Eur J Vasc Surg 6, 343-345 (1992)
LEADING ARTICLE Intimal Hyperplasia M, K. O'Malley Charing Cross and Westminster Medical School, Fulham Palace Road, London W6 8RF, U.K.
The persistent expansion of cytological and molecular cardiovascular research has attracted the interest of vascular surgeons over the last decade in particular. Prior to this there were more compelling technical and diagnostic problems relating to the clinical practice of vascular surgery. However, as the indications for surgery and surgical techniques have become somewhat standardised the emphasis has switched to the pathogenesis of peripheral vascular disease, the interaction of the bloodstream with the vessel wall and especially the prevention of recurrent stenosis. It is now apparent that any form of endothelial trauma will produce a thickened neointima as part of the healing response. This process, known as intimal hyperplasia, is seen following vascular reconstruction, balloon angioplasty, organ transplantation, angiography, vascular access and atherectomy and a recent study suggests that it may be the single most significant factor affecting long-term patency. 1 The essential feature of intimal hyperplasia is vascular smooth muscle cell proliferation which occurs following migration from the media. This should probably be thought of as the vessel wall's natural reparative response to trauma but often it will continue unchecked giving rise to clearly harmful side effects. There is evidence to suggest that the extent of the hyperplastic response is related to the severity of the injury but while there is a considerable amount of information regarding the onset of this process, very little is known about how it stops. Furthermore, there is surprisingly little known about the natural history of intimal hyperplasia in man but it is known that it may progress for up to 2 years. On the other hand, after an initial period of proliferation, it may actually regress. Its duration is of more than academic interest as recurrent stenosis Please address all correspondenceto: M. K. O'Malley,Department of Surgery, Mater MisericordiaeHospital, EcclesStreet, Dublin 7, Republic of Ireland. 0950-821X/92/040343+ 03 $03.00/0© 1992Grune & StrattonLtd.
within 2 years is likely to be due to intimal hyperplasia at the site of reconstruction, whereas a longer interval suggests progressive atherosclerosis usually in the distal vessels but also possibly in the inflow tract. This is not to say that intimal hyperplasia and atherosclerosis are unrelated as there is strong experimental evidence to show that the development of intimal hyperplasia following endothelial denudation predisposes to lipid incorporation in the vessel wall and the formation of an atherosclerotic plaque. 2 It has to be appreciated that neointimal hyperplasia occurs at different sites following different procedures but will not always have the same sequelae. After coronary angioplasty there is a 35% restenosis rate at 6 months and most of these patients have recurrent symptoms, 3 while in a recent consecutive series of infrainguinal vein bypass grafts 42% required subsequent revision because of intimal hyperplasia. ~ However, although approximately 10% of patients develop restenosis within 12 months of carotid endarterectomy, there is an extremely low incidence of recurrent symptoms. 4 This highlights the fact that most extracranial cerebrovascular transient ischaemic attacks (TIAs) are due to embolic episodes rather than haemodynamic factors as the recurrent stenosis presents a smooth uniform luminal surface. It is inappropriate, however, to think of intimal hyperplasia as a purely mechanical obstruction. When it is considered that the vessel wall has lost its normal endothelial layer, at least transiently, and that the vascular smooth muscle cells are transformed from a quiescent state to a proliferative phase, it is not surprising that many normal physiological functions of the vessel wall are also altered. To appreciate this further it is helpful to look at the pathogenesis of smooth muscle cell proliferation. Following endothelial denudation the internal elastic lamina is exposed to the bloodstream and immediately attracts platelets which form aggregates
344
M.K. O'Malley
together with erythrocytes, monocytes and neutrophils. In a rabbit model the first evidence of a regenerating intima is seen within 3-5 days. By the 8th day several layers of smooth muscle cells are seen on the luminal side of the internal elastic lamina and this proliferation continues for up to 4 weeks after the trauma. Any further increase in the intimal thickening is due to the deposition of matrix between the smooth muscle cells.S In the human this process takes considerably longer and it is generally thought that the neointimal thickening may continue to increase for up to two years. Following a number of important studies from Ross's group the central role of the platelet was highlighted. 6 It was suggested that the platelet secretes a growth factor (PDGF) following adherence to the internal elastic lamina and that this growth factor promotes smooth muscle cell migration and proliferation. However, continuing studies from this and other groups have shown that the situation is a lot more complex. It is now known that other cells, including endothelial cells, macrophages and smooth muscle cells, can also produce PDGF. It has also been shown that there are many other growth factors which may at least contribute to the smooth muscle cell proliferation including transforming growth factors alpha and beta, interleukin-1, macrophage derived growth factor and, most recently, fibroblast growth factor.7 Furthermore, it is apparent that there are also naturally occurring smooth muscle cell inhibitors such as heparin, interferon gamma and PGE-1 which presumably exist in balance with the smooth muscle cell growth factors~ When it is also considered that shear stress on the vessel wall, altered compliance and blood flow rates may be integral to the development of intimal hyperplasia and that certain dietary elements, such as fish oils, may regulate growth factor secretion it becomes obvious that this is a multi-facetted process. The complexity of the pathogenesis of intimal hyperplasia is reflected in the physiological disturbance of the vessel wall. There is evidence of increased clotting activity and increased plasminogen-activation while low flow in vein grafts is associated with increased fibrinogen and increasing intimal hyperplasia. There is also increased connective tissue production, particularly type I collagen which is involved in the development of atherosclerotic plaques. It also appears that the contractility of the vessel wall is greatly increased in response to catecholamines both immediately following endothelial denudation and during the subsequent development of intimal hyperplasia. 8 Eur J Vasc Surg Vol 6, July 1992
There has been considerable interest in a pharmacological approach to the reduction of intimal hyperplasia with the anti-platelet drugs being the most intensively investigated. Although increased patency in coronary vein grafts at one year has been reported it is not clear that this is due to a decrease in intimal hyperplasia rather than a decrease in acute thrombotic events. 9 In general the anti-platelet drugs have been disappointing but this might have been expected following the demonstration that intimal hyperplasia develops normally in severely thrombocytopaenic rabbits. Other drugs which have shown promise in experimental studies include calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, 1° heparin, 11 steroids and alpha1 adrenergic antagonists.12 However, given the multifactorial nature of the aetiology of intimal hyperplasia it is not surprising that those studied have so far been less than convincing in humans. It may be that a single pharmacological agent will not prove capable of controlling this smooth muscle cell proliferation and, perhaps, we need to look at more biological methods such as the introduction of genes with specific growth factors or inhibitors into the smooth muscle cells of the vessel wall. A major obstacle in our search for the means of controlling or reducing intimal hyperplasia remains a suitable non-invasive technique which will reliably monitor its development. Angiography is invasive and does not provide sufficient information while routine non-invasive assessment is not sufficiently sensitive. However, in our department we have preliminary evidence to suggest that the colour-coded duplex scanner is sufficiently sensitive to measure the thickness of the individual layers of a large vessel such as the common femoral artery reproducibly. Should this prove to be the case it will greatly facilitate clinical trials and, hopefully, bring us closer to controlling intimal hyperplasia using the more recent endovascular techniques which are now being evaluated, in addition to the currently accepted means of vascular surgery.
References 1 TOWNEJB. Role of fibrointimal hyperplasia in vein graft failure. J Vasc Surg 1989; 10: 583-585. 2 MOORE S. Thromboatherosclerosis in normolipernic rabbits: a result of continued endothelial damage. Lab Invest 1973; 29: 478487. 3 ROUBIN GS, KING SB, DOUGLASJS. Restenosis after percutaneous transluminal coronary angioplasty; the Emory University Hospital experience. Am J Cardiol 1987; 60: 39B-43B. 4 ALDOORI MI, BAIRD RN. Prospective assessment of carotid
Intimal Hyperplasia
endarterectomy by clinical and ultrasound methods. Br J Surg 1987; 74: 926-929. 5 CLowEs AW, CLOWESMM, REIOYMA. Kinetics of cellular proliferation after arterial injury. III. Endothelial and smooth muscle cell growth in chronically denuded vessels. Lab Invest 1986; 54: 295-303. 6 Ross R, GLOMSETJA. The pathogenesis of atherosclerosis. N Engl J Med 1976; 295: 420-425. 7 LINDNERV, REIDYMA. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Procl Nat Acad Sci USA 1991; 88: 3739-3743. 80'MALLEY MK, MORRISJJ, MAKHOULRG, MIKATEM, HAGENPO. Norepinephrine-induced vasoconstriction is increased in intimal hyperplastic arteries of the dog. Surgery 1987; 2: 217223. 9 CHESEBROJH, FUSTERV, ELVEBACKLR et al. Effect of dipyrida-
345
mole and aspirin on late vein graft patency after coronary bypass operations. N Engl ] Med 1984; 310: 209-214. 10 O'DoNOHOE MK, SCHWARZLB, RADIC ZS et al. Reduction of intimal hyperplasia in experimental vein grafts by the angiotensin-converting enzyme inhibitor captopril. Surg Forum 1990; XLI: 317-318. 11 CLOWESAW, CLOwEsMM. Kinetics of cellular proliferation after arterial injury: IV. Heparin inhibits rat smooth muscle mitogenesis and migration. Circ Res 1986; 58: 839-845. 12 O'MALLEYMK, MCDERMOTTEWM, MEHIGAND, O'HIGGINS NJ. Role for prazosin in reducing the development of rabbit intimal hyperplasia after endothelial denudation. Br J Surg 1989; 76: 936-968. Accepted 26 October 1991
Eur J Vasc Surg Vol 6, July 1992
LEADING ARTICLE Intimal Hyperplasia M, K. O'Malley Charing Cross and Westminster Medical School, Fulham Palace Road, London W6 8RF, U.K.
The persistent expansion of cytological and molecular cardiovascular research has attracted the interest of vascular surgeons over the last decade in particular. Prior to this there were more compelling technical and diagnostic problems relating to the clinical practice of vascular surgery. However, as the indications for surgery and surgical techniques have become somewhat standardised the emphasis has switched to the pathogenesis of peripheral vascular disease, the interaction of the bloodstream with the vessel wall and especially the prevention of recurrent stenosis. It is now apparent that any form of endothelial trauma will produce a thickened neointima as part of the healing response. This process, known as intimal hyperplasia, is seen following vascular reconstruction, balloon angioplasty, organ transplantation, angiography, vascular access and atherectomy and a recent study suggests that it may be the single most significant factor affecting long-term patency. 1 The essential feature of intimal hyperplasia is vascular smooth muscle cell proliferation which occurs following migration from the media. This should probably be thought of as the vessel wall's natural reparative response to trauma but often it will continue unchecked giving rise to clearly harmful side effects. There is evidence to suggest that the extent of the hyperplastic response is related to the severity of the injury but while there is a considerable amount of information regarding the onset of this process, very little is known about how it stops. Furthermore, there is surprisingly little known about the natural history of intimal hyperplasia in man but it is known that it may progress for up to 2 years. On the other hand, after an initial period of proliferation, it may actually regress. Its duration is of more than academic interest as recurrent stenosis Please address all correspondenceto: M. K. O'Malley,Department of Surgery, Mater MisericordiaeHospital, EcclesStreet, Dublin 7, Republic of Ireland. 0950-821X/92/040343+ 03 $03.00/0© 1992Grune & StrattonLtd.
within 2 years is likely to be due to intimal hyperplasia at the site of reconstruction, whereas a longer interval suggests progressive atherosclerosis usually in the distal vessels but also possibly in the inflow tract. This is not to say that intimal hyperplasia and atherosclerosis are unrelated as there is strong experimental evidence to show that the development of intimal hyperplasia following endothelial denudation predisposes to lipid incorporation in the vessel wall and the formation of an atherosclerotic plaque. 2 It has to be appreciated that neointimal hyperplasia occurs at different sites following different procedures but will not always have the same sequelae. After coronary angioplasty there is a 35% restenosis rate at 6 months and most of these patients have recurrent symptoms, 3 while in a recent consecutive series of infrainguinal vein bypass grafts 42% required subsequent revision because of intimal hyperplasia. ~ However, although approximately 10% of patients develop restenosis within 12 months of carotid endarterectomy, there is an extremely low incidence of recurrent symptoms. 4 This highlights the fact that most extracranial cerebrovascular transient ischaemic attacks (TIAs) are due to embolic episodes rather than haemodynamic factors as the recurrent stenosis presents a smooth uniform luminal surface. It is inappropriate, however, to think of intimal hyperplasia as a purely mechanical obstruction. When it is considered that the vessel wall has lost its normal endothelial layer, at least transiently, and that the vascular smooth muscle cells are transformed from a quiescent state to a proliferative phase, it is not surprising that many normal physiological functions of the vessel wall are also altered. To appreciate this further it is helpful to look at the pathogenesis of smooth muscle cell proliferation. Following endothelial denudation the internal elastic lamina is exposed to the bloodstream and immediately attracts platelets which form aggregates
344
M.K. O'Malley
together with erythrocytes, monocytes and neutrophils. In a rabbit model the first evidence of a regenerating intima is seen within 3-5 days. By the 8th day several layers of smooth muscle cells are seen on the luminal side of the internal elastic lamina and this proliferation continues for up to 4 weeks after the trauma. Any further increase in the intimal thickening is due to the deposition of matrix between the smooth muscle cells.S In the human this process takes considerably longer and it is generally thought that the neointimal thickening may continue to increase for up to two years. Following a number of important studies from Ross's group the central role of the platelet was highlighted. 6 It was suggested that the platelet secretes a growth factor (PDGF) following adherence to the internal elastic lamina and that this growth factor promotes smooth muscle cell migration and proliferation. However, continuing studies from this and other groups have shown that the situation is a lot more complex. It is now known that other cells, including endothelial cells, macrophages and smooth muscle cells, can also produce PDGF. It has also been shown that there are many other growth factors which may at least contribute to the smooth muscle cell proliferation including transforming growth factors alpha and beta, interleukin-1, macrophage derived growth factor and, most recently, fibroblast growth factor.7 Furthermore, it is apparent that there are also naturally occurring smooth muscle cell inhibitors such as heparin, interferon gamma and PGE-1 which presumably exist in balance with the smooth muscle cell growth factors~ When it is also considered that shear stress on the vessel wall, altered compliance and blood flow rates may be integral to the development of intimal hyperplasia and that certain dietary elements, such as fish oils, may regulate growth factor secretion it becomes obvious that this is a multi-facetted process. The complexity of the pathogenesis of intimal hyperplasia is reflected in the physiological disturbance of the vessel wall. There is evidence of increased clotting activity and increased plasminogen-activation while low flow in vein grafts is associated with increased fibrinogen and increasing intimal hyperplasia. There is also increased connective tissue production, particularly type I collagen which is involved in the development of atherosclerotic plaques. It also appears that the contractility of the vessel wall is greatly increased in response to catecholamines both immediately following endothelial denudation and during the subsequent development of intimal hyperplasia. 8 Eur J Vasc Surg Vol 6, July 1992
There has been considerable interest in a pharmacological approach to the reduction of intimal hyperplasia with the anti-platelet drugs being the most intensively investigated. Although increased patency in coronary vein grafts at one year has been reported it is not clear that this is due to a decrease in intimal hyperplasia rather than a decrease in acute thrombotic events. 9 In general the anti-platelet drugs have been disappointing but this might have been expected following the demonstration that intimal hyperplasia develops normally in severely thrombocytopaenic rabbits. Other drugs which have shown promise in experimental studies include calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, 1° heparin, 11 steroids and alpha1 adrenergic antagonists.12 However, given the multifactorial nature of the aetiology of intimal hyperplasia it is not surprising that those studied have so far been less than convincing in humans. It may be that a single pharmacological agent will not prove capable of controlling this smooth muscle cell proliferation and, perhaps, we need to look at more biological methods such as the introduction of genes with specific growth factors or inhibitors into the smooth muscle cells of the vessel wall. A major obstacle in our search for the means of controlling or reducing intimal hyperplasia remains a suitable non-invasive technique which will reliably monitor its development. Angiography is invasive and does not provide sufficient information while routine non-invasive assessment is not sufficiently sensitive. However, in our department we have preliminary evidence to suggest that the colour-coded duplex scanner is sufficiently sensitive to measure the thickness of the individual layers of a large vessel such as the common femoral artery reproducibly. Should this prove to be the case it will greatly facilitate clinical trials and, hopefully, bring us closer to controlling intimal hyperplasia using the more recent endovascular techniques which are now being evaluated, in addition to the currently accepted means of vascular surgery.
References 1 TOWNEJB. Role of fibrointimal hyperplasia in vein graft failure. J Vasc Surg 1989; 10: 583-585. 2 MOORE S. Thromboatherosclerosis in normolipernic rabbits: a result of continued endothelial damage. Lab Invest 1973; 29: 478487. 3 ROUBIN GS, KING SB, DOUGLASJS. Restenosis after percutaneous transluminal coronary angioplasty; the Emory University Hospital experience. Am J Cardiol 1987; 60: 39B-43B. 4 ALDOORI MI, BAIRD RN. Prospective assessment of carotid
Intimal Hyperplasia
endarterectomy by clinical and ultrasound methods. Br J Surg 1987; 74: 926-929. 5 CLowEs AW, CLOWESMM, REIOYMA. Kinetics of cellular proliferation after arterial injury. III. Endothelial and smooth muscle cell growth in chronically denuded vessels. Lab Invest 1986; 54: 295-303. 6 Ross R, GLOMSETJA. The pathogenesis of atherosclerosis. N Engl J Med 1976; 295: 420-425. 7 LINDNERV, REIDYMA. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Procl Nat Acad Sci USA 1991; 88: 3739-3743. 80'MALLEY MK, MORRISJJ, MAKHOULRG, MIKATEM, HAGENPO. Norepinephrine-induced vasoconstriction is increased in intimal hyperplastic arteries of the dog. Surgery 1987; 2: 217223. 9 CHESEBROJH, FUSTERV, ELVEBACKLR et al. Effect of dipyrida-
345
mole and aspirin on late vein graft patency after coronary bypass operations. N Engl ] Med 1984; 310: 209-214. 10 O'DoNOHOE MK, SCHWARZLB, RADIC ZS et al. Reduction of intimal hyperplasia in experimental vein grafts by the angiotensin-converting enzyme inhibitor captopril. Surg Forum 1990; XLI: 317-318. 11 CLOWESAW, CLOwEsMM. Kinetics of cellular proliferation after arterial injury: IV. Heparin inhibits rat smooth muscle mitogenesis and migration. Circ Res 1986; 58: 839-845. 12 O'MALLEYMK, MCDERMOTTEWM, MEHIGAND, O'HIGGINS NJ. Role for prazosin in reducing the development of rabbit intimal hyperplasia after endothelial denudation. Br J Surg 1989; 76: 936-968. Accepted 26 October 1991
Eur J Vasc Surg Vol 6, July 1992
