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Role of lymphostasis in accelerated atherosclerosis in transplanted hearts
LETTERS
ROLE OF LYMPHOSTASIS IN ACCELERATED ATHEROSCLEROSIS IN TRANSPLANTED HEARTS Although the rate of early rejection of transplanted hearts has declined, accelerated atherosclerosis has become the maj or obstacle to transplant survival. Most heart transplant recipients who do not die acutely of rej ection or infection have accelerated atherosclerosis,122 the cause of which is unclear. Chronic rejection may act in synergism with hyperlipidemia to stimulate accelerated atherosclerosis.1,3,4Damage to arterial endothelium by chronic rejection may initiate a cascade of events that includes intimal lipid accumulation and myointimal proliferation. However, obstruction of lymphatic outflow from the transplanted heart may be an overlooked contributing cause of accelerated atherosclerosis. Several studies suggest that lymphostasis has no role in accelerated atherosclerosis, indeed that significant lymphostasis does not even occur. Right ventridular biopsy specimens from transplant recipients fail to show the endocardial edema expected with lymphatic engorgment.5r6 Noninvasive left ventricular mass measurements fail to demonstrate significant myocardial edema,5s6 and necropsystudiesfailtoshowmyocardialedema in noninfarcted myocardium.z Other reports suggest that regeneration of severed lymphaticsoccursandeliminateslymphostasis. Initial communication between disrupted lymphatics has been observed as early as 7 days after interruption of the channels.7 Although lymphatic channels may not penetrate scartissuein earlystagesof healing, continuity has reportedly been reestablished by arborization across the wound.7 Lymphatic regeneration has never been demonstrated in human cardiac allografts; however, survival of nonhuman allografts is associated with reestablishment of lymphatic drainage.8,g Finally, the observation that obliterative intimal proliferation does not occur until at least 1 month after transplantationlO suggests that acute lymphatic disruption has no relation to accelerated atherosclerosis. Evidence that lymphostasis has an important role in accelerated atherosclerosis, how-
* Letters (from the United States) concerning a particular article in the Journal must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 double-spaced typewritten pages. Two copies must be submitted.
ever, is more persuasive. A lack of clinical evidence of lymphostasis does not exclude its presence in transplanted hearts. Epicardial lymphatic channels, which are subjected to the least external pressure by myocardium, would be most likely to experience inadequate lymphatic drainage. Biopsy specimens of the epicardium have been obtained. Furthermore, anatomic obstruction and stasis of flow in lymphatic channels are not equivalent. Chronic stasis of lymph may occur without obvious anatomic evidence. Lymphostasis has been associated with thickening of the arterial intima, an early finding in atherosclerosis. Jellinek et all1 ligated cardiac lymph nodes in dogs and noted plasma accumulation in the subendothelium of coronary arteries within 6 days. SimP examined resected colon carcinoma specimens and found atherosclerotic changes only in thosesectionsofarteriesinwhichtumorinfiltrates obstructed lymphatic drainage. Interference with flow in lymphatic channels can lead to altered transport through the arterial wall of plasma components. The subsequentproteinstasisandintimaledemamay stimulate local reactions, such as platelet adherence or myointimal proliferation, that would predispose the vessel to atherosclerosis. The lymphostasis may also disturb the balance of liuonroteins in the arterial wa11.13 High-density lipoprotein, whichselectively passes through arterial endothelium and binds cholesterol, may be unable to drain through lymphatics and carry cholesterol to the liver. Low-density lipoprotein, which transports lipids into the arterial wall and is metabolized at the vessel wall, would continue to deposit cholesterol and triglycerides, even in the presence of lymphostasis. The relation of chronic rejection and hyperlipidemia to accelerated atherosclerosis has not been clearly elucidated. Studies have demonstrated that nearly uniform development of accelerated atherosclerosis in heterotopically transplanted hearts occurs despite widely varying degrees of immunosuppression and hypercholesterolemia.3s4 Cholesterol levels correlate better with linid content in atherosclerotic lesions than with the degree of myointimal proliferation in the arterial wall. Furthermore, the presence of chronic rejection in transplant recipients is not consistent. Only one-half of patients with accelerated atherosclerosis demonstrate Bcell antibodies indicative of chronic rejecti0n.l Thus, chronic rejection and hyperlipidemia probably cannot alone account for the process of accelerated atherosclerosis. Lymphostasis may contribute to the development of accelerated atherosclerosis by several mechanisms. First, lymphatic ob-
430
struction, which impairs myocardial healing capacity14 will hinder the repair of an intima persistently damaged by chronic rejection. Second, by inducing protein stasis in the arterial wall, lymphostasis may stimulate local reactions such as platelet adherence or myointimal proliferation. Third, by disturbing the balance of lipoproteins, lympyostasis may cause accumulation of cholesterol in the arterial wall. MEHMET C. 02, MD, MBA New York, New York
CHARLES S. ROBERTS, MD St. Louis, Missouri
GERALD M. LEMOLE, MD Wilmington, Delaware 13 July 1986
1. Hess ML, Hastillo A, Mohanakumar T, Cowley
MJ,Vetrovac G, Szentpetery S, WolfgangTC, LowerRR.Acceleratedatherosclerosisincardiac transplantation: role of cytotoxic B-cell antibodies and hyperlipidemia.Circufation1983;68:suppfII:II-94II-101.
2. Uys CJ, Rose AG. Pathologic findings in Jongterm cardiac transplants. Arch PathoJ Lab Med 1984;108:112-116. 3. Alonso DR, Stark HA, Minick CR. Studies on the nathoeenesis of atherosclerosis induced in rabbit cardiac ollografts by the synergy ofgraftrejection and hypercholesterolmeia. Am J Pathol 1977;87: 415-442 4. Laden AMK. Experimental atherosclerosis in rat and rabbit cardiac transplants. Arch Pathol Lab Med 1984;108:112-116. 5. Hess ML, Hastillo A, Wolfgang TC, Lower RR. The noninvasive diagnosis of acute and chronic cardiac ollograft rejection. Heart Transplantation 1981;1:31-38. 6. Sagar KB, Hastillo A, Wolfgang TC, Lower RR, Hess ML. Left ventricular mass by M-mode echocardiography in cardiac transplant patients with acuterejection.CircuJationI981;64:suppJII:II-21611-220. 7. Miller AJ. Lymphatics of the Heart. New York: Raven Press, 1982:107. 8. Malek P. Some problems of lymphatic stasis in renal transplantation. Experientia [SuppJj 1967; I4:192-196. 9. Scothorne RJ. Lymphatic repair and the genesis of homograft immunity. Ann NY Acad Sci 1958;73: 673-675. 10. Bieber Cp, Stinson EB, Shumway NE, Payne R, Kosek J. Cardiac transplantation in man: cardiac allograft pathology. Circulation 1979;41:753-772. 11. Jellinek H, Gabor G, Solti F, Veress B. The problem of the coronary changes due to disturbances of vascuJarwaJJpermeabiJity.AngioJogyl967;18:I79187. 12. Sims FH. The arterial wall in malignant disease. Atherosclerosis 1979;32:445-450. 13. Lemole GM. The role of Iymphostasis in atherosclerosis. Ann Thorac Surg 1981;31:290-293. 14. Szalvy L, Douglass FA, Hollenberg NK, Abrahms HL. Cardiac lymph and lymphatics in normal and infarcted myocardium. Am Heart J 1980;100:323-331. I
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ROLE OF LYMPHOSTASIS IN ACCELERATED ATHEROSCLEROSIS IN TRANSPLANTED HEARTS Although the rate of early rejection of transplanted hearts has declined, accelerated atherosclerosis has become the maj or obstacle to transplant survival. Most heart transplant recipients who do not die acutely of rej ection or infection have accelerated atherosclerosis,122 the cause of which is unclear. Chronic rejection may act in synergism with hyperlipidemia to stimulate accelerated atherosclerosis.1,3,4Damage to arterial endothelium by chronic rejection may initiate a cascade of events that includes intimal lipid accumulation and myointimal proliferation. However, obstruction of lymphatic outflow from the transplanted heart may be an overlooked contributing cause of accelerated atherosclerosis. Several studies suggest that lymphostasis has no role in accelerated atherosclerosis, indeed that significant lymphostasis does not even occur. Right ventridular biopsy specimens from transplant recipients fail to show the endocardial edema expected with lymphatic engorgment.5r6 Noninvasive left ventricular mass measurements fail to demonstrate significant myocardial edema,5s6 and necropsystudiesfailtoshowmyocardialedema in noninfarcted myocardium.z Other reports suggest that regeneration of severed lymphaticsoccursandeliminateslymphostasis. Initial communication between disrupted lymphatics has been observed as early as 7 days after interruption of the channels.7 Although lymphatic channels may not penetrate scartissuein earlystagesof healing, continuity has reportedly been reestablished by arborization across the wound.7 Lymphatic regeneration has never been demonstrated in human cardiac allografts; however, survival of nonhuman allografts is associated with reestablishment of lymphatic drainage.8,g Finally, the observation that obliterative intimal proliferation does not occur until at least 1 month after transplantationlO suggests that acute lymphatic disruption has no relation to accelerated atherosclerosis. Evidence that lymphostasis has an important role in accelerated atherosclerosis, how-
* Letters (from the United States) concerning a particular article in the Journal must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 double-spaced typewritten pages. Two copies must be submitted.
ever, is more persuasive. A lack of clinical evidence of lymphostasis does not exclude its presence in transplanted hearts. Epicardial lymphatic channels, which are subjected to the least external pressure by myocardium, would be most likely to experience inadequate lymphatic drainage. Biopsy specimens of the epicardium have been obtained. Furthermore, anatomic obstruction and stasis of flow in lymphatic channels are not equivalent. Chronic stasis of lymph may occur without obvious anatomic evidence. Lymphostasis has been associated with thickening of the arterial intima, an early finding in atherosclerosis. Jellinek et all1 ligated cardiac lymph nodes in dogs and noted plasma accumulation in the subendothelium of coronary arteries within 6 days. SimP examined resected colon carcinoma specimens and found atherosclerotic changes only in thosesectionsofarteriesinwhichtumorinfiltrates obstructed lymphatic drainage. Interference with flow in lymphatic channels can lead to altered transport through the arterial wall of plasma components. The subsequentproteinstasisandintimaledemamay stimulate local reactions, such as platelet adherence or myointimal proliferation, that would predispose the vessel to atherosclerosis. The lymphostasis may also disturb the balance of liuonroteins in the arterial wa11.13 High-density lipoprotein, whichselectively passes through arterial endothelium and binds cholesterol, may be unable to drain through lymphatics and carry cholesterol to the liver. Low-density lipoprotein, which transports lipids into the arterial wall and is metabolized at the vessel wall, would continue to deposit cholesterol and triglycerides, even in the presence of lymphostasis. The relation of chronic rejection and hyperlipidemia to accelerated atherosclerosis has not been clearly elucidated. Studies have demonstrated that nearly uniform development of accelerated atherosclerosis in heterotopically transplanted hearts occurs despite widely varying degrees of immunosuppression and hypercholesterolemia.3s4 Cholesterol levels correlate better with linid content in atherosclerotic lesions than with the degree of myointimal proliferation in the arterial wall. Furthermore, the presence of chronic rejection in transplant recipients is not consistent. Only one-half of patients with accelerated atherosclerosis demonstrate Bcell antibodies indicative of chronic rejecti0n.l Thus, chronic rejection and hyperlipidemia probably cannot alone account for the process of accelerated atherosclerosis. Lymphostasis may contribute to the development of accelerated atherosclerosis by several mechanisms. First, lymphatic ob-
430
struction, which impairs myocardial healing capacity14 will hinder the repair of an intima persistently damaged by chronic rejection. Second, by inducing protein stasis in the arterial wall, lymphostasis may stimulate local reactions such as platelet adherence or myointimal proliferation. Third, by disturbing the balance of lipoproteins, lympyostasis may cause accumulation of cholesterol in the arterial wall. MEHMET C. 02, MD, MBA New York, New York
CHARLES S. ROBERTS, MD St. Louis, Missouri
GERALD M. LEMOLE, MD Wilmington, Delaware 13 July 1986
1. Hess ML, Hastillo A, Mohanakumar T, Cowley
MJ,Vetrovac G, Szentpetery S, WolfgangTC, LowerRR.Acceleratedatherosclerosisincardiac transplantation: role of cytotoxic B-cell antibodies and hyperlipidemia.Circufation1983;68:suppfII:II-94II-101.
2. Uys CJ, Rose AG. Pathologic findings in Jongterm cardiac transplants. Arch PathoJ Lab Med 1984;108:112-116. 3. Alonso DR, Stark HA, Minick CR. Studies on the nathoeenesis of atherosclerosis induced in rabbit cardiac ollografts by the synergy ofgraftrejection and hypercholesterolmeia. Am J Pathol 1977;87: 415-442 4. Laden AMK. Experimental atherosclerosis in rat and rabbit cardiac transplants. Arch Pathol Lab Med 1984;108:112-116. 5. Hess ML, Hastillo A, Wolfgang TC, Lower RR. The noninvasive diagnosis of acute and chronic cardiac ollograft rejection. Heart Transplantation 1981;1:31-38. 6. Sagar KB, Hastillo A, Wolfgang TC, Lower RR, Hess ML. Left ventricular mass by M-mode echocardiography in cardiac transplant patients with acuterejection.CircuJationI981;64:suppJII:II-21611-220. 7. Miller AJ. Lymphatics of the Heart. New York: Raven Press, 1982:107. 8. Malek P. Some problems of lymphatic stasis in renal transplantation. Experientia [SuppJj 1967; I4:192-196. 9. Scothorne RJ. Lymphatic repair and the genesis of homograft immunity. Ann NY Acad Sci 1958;73: 673-675. 10. Bieber Cp, Stinson EB, Shumway NE, Payne R, Kosek J. Cardiac transplantation in man: cardiac allograft pathology. Circulation 1979;41:753-772. 11. Jellinek H, Gabor G, Solti F, Veress B. The problem of the coronary changes due to disturbances of vascuJarwaJJpermeabiJity.AngioJogyl967;18:I79187. 12. Sims FH. The arterial wall in malignant disease. Atherosclerosis 1979;32:445-450. 13. Lemole GM. The role of Iymphostasis in atherosclerosis. Ann Thorac Surg 1981;31:290-293. 14. Szalvy L, Douglass FA, Hollenberg NK, Abrahms HL. Cardiac lymph and lymphatics in normal and infarcted myocardium. Am Heart J 1980;100:323-331. I
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