnosis and perhaps be an early stage of the atherosclerotic plaque/° The carotid vein graft model used in our study was first described by Murday et al. 11 and was
extensively investigated by Zwolak et al. 1~ Zwolak et al. showed that at 1 hour after operation endothefium near the anastomosis was denuded. The endothelial surface was reestablished by 2 weeks. Smooth muscle cell replication was maximal at 1 week and returned to normal at 12 and 24 weeks. After 4 weeks smooth muscle cell mass and deoxyribonucleic acid (DNA) content did not increase. Further increases in graft wall area, which was maximal at 12 weeks, was due to accumulation of connective tissue. 13 Several methods have been used to experimentallyinhibit neointimal hyperplasia in vein grafts. Physical factors that have been studied include vein harvesting techniques and hemodynamic variables. Adcock et a1.14 investigated the role of endothelial preservation in canine carotid grafts using the jugular vein. By altering their harvesting preparation techniques they were able to preserve endothelial cell fining, which resulted in less intimal medial thickening. Dobrin et al. Is in the canine vein grafts model showed that intimal hyperplasia was associated with low flow velocity, a factor correlated with low shear stress. Morinaga et al/6 noted more intimal thickening when canine vein grafts were placed in poor outflow conditions. Several pharmacologic interventions have also been studied. Antiplatelet agents such as aspirin and dipyridamole, which are so widely used clinically, have shown variable results inhibiting neointimal
478
Calcagno et al.
hyperplasia in experimental models. Sarris et al. ~7did not find aspirin alone to be effective in the canine vein graft. However, the combination of aspirin and dipyridamole inhibited neointimal hyperplasia in monkey iliac vein grafts. 18 This drug combination may act through inhibiting lipid deposition in the vascular wall.19 The omega-3 fatty acids are thought to exert their effects through modified eicosanoid synthesis, alteration of lipoprotein metabolism, and alteration of mitogen production by the vessel wall. Several groups have independently demonstrated inhibition of intimal thickening by omega-3 fatty acids in the hypocholesterolemic canine vein graft model. 17,20,21The addition of dipyridamole to the fish oil further decreased the intimal thickness. 21 The success of some of these experimental methods of inhibiting neointimal hyperplasia has not been shown in peripheral vein grafts in any randomized clinical trial. 9 This lack of proven clinical benefit led us to adopt a different approach. Work with angiopeptin inhibition of neointimal hyperplasia in our laboratories has been in arterial models. In a rat carotid air drying model angiopeptin decreased neointimal hyperplasia. This effect was shown in vitro to be through inhibition of smooth muscle cell proliferation. 4"5 In the rabbit balloon injury model angiopeptin also decreased neointimal hyperplasia. 6 In this model angiopeptin was shown in vivo to also inhibit smooth muscle cell proliferation. 7 In the rabbit heart transplant model angiopeptin decreased neointimal hyperplasia in the coronary arteries and aorta,8 The mechanism through which angiopeptin inhibits neointimal hyperplasia is not known, but three theories have evolved from studies in the arterial system. Angiopeptin is a long-acting synthetic analog of somatostatin, which inhibits growth hormone and insulin-like growth factor. Originally it was thought that angiopeptin inhibited neointimal hyperplasia through this mechanism. However, Lundergan et al.4 compared angiopeptin with four other synthetic somatostatin analogs. All analogs showed inhibition of growth hormone release but not all inhibited neointimal hyperplasia, making a somatostatin mediated mechanism unlikely.4 A second possible mechanism is through a direct interaction with vascular smooth muscle cells preventing their proliferation. This mechanism is supported by further in vitro studies of arteries stripped of intima and adventitia, which showed inhibition of smooth muscle cell proliferation by angiopeptin, s A third possibility is an effect through interfering with growth factor receptors or their intracellular expression. In rat smooth
)'ournalof VASCULAR SURGERY
muscle culture angiopeptin resulted in a decrease in angiotension II receptors. Angiotension II is a known mitogen for smooth muscle cells, so angiopeptin may modulate smooth muscle responsiveness to other growth factors by altering receptor expression. 22 These mechanisms remain to be studied in vein grafts. This study indicates that angiopeptin has the same inhibitory effect on neointimal hyperplasia in vein grafts as was seen in several models of arterial neointimal hyperplasia. Although the mechanisms of neointimal hyperplasia formation in vein grafts and arteries is not completely understood, the similar inhibitory effects of angiopeptin may indicate a similar mechanism. The inhibitory effect of angiopeptin on neointimal hyperplasia in vein grafts may find clinical usefulness in maintaining vein graft patency. REFERENCES 1. Carrel A, Guthrie CC. t~esults of the biterminal transplantation of veins. Am J Med Sci 1906;132:415-22. 2. LiCalzi LK, Stensel HC Jr. Failure of autogenous reversed saphenous vein femoropopliteal grafting: pathophysiology and prevention. Surgery 1982;91:352-8. 3. Birinyi LK, LoGerfo FW. Intimal hyperplasia: evolving concepts of pathophysiology and therapy. Perspect Vase Surg 1989;2:97-111. 4. Lundergan C, Foegh ML, Vargas R, et al. Inhibition of myointimal proliferation of the rat carotid artery by the peptides, angiopeptin and BIM 23034. Atherosclerosis 1989; 80:49-55. 5. Vargas R, Bormes GW, Wroblewska B, Foegh ML, Kot PA, Ramwell PW. Angiopeptin inhibits thymidine incorporation in rat carotid artery in vitro. Transplant Proc !989;21: 3702-4. 6. Conte JV, Foegh ML, Calcagno D, Wallace RB, RamwelL PW. Peptide inhibition ofmyointimal proliferation following angioplasty in rabbits. Transplant Proc 1989;21:3686-8. 7. Asotra S, Foegh ML, Conte JV, Cai BR, Ramwell PW. Inhibition of H-thymidine incorporation by angiopeptin in the aorta of rabbits after balloon angioplasty. Transplant Proc 1989;21(4) :3695-6. 8. Foegh ML, Khirabadi BS, Chambers E, l~amwell PW. Peptide inhibition of accelerated transplant atherosclerosis. Transplant Proc 1989;21:3674-6. 9. Faxon DP, Sanborn TA, Weber VJ, et al. Restenosis following transluminal angioplasty in experimental atherosclerosis. Arteriosclerosis 1984;4:189-95. 10. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med 1986;314:488-500. 11. Murday AJ, Gershlick AH, Syndercombe-Court YD, et al. Intimal hyperplasia in arterial autogenous vein grafts: a new animal model. Cardiovasc Res 1983;17:446-51. 12. Zwolak RM, Kirkman TR, Clowes AW. Atherosclerosis in rabbit vein grafts. Arteriosclerosis 1989;9:374-9. 13. Zwolak RM, Adams MC, Clowes AW. Kinetics of vein graft hyperplasia: association with tangential stress. J VAsc SURG 1987;5:]L26-36,
Volume 13 Number 4 April 1991
14. Adcock GD, Adcock OT Jr, Wheeler JR, et al. Arterialization of reversed autogenous vein grafts: quantitative light and electron microscopy of canine jugular vein grafts harvested and implanted by standard or improved techniques. J VAsc SURG 1987;6:283-95. 15. Dobrin PB, Littooy FN, Endear ED. Mechanical factors predisposing to intimal hyperplasia and medial thickening in autogenous vein grafts. Surgery 1989;105:393-400. 16. Morinaga K, Eguchi H, Miyazaki T, Okadome K, Sugimacki K. Development and regression of intimal thickening of arterially transplanted autologons vein grafts in dogs. J VAsc SURG 1987;5:719-30. 17. Sarris GE, Farm JI, Sokoloff MH, et al. Mechanisms responsible for inhibition of vein graft arteriosclerosis by fish-oil. Circulation(Suppl. 1) 1989;80:109-23. 18. McCann RL, Hagen PO, Fuchs JCA. Aspirin and dipyridamole decrease intimal hyperplasia in experimental vein grafts. Ann Surg 1980;191:238-43.
Inhibition of neointimal hyperplasia in vein grafts 479
19. Boerboom LE, Olinger GN, Liu TZ, Rodriguez ER, Ferrans VJ, Kisseboh AH. Histologic, morphometric, and biochemical evolution of vein bypass grafts in a nonhuman primate model. II. Modification of early changes by platelet inhibition with aspirin and dipyridamole. ~ Thorac Cardiovasc Surg 1990;99:107-12. 20. CahiU PD, Sarris GE, Cooper AD, et al. Inhibition of vein graft intimal thickening by cicosapentanoic acid: reduced thromboxane production without change in lipoprotein levels or low-density lipoproteins receptor density. ~ VAsc SURG 1988;7(1):108-18. 21. Landymore RW, Cameron CA, Sheridan BL, MacAuley MA. Reduction of intimal hyperplasia in canine autologous vein grafts with cod-liver oil and dipyridamole. Can J Surg 1986;29:357-8. 22. Diglio CA, Grammas P. In vitro response of vascular smooth muscle cells to angiopeptin. FASEB J 1990;4:393(A334).
Thickening of vein grafts when placed in the arterial system has been noted since the work of Carrel and Guthrie in 1906.1 Although this thickening can be an appropriate adaptive response of the vein to the new arterial environment, it can also be a pathologic process resulting in vein graft failure. 2 Clinical prevention of neointimal hyperplasia in peripheral vein grafts by platelet inhibitors or other interventions has never been demonstrated in a prospective trial. 3 Neointimal hyperplasia in these peripheral vein grafts may occur by a mechanism ~nique to vein grafts or by a process similar to neointimal hyperplasia in arteries. Earlier work in our laboratory with successful inhibition of arterial neointimal hyperplasia with a novel octapeptide, angiopeptin, 4-s prompted us to study the effects of angiopeptin on neointimal hyperplasia in vein grafts. METHODS Twenty-two male New Zealand white rabbits (Hazelton Research, Denver, Pa.) weighing 2.5 to Presented at the Society"for Vascular Surgery,VascularForum II, at the Forty-fourthAnnualMeetingof the Societyfor Vascular Surgery, Los Angeles, Calif.,June 6, 1990. Supported in part by National Heart, Lung, and Blood Institute IP40069 and Henri BeaufourInstitute. Reprint requests: David Calcagno,MD, GeorgetownUniversity, Department of Surgery, 3800 ReservoirRd., Washington,DC 20007-2197. 24/1/26866
2.8 kg were randomized to receive angiopeptin (20 ~g/kg/day) or saline by subcutaneous injection in two divided doses. Injections were begun 1 day before operation and continued until the animals were killed. Rabbits were maintained under 12-hour light schedule and fed regular rabbit lab chow diet (No. 5321; Purina Mills, St. Louis, Mo.). All animals were kept in single cages in an accredited facility. The operative procedure was performed under aseptic conditions with ketamine and xylazine anesthesia. The left carotid artery and jugular vein were exposed through a vertical neck incision. The animals were given 1000 units of heparin intravenously, and the jugular vein was reversed and placed as an end-toend interposition graft in the carotid artcry. Anastomoses were performed with 8-0 Prolene suture (Ethicon, Inc. Somerville, N.J.) by means of x 8 magnification. After the third postoperative week animals were again ancsthetized, and the grafts were examined for patency. The animals were killed and the thoracic aorta canulated for in situ perfusion of the carotid vein grafts at 80 mm H g with 10% buffered formalin. The grafts and the adjacent carotid artery segments were removed for histologic sections. Animal care complied with the "Principles of Laboratory Animal Care" and the "Guide for the Care and Use of Laboratory Animals ( N I H Publication No. 80-23, revised 1985). 475
476
Journal of VASCULAR SURGERY
Calcagno et al.
Fig. 1. Histologic sections of (A) control and (B) experimental vein grafts. The area of neointimal hyperplasia is on the luminal side of the internal elastic lamina, which is highlighted by Gomori's stain. (Original magnification × 125.)
Sections were taken from the proximal and distal carotid artery as well as at five regions of the graft (one near each anastomosis and the remaining three along the midportion). The tissues were stained for elastin (Gomori's aldehyde fuchsin method) to demonstrate the internal elastic lamina. Neointimal hyperplasia was defined as the area on the luminal side of the internal elastic lamina. The area of neointimal hyperplasia for each section was determined by use of a digitizing system (The Morphometer, Woods Hole, Mass.) attached to a light microscope at x 100 magnification. Since no difference in neointimal hyperplasia area was found in the proximal, midsection, and distal sections of individual
grafts, these areas were averaged for each graft, and control and experimental groups were compared by use of Student's unpaired t test. RESULTS The operative procedure was performed in 22 rabbits (9 experimental, 13 controls). Four technical failures occurred leaving 7 experimental and 11 control rabbits available for analysis at 3 weeks. Histologic sections of control and experimental grafts are shown in Fig. 1. Neointimal hyperplasia in the control animals was 0.080 + 0.017 m m 2 (mean + SEM), whereas neointimal hyperplasia in the angiopeptin group was 0.022 + 0.006 m m 2
Volume 13 Number 4 April 1991
Inhibition of neointimal hyperplasia in vein grafts
100
80
477
Vein Graft Neointimal Area (lxlo-%m ~ )
H p-O.02
60
40
20
Control n-ll
Angiopeptin n-7
Fig. 2. The area of neointimal hyperplasia was significantly less in the angiopeptin group,
(mean + SEM) (p = 0.02) (Fig. 2). The neointimal hyperplasia did not show a significant predilection for either the proximal or distal anastomatic sites or midportions of the grafts. N o significant neointimal hyperplasia was noted in the arterial segments in either group. DISCUSSION This study showed that angiopeptin, an octapeptide, inhibits neointimal hyperplasia in rabbit carotid vein grafts. N o difference in neointimal hy-perplasia was noted in the proximal, midsection, or distal portions of individual grafts, although this could be due to the short overall graft length. Very little neointimal hyperplasia was found in the proximal and distal artery sites in both the carotid and experimental groups. Neointim~J hyperplasia is a leading cause of vein graft failure. ~ Neointimal hyperplasia has been extensively studied i[n arteries and occurs as smooth muscle cells from the media migrate through the internal elastic lamina and proliferate. Morphologically the lesion ofneointimal hyperplasia is usually disordered without layered architectural organization.9 Narrowing of the vascular lumen by neointimal hyperplasia may- cause stcnosis and perhaps be an early stage of the atherosclerotic plaque/° The carotid vein graft model used in our study was first described by Murday et al. 11 and was
extensively investigated by Zwolak et al. 1~ Zwolak et al. showed that at 1 hour after operation endothefium near the anastomosis was denuded. The endothelial surface was reestablished by 2 weeks. Smooth muscle cell replication was maximal at 1 week and returned to normal at 12 and 24 weeks. After 4 weeks smooth muscle cell mass and deoxyribonucleic acid (DNA) content did not increase. Further increases in graft wall area, which was maximal at 12 weeks, was due to accumulation of connective tissue. 13 Several methods have been used to experimentallyinhibit neointimal hyperplasia in vein grafts. Physical factors that have been studied include vein harvesting techniques and hemodynamic variables. Adcock et a1.14 investigated the role of endothelial preservation in canine carotid grafts using the jugular vein. By altering their harvesting preparation techniques they were able to preserve endothelial cell fining, which resulted in less intimal medial thickening. Dobrin et al. Is in the canine vein grafts model showed that intimal hyperplasia was associated with low flow velocity, a factor correlated with low shear stress. Morinaga et al/6 noted more intimal thickening when canine vein grafts were placed in poor outflow conditions. Several pharmacologic interventions have also been studied. Antiplatelet agents such as aspirin and dipyridamole, which are so widely used clinically, have shown variable results inhibiting neointimal
478
Calcagno et al.
hyperplasia in experimental models. Sarris et al. ~7did not find aspirin alone to be effective in the canine vein graft. However, the combination of aspirin and dipyridamole inhibited neointimal hyperplasia in monkey iliac vein grafts. 18 This drug combination may act through inhibiting lipid deposition in the vascular wall.19 The omega-3 fatty acids are thought to exert their effects through modified eicosanoid synthesis, alteration of lipoprotein metabolism, and alteration of mitogen production by the vessel wall. Several groups have independently demonstrated inhibition of intimal thickening by omega-3 fatty acids in the hypocholesterolemic canine vein graft model. 17,20,21The addition of dipyridamole to the fish oil further decreased the intimal thickness. 21 The success of some of these experimental methods of inhibiting neointimal hyperplasia has not been shown in peripheral vein grafts in any randomized clinical trial. 9 This lack of proven clinical benefit led us to adopt a different approach. Work with angiopeptin inhibition of neointimal hyperplasia in our laboratories has been in arterial models. In a rat carotid air drying model angiopeptin decreased neointimal hyperplasia. This effect was shown in vitro to be through inhibition of smooth muscle cell proliferation. 4"5 In the rabbit balloon injury model angiopeptin also decreased neointimal hyperplasia. 6 In this model angiopeptin was shown in vivo to also inhibit smooth muscle cell proliferation. 7 In the rabbit heart transplant model angiopeptin decreased neointimal hyperplasia in the coronary arteries and aorta,8 The mechanism through which angiopeptin inhibits neointimal hyperplasia is not known, but three theories have evolved from studies in the arterial system. Angiopeptin is a long-acting synthetic analog of somatostatin, which inhibits growth hormone and insulin-like growth factor. Originally it was thought that angiopeptin inhibited neointimal hyperplasia through this mechanism. However, Lundergan et al.4 compared angiopeptin with four other synthetic somatostatin analogs. All analogs showed inhibition of growth hormone release but not all inhibited neointimal hyperplasia, making a somatostatin mediated mechanism unlikely.4 A second possible mechanism is through a direct interaction with vascular smooth muscle cells preventing their proliferation. This mechanism is supported by further in vitro studies of arteries stripped of intima and adventitia, which showed inhibition of smooth muscle cell proliferation by angiopeptin, s A third possibility is an effect through interfering with growth factor receptors or their intracellular expression. In rat smooth
)'ournalof VASCULAR SURGERY
muscle culture angiopeptin resulted in a decrease in angiotension II receptors. Angiotension II is a known mitogen for smooth muscle cells, so angiopeptin may modulate smooth muscle responsiveness to other growth factors by altering receptor expression. 22 These mechanisms remain to be studied in vein grafts. This study indicates that angiopeptin has the same inhibitory effect on neointimal hyperplasia in vein grafts as was seen in several models of arterial neointimal hyperplasia. Although the mechanisms of neointimal hyperplasia formation in vein grafts and arteries is not completely understood, the similar inhibitory effects of angiopeptin may indicate a similar mechanism. The inhibitory effect of angiopeptin on neointimal hyperplasia in vein grafts may find clinical usefulness in maintaining vein graft patency. REFERENCES 1. Carrel A, Guthrie CC. t~esults of the biterminal transplantation of veins. Am J Med Sci 1906;132:415-22. 2. LiCalzi LK, Stensel HC Jr. Failure of autogenous reversed saphenous vein femoropopliteal grafting: pathophysiology and prevention. Surgery 1982;91:352-8. 3. Birinyi LK, LoGerfo FW. Intimal hyperplasia: evolving concepts of pathophysiology and therapy. Perspect Vase Surg 1989;2:97-111. 4. Lundergan C, Foegh ML, Vargas R, et al. Inhibition of myointimal proliferation of the rat carotid artery by the peptides, angiopeptin and BIM 23034. Atherosclerosis 1989; 80:49-55. 5. Vargas R, Bormes GW, Wroblewska B, Foegh ML, Kot PA, Ramwell PW. Angiopeptin inhibits thymidine incorporation in rat carotid artery in vitro. Transplant Proc !989;21: 3702-4. 6. Conte JV, Foegh ML, Calcagno D, Wallace RB, RamwelL PW. Peptide inhibition ofmyointimal proliferation following angioplasty in rabbits. Transplant Proc 1989;21:3686-8. 7. Asotra S, Foegh ML, Conte JV, Cai BR, Ramwell PW. Inhibition of H-thymidine incorporation by angiopeptin in the aorta of rabbits after balloon angioplasty. Transplant Proc 1989;21(4) :3695-6. 8. Foegh ML, Khirabadi BS, Chambers E, l~amwell PW. Peptide inhibition of accelerated transplant atherosclerosis. Transplant Proc 1989;21:3674-6. 9. Faxon DP, Sanborn TA, Weber VJ, et al. Restenosis following transluminal angioplasty in experimental atherosclerosis. Arteriosclerosis 1984;4:189-95. 10. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med 1986;314:488-500. 11. Murday AJ, Gershlick AH, Syndercombe-Court YD, et al. Intimal hyperplasia in arterial autogenous vein grafts: a new animal model. Cardiovasc Res 1983;17:446-51. 12. Zwolak RM, Kirkman TR, Clowes AW. Atherosclerosis in rabbit vein grafts. Arteriosclerosis 1989;9:374-9. 13. Zwolak RM, Adams MC, Clowes AW. Kinetics of vein graft hyperplasia: association with tangential stress. J VAsc SURG 1987;5:]L26-36,
Volume 13 Number 4 April 1991
14. Adcock GD, Adcock OT Jr, Wheeler JR, et al. Arterialization of reversed autogenous vein grafts: quantitative light and electron microscopy of canine jugular vein grafts harvested and implanted by standard or improved techniques. J VAsc SURG 1987;6:283-95. 15. Dobrin PB, Littooy FN, Endear ED. Mechanical factors predisposing to intimal hyperplasia and medial thickening in autogenous vein grafts. Surgery 1989;105:393-400. 16. Morinaga K, Eguchi H, Miyazaki T, Okadome K, Sugimacki K. Development and regression of intimal thickening of arterially transplanted autologons vein grafts in dogs. J VAsc SURG 1987;5:719-30. 17. Sarris GE, Farm JI, Sokoloff MH, et al. Mechanisms responsible for inhibition of vein graft arteriosclerosis by fish-oil. Circulation(Suppl. 1) 1989;80:109-23. 18. McCann RL, Hagen PO, Fuchs JCA. Aspirin and dipyridamole decrease intimal hyperplasia in experimental vein grafts. Ann Surg 1980;191:238-43.
Inhibition of neointimal hyperplasia in vein grafts 479
19. Boerboom LE, Olinger GN, Liu TZ, Rodriguez ER, Ferrans VJ, Kisseboh AH. Histologic, morphometric, and biochemical evolution of vein bypass grafts in a nonhuman primate model. II. Modification of early changes by platelet inhibition with aspirin and dipyridamole. ~ Thorac Cardiovasc Surg 1990;99:107-12. 20. CahiU PD, Sarris GE, Cooper AD, et al. Inhibition of vein graft intimal thickening by cicosapentanoic acid: reduced thromboxane production without change in lipoprotein levels or low-density lipoproteins receptor density. ~ VAsc SURG 1988;7(1):108-18. 21. Landymore RW, Cameron CA, Sheridan BL, MacAuley MA. Reduction of intimal hyperplasia in canine autologous vein grafts with cod-liver oil and dipyridamole. Can J Surg 1986;29:357-8. 22. Diglio CA, Grammas P. In vitro response of vascular smooth muscle cells to angiopeptin. FASEB J 1990;4:393(A334).
