Volume 13 Number 5 May 1991
eration. 3'4 In view of the profound changes that can be induced experimentally merely by altering blood flow, s compensatory connective tissue proliferation and degenerative changes can be expected in the xanthomatous intimal thickening of cholesterol-fed animals, since foam cell lesions would have little cohesion, no protective connective tissue, and inadequate viscoelastic properties to withstand arterial hemodynamics. Secondary changes induced by blood flow disturbances could thus be expected in the artery wall. They would be aggravated by the scarred wall after lipid depletion. Under the circumstances the report of Zarins et al.~ does not provide support for the thesis that cholesterol-induced vascular lesions induce atherosclerotic aneurysms. Tilson 2 alleges atherosclerosis does not usually lead to loss o f tensile strength. Yet intimal tears, ulcerations, and aneurysms are indicative of loss of tensile strength and are most prevalent in the abdominal aorta, where atherosclerosis is most severe and associated with profound medial thinning and gradual yield? Aneurysms may also form by progressive dilation of the residual medial and adventitial remnants of the base of an atherosclerotic ulcer? Atherosclerosis may develop in an experimental aneurysm or a human berry aneurysm as the result of disturbed blood flow, 5 but accelerated advanced atberosclerosis and aneurysms may form in the coronary venous bypass graft or the vein of an arteriovenous shunt in man or an herbivorous animal. "~''~Their accelerated rate of development can be attributed to the unusually severe hemodynamic stresses on tissues that are not architecturally designed to withstand such hemodynamics. Poststenotic dilation, berry aneurysm formation, and mural atrophy can all be induced by severe and unusual hemodynamic stress? It is not necessary to invoke a genetic defect. Lathyrism and hypertension merely act as aggravating factors in berry aneurysm formation, and certain hereditary connective tissue disorders may act as predisposing factors with a variable degree of expression? It is well to remember that the vascular complications in Marian's syndrome are acquired. They are not present at birth but like the secondary skeletal and joint degenerative changes, are induced by stress and usage after some years of exposure. The same may be said of the vascular lesions. Because lathyritic factors can be used to produce berry aneurysms, it does not follow that all berry aneurysms are associated with lathyrism. Likewise, because some aneurysms, whether cerebral or aortic, are associated with some hereditary connective tissue disorder, it is inappropriate to speculate that all such aneurysms are due to inherited connective tissue disorders. For these reasons there is insufficient evidence to support the concept that cholesterol feeding induces aneurysm formation ~or that an inherited connective tissue defect underlies atherosclerotic aneurysms. 2 William E. Stehbens, M D
Department of Pathology Wellington School of Medicine P.O. Box 7343 Wellington South New Zealand
Letters to the Editors
767
REFERENCES 1. Zarins CK, Glagov S, Vcsselinovitch D, Wissler RW. Aneurysm formation in experimental atherosclerosis: relationship to plaque evolution. J VAsc SUaG 1990;12:246-56. 2. Tilson MD. Atherosclerosis and aneurysm disease. Editorial. J VAsc SUV,G 1990;12:371-2. 3. Stehbens WE. Hemodynamics and the blood vessel wall. Springfield: CC Thomas, 1979. 4. Stehbens WE. Vascular complications in experimental atherosclerosis. Progr Cardiovasc Dis 1986;29:221-37, 5. Stehbens WE. The lipid hypothesis and the role of hemodynamics in atherogenesis. Progr Cardiovasc Dis 1990;33:11936. 6. Stehbens WE. Etiology of intracranial berry aneurysms-a review. J Neurosurg 1989;70:823-31.
Aneurysm formation in experimental atherosclerosis: relationship to plaque evolution To the Editors:
I have read with great interest the article by Zarins, et aL (J VASe Svv,c 1990;12:246-56) on aneurysm formation in experimental atherosclerosis. I am quite concerned about the conclusions that they reached that their data "support the thesis that aneurysm formation is a manifestation of atherosclerosis." Within the last 10 years six studies have screened 1352 first-degree relatives of patients with abdominal aortic aneurysms, and 16% of these first-degree relatives had abdominal aortic aneurysms.~'2 In addition, four different laboratories since 1980 have reported on the abnormalities in the proteolytic activity of circulating neutrophils and of the aortic wall in patients with aneurysms? -6 Furthermore, clinical observations that aneurysm patients are different from atherosclerotic patients include the occurrence of multiple aneurysms in the same patients, generalized arteriomegaly in subsets of patients with aneurysms, and the fact that it is unusual if not rare for patients with significant progressive arterial insufficiency of their lower extremities to have aneurysmal disease. Dr. Zarins makes little mention of any of these clinical, biochemical, and genetic reports that support the concept that aneurysms are a manifestation of atherosclerosis. As mentioned by Tilson 7 in his editorial, the occurrence o f four aneurysms in 31 animals o f the experimental group versus zero in the control group is by no means statistically significant and is probably a random occurrence. In addition, four of the five monkeys that developed aneurysms were on a regression diet and cholestyramine. I know of no studies that indicate that patients with abdominal aortic aneurysrns are on these types of diets before the time that they developed aneurysms, and in fact, almost all patients with aneurysms are on a high fat, high cholesterol diet at the time of their diagnosis. I am in agreement with Dr. Zarins that atherosclerosis is a prominent feature in patients with abdominal aortic aneurysms, and I believe that atherosclerosis may actually be the inciting event for the development of aneurysms; however, his experimental data do not support the thesis
768
Journal of VASCULAR SURGERY
Letters to the Editors
that aneurysms are simply one type of manifestation of atherosclerosis. Our current data suggest that patients with aneurysms may actually react differently to the inciting event of the atherosclerotic process, that is, that the smooth muscle cell within the arterial wall and the circulating neutrophil deliver an increased amount of proteases in response to the atherosclerotic process. On a chronic basis, we believe that the continued stimulation of the smooth muscle cell and its delivery of proteolytic enzymes to the aortic wall results in aneurysm formation. In that sense, aneurysms would only occur if the atherosclerotic process is present; however, the underlying pathophysiology is most probably a defect in the proteolytic process. Jon R. Cohen, BiD
Department of Surgery Long Island Jewish Medical Center New Hyde Park, NY 11042 REFERENCES
1. Norrgard O, Rais O, Angquist KA. Familial occurrence of abdominal aortic aneurysms. Surgery 1984;95:650-6. 2. Johansen K, Koepsell T. Familial tendency for abdominal aortic aneurysms. JAMA 1986;256:1934-6. 3. BusutiURW, Rinderbreicht H, Flesher A, Carmack C. Elastase activity: the role of elastase in aortic aneurysm formation. J Surg Res 1982;32:214-7. 4. Cannon DJ, Read RC. Blood elastolytic activity in patients with aortic aneurysm. Ann Thorac Surg 1982;34:10-15. 5. Cohen JR, Mandell C, Chang J, Wise L. Elastin metabolism of the infrarenal aorta. J VAsc SURG 1988;7:210-4. 6. Powell J, Greenhalgh RM. Cellular, enzymatic, and genetic factors in the pathogenesis of abdominal aortic aneurysms. J VAsc SURG 1989;9:297-304. 7. Tilson MD. Atherosclerosis and aneurysm disease. J Vasc SURG 1990;12:371-2.
Reply To the Editors:
Dr. Cohen thinks that atherosclerosis may be the inciting event for the development of aneurysms, but he questions whether our finding of aneurysms in 4 of 31 cynomolgus monkeys subjected to an atherogenic regimen for a prolonged period of time (greater than 16 months) supports the concept that aneurysm formation is a manifestation of atherosclerosis. We think that it does in this experimental model, because aneurysm formation does not occur spontaneously in the two species studied. A relatively long period of diet induction was necessary, and the difference in incidence of aneurysm formation between cynomolgus monkeys (13%) and rhesus monkeys (1%) after prolonged experimental lipid manipulation suggests a difference in susceptibility for the two species studied. The relationship between plaque evolution and aneurysm formation in this experimental model is supported by pathologic examination, which demonstrated media destruction associated with plaque formation in the cynomolgus monkey and only minimal media changes in the rhesus monkey. Evidence has been presented in earlier
studies that experimental atherosclerosis in the cynomolgus results in greater involvement and disruption of the media than is seen in the rhesus, l Other investigations in which the media has been destroyed also resulted in aneurysm f o r m a t i o n 9 These findings emphasize the important role of media erosion and atrophy as seen regularly in association with atherosderosis in aneurysm formation. The species differences in the manner of arterial involvement in the monkeys also suggests that genetic or acquired differences in tissue reaction may play a role. Nevertheless, aneurysms occurred only in the presence of atherogencsis. Our observation that the duration of exposure to atherogenie stimuli is an important factor is consistent with the evolution of pathologic changes in the artery wall, and it is consistent with the clinical observation that patients operated on for abdominal aortic aneurysms are, on the average, 10 years older than those undergoing aortofemoral bypass procedures for occlusive disease. The possible role of regression ofatherosclerotic lesions in the development of aneurysms is suggested by our finding that three of the four monkeys that developed aneurysms were on cholesterol lowering protocols. Although this by no means proves this relationship, subsequent controlled regression studies in our laboratory with cholesterol lowering by removal of the high cholesterol diet, and without the use of cholesterol lowering drugs, supports this observation. Furthermore, most patients with abdominal aortic aneurysms have normal serum cholesterol levels, and we have recently been impressed by aneurysm formation in several patients on cholesterol lowering drugs. Dr. Cohen's observation that 16% of patients with abdominal aortic aneurysms have first-degree relatives with abdominal aortic aneurysms is not a convincing argument for excluding the role of atherosclerosis in aneurysm formation. Indeed, 84% of patients with aneurysms have no familial history of aneurysm formation. However, this does not signify that genetic factors are not important in aneurysm formation. Genetic factors play an important role in all facets of life and play an important role in the susceptibility or resistance to various diseases. Genetic factors are certainly known to be important in the development of atherosclerosis and in particular of coronary artery disease. It would not be surprising if genetic factors also affected those individual reactions to atherogenesis that may underlie the tendency to aneurysm formation. Whether identification of specific individual genes that determine aneurysm formation will, as Dr. Tilson suggests, 4 result in a dearer understanding of the pathogenesis ofaneurysm formation remains to be seen. As with many other disease entities, the pathogenesis of abdominal aortic aneurysm is likely to involve the interaction of a genetic predisposition and an acquired condition such as atherosclerosis. Christopher K. Zarins, ~4D
Department of Surgery University of Chicago 5841 S. Maryland Ave. Chicago, IL 60637
eration. 3'4 In view of the profound changes that can be induced experimentally merely by altering blood flow, s compensatory connective tissue proliferation and degenerative changes can be expected in the xanthomatous intimal thickening of cholesterol-fed animals, since foam cell lesions would have little cohesion, no protective connective tissue, and inadequate viscoelastic properties to withstand arterial hemodynamics. Secondary changes induced by blood flow disturbances could thus be expected in the artery wall. They would be aggravated by the scarred wall after lipid depletion. Under the circumstances the report of Zarins et al.~ does not provide support for the thesis that cholesterol-induced vascular lesions induce atherosclerotic aneurysms. Tilson 2 alleges atherosclerosis does not usually lead to loss o f tensile strength. Yet intimal tears, ulcerations, and aneurysms are indicative of loss of tensile strength and are most prevalent in the abdominal aorta, where atherosclerosis is most severe and associated with profound medial thinning and gradual yield? Aneurysms may also form by progressive dilation of the residual medial and adventitial remnants of the base of an atherosclerotic ulcer? Atherosclerosis may develop in an experimental aneurysm or a human berry aneurysm as the result of disturbed blood flow, 5 but accelerated advanced atberosclerosis and aneurysms may form in the coronary venous bypass graft or the vein of an arteriovenous shunt in man or an herbivorous animal. "~''~Their accelerated rate of development can be attributed to the unusually severe hemodynamic stresses on tissues that are not architecturally designed to withstand such hemodynamics. Poststenotic dilation, berry aneurysm formation, and mural atrophy can all be induced by severe and unusual hemodynamic stress? It is not necessary to invoke a genetic defect. Lathyrism and hypertension merely act as aggravating factors in berry aneurysm formation, and certain hereditary connective tissue disorders may act as predisposing factors with a variable degree of expression? It is well to remember that the vascular complications in Marian's syndrome are acquired. They are not present at birth but like the secondary skeletal and joint degenerative changes, are induced by stress and usage after some years of exposure. The same may be said of the vascular lesions. Because lathyritic factors can be used to produce berry aneurysms, it does not follow that all berry aneurysms are associated with lathyrism. Likewise, because some aneurysms, whether cerebral or aortic, are associated with some hereditary connective tissue disorder, it is inappropriate to speculate that all such aneurysms are due to inherited connective tissue disorders. For these reasons there is insufficient evidence to support the concept that cholesterol feeding induces aneurysm formation ~or that an inherited connective tissue defect underlies atherosclerotic aneurysms. 2 William E. Stehbens, M D
Department of Pathology Wellington School of Medicine P.O. Box 7343 Wellington South New Zealand
Letters to the Editors
767
REFERENCES 1. Zarins CK, Glagov S, Vcsselinovitch D, Wissler RW. Aneurysm formation in experimental atherosclerosis: relationship to plaque evolution. J VAsc SUaG 1990;12:246-56. 2. Tilson MD. Atherosclerosis and aneurysm disease. Editorial. J VAsc SUV,G 1990;12:371-2. 3. Stehbens WE. Hemodynamics and the blood vessel wall. Springfield: CC Thomas, 1979. 4. Stehbens WE. Vascular complications in experimental atherosclerosis. Progr Cardiovasc Dis 1986;29:221-37, 5. Stehbens WE. The lipid hypothesis and the role of hemodynamics in atherogenesis. Progr Cardiovasc Dis 1990;33:11936. 6. Stehbens WE. Etiology of intracranial berry aneurysms-a review. J Neurosurg 1989;70:823-31.
Aneurysm formation in experimental atherosclerosis: relationship to plaque evolution To the Editors:
I have read with great interest the article by Zarins, et aL (J VASe Svv,c 1990;12:246-56) on aneurysm formation in experimental atherosclerosis. I am quite concerned about the conclusions that they reached that their data "support the thesis that aneurysm formation is a manifestation of atherosclerosis." Within the last 10 years six studies have screened 1352 first-degree relatives of patients with abdominal aortic aneurysms, and 16% of these first-degree relatives had abdominal aortic aneurysms.~'2 In addition, four different laboratories since 1980 have reported on the abnormalities in the proteolytic activity of circulating neutrophils and of the aortic wall in patients with aneurysms? -6 Furthermore, clinical observations that aneurysm patients are different from atherosclerotic patients include the occurrence of multiple aneurysms in the same patients, generalized arteriomegaly in subsets of patients with aneurysms, and the fact that it is unusual if not rare for patients with significant progressive arterial insufficiency of their lower extremities to have aneurysmal disease. Dr. Zarins makes little mention of any of these clinical, biochemical, and genetic reports that support the concept that aneurysms are a manifestation of atherosclerosis. As mentioned by Tilson 7 in his editorial, the occurrence o f four aneurysms in 31 animals o f the experimental group versus zero in the control group is by no means statistically significant and is probably a random occurrence. In addition, four of the five monkeys that developed aneurysms were on a regression diet and cholestyramine. I know of no studies that indicate that patients with abdominal aortic aneurysrns are on these types of diets before the time that they developed aneurysms, and in fact, almost all patients with aneurysms are on a high fat, high cholesterol diet at the time of their diagnosis. I am in agreement with Dr. Zarins that atherosclerosis is a prominent feature in patients with abdominal aortic aneurysms, and I believe that atherosclerosis may actually be the inciting event for the development of aneurysms; however, his experimental data do not support the thesis
768
Journal of VASCULAR SURGERY
Letters to the Editors
that aneurysms are simply one type of manifestation of atherosclerosis. Our current data suggest that patients with aneurysms may actually react differently to the inciting event of the atherosclerotic process, that is, that the smooth muscle cell within the arterial wall and the circulating neutrophil deliver an increased amount of proteases in response to the atherosclerotic process. On a chronic basis, we believe that the continued stimulation of the smooth muscle cell and its delivery of proteolytic enzymes to the aortic wall results in aneurysm formation. In that sense, aneurysms would only occur if the atherosclerotic process is present; however, the underlying pathophysiology is most probably a defect in the proteolytic process. Jon R. Cohen, BiD
Department of Surgery Long Island Jewish Medical Center New Hyde Park, NY 11042 REFERENCES
1. Norrgard O, Rais O, Angquist KA. Familial occurrence of abdominal aortic aneurysms. Surgery 1984;95:650-6. 2. Johansen K, Koepsell T. Familial tendency for abdominal aortic aneurysms. JAMA 1986;256:1934-6. 3. BusutiURW, Rinderbreicht H, Flesher A, Carmack C. Elastase activity: the role of elastase in aortic aneurysm formation. J Surg Res 1982;32:214-7. 4. Cannon DJ, Read RC. Blood elastolytic activity in patients with aortic aneurysm. Ann Thorac Surg 1982;34:10-15. 5. Cohen JR, Mandell C, Chang J, Wise L. Elastin metabolism of the infrarenal aorta. J VAsc SURG 1988;7:210-4. 6. Powell J, Greenhalgh RM. Cellular, enzymatic, and genetic factors in the pathogenesis of abdominal aortic aneurysms. J VAsc SURG 1989;9:297-304. 7. Tilson MD. Atherosclerosis and aneurysm disease. J Vasc SURG 1990;12:371-2.
Reply To the Editors:
Dr. Cohen thinks that atherosclerosis may be the inciting event for the development of aneurysms, but he questions whether our finding of aneurysms in 4 of 31 cynomolgus monkeys subjected to an atherogenic regimen for a prolonged period of time (greater than 16 months) supports the concept that aneurysm formation is a manifestation of atherosclerosis. We think that it does in this experimental model, because aneurysm formation does not occur spontaneously in the two species studied. A relatively long period of diet induction was necessary, and the difference in incidence of aneurysm formation between cynomolgus monkeys (13%) and rhesus monkeys (1%) after prolonged experimental lipid manipulation suggests a difference in susceptibility for the two species studied. The relationship between plaque evolution and aneurysm formation in this experimental model is supported by pathologic examination, which demonstrated media destruction associated with plaque formation in the cynomolgus monkey and only minimal media changes in the rhesus monkey. Evidence has been presented in earlier
studies that experimental atherosclerosis in the cynomolgus results in greater involvement and disruption of the media than is seen in the rhesus, l Other investigations in which the media has been destroyed also resulted in aneurysm f o r m a t i o n 9 These findings emphasize the important role of media erosion and atrophy as seen regularly in association with atherosderosis in aneurysm formation. The species differences in the manner of arterial involvement in the monkeys also suggests that genetic or acquired differences in tissue reaction may play a role. Nevertheless, aneurysms occurred only in the presence of atherogencsis. Our observation that the duration of exposure to atherogenie stimuli is an important factor is consistent with the evolution of pathologic changes in the artery wall, and it is consistent with the clinical observation that patients operated on for abdominal aortic aneurysms are, on the average, 10 years older than those undergoing aortofemoral bypass procedures for occlusive disease. The possible role of regression ofatherosclerotic lesions in the development of aneurysms is suggested by our finding that three of the four monkeys that developed aneurysms were on cholesterol lowering protocols. Although this by no means proves this relationship, subsequent controlled regression studies in our laboratory with cholesterol lowering by removal of the high cholesterol diet, and without the use of cholesterol lowering drugs, supports this observation. Furthermore, most patients with abdominal aortic aneurysms have normal serum cholesterol levels, and we have recently been impressed by aneurysm formation in several patients on cholesterol lowering drugs. Dr. Cohen's observation that 16% of patients with abdominal aortic aneurysms have first-degree relatives with abdominal aortic aneurysms is not a convincing argument for excluding the role of atherosclerosis in aneurysm formation. Indeed, 84% of patients with aneurysms have no familial history of aneurysm formation. However, this does not signify that genetic factors are not important in aneurysm formation. Genetic factors play an important role in all facets of life and play an important role in the susceptibility or resistance to various diseases. Genetic factors are certainly known to be important in the development of atherosclerosis and in particular of coronary artery disease. It would not be surprising if genetic factors also affected those individual reactions to atherogenesis that may underlie the tendency to aneurysm formation. Whether identification of specific individual genes that determine aneurysm formation will, as Dr. Tilson suggests, 4 result in a dearer understanding of the pathogenesis ofaneurysm formation remains to be seen. As with many other disease entities, the pathogenesis of abdominal aortic aneurysm is likely to involve the interaction of a genetic predisposition and an acquired condition such as atherosclerosis. Christopher K. Zarins, ~4D
Department of Surgery University of Chicago 5841 S. Maryland Ave. Chicago, IL 60637
