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Accelerated coronary arteriosclerosis in cardiac transplant recipients
Glenn R. Barnhart, Edward A. Pascoe, A. Scott Mills Szabolcs Szentpetery, David M. Eich T. Mohanakumar, Andrea Hastillo James A. Thompson, Michael L. Hess Richard R. Lower
2 Accelerated Coronary Arteriosclerosis in Cardiac Transplant Recipients
The premature development of coronary artery obstructive disease in patients after cardiac transplantation currently ranks as the leading cause of death in those who survive the first postoperative year. This accelerated form of atherosclerosis or arteriosclerosis was noted by several observers within a few years after the start of clinical heart transplantation. The second patient transplanted by the Capetown group in 1968, Dr. Philip Blaiberg, received much media attention as the longest survivor until his death at 19 months. The autopsy showed a striking degree of coronary atherosclerosis despite the fact that the donor heart had been obtained from a 24-year-old male with presumably normal coronary arteries.' This complication of cardiac transplantation, which often caused the sudden death of patients who had survived the rigors of the early posttransplant course, undoubtedly influenced some groups to discontinue their heart transplant programs in the 1970s. Even before human trials were initiated, coronary obstructive lesions were noted in dogs which lived for several months after cardiac transplantatioru? this finding was recognized as a potential detriment to prolonged survival. The coronary obstructions in dogs were especially noteworthy since atherogenesis was obviously not a factor. The inescapable conclusion was that these obstructions were the result of chronic immune injury to the vascular endothelium. In the early years of clinical cardiac transplantation, our attention was focused primarily on improving methods of immunosuppression to avoid or treat early rejection and to minimize the risk of infection. With progress in these areas, early survival improved and patients achieved more rapid rehabilitation. The procedure then became much more widely accepted, and the number of patients transplanted rapidly increased. Consequently, many more surviving patients were observed to develop coronary artery disease in their grafts. This problem has TRANSPLANTATION REVIEWS, VOLUME1 ISBN 0-8089-1884·2
© 1987 by Grune & Stratton, Inc.
All rights reserved.
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become the major detriment to long-term survival. Considerations of accelerated graft arteriosclerosis which we will address in this review include factors which may predispose to its development, theories of pathogenesis, methods for diagnosis, and treatment options.
CLINICAL OBSERVATIONS
Three of our earliest transplant patients are illustrative of the problem. The second patient transplanted at the Medical ColIege of Virginia in 1968 was a 43-year-old male with end-stage coronary artery disease consisting of chronic congestive heart failure from multiple myocardial infarctions. He received the heart of a 17-year-old donor. No human leukocyte antigen (HLA) mismatch was identified. His course was relatively benign, with two early rejection episodes identified and treated with pulses of methylprednisolone. Maintenance therapy after the first year included azathioprine, 175 rng/day, and prednisone, 20 mg/daily. He returned to an active life and was the world's longest surviving patient until his rather sudden death 6.5 years after the transplant. At autopsy the left ventricle and septum demonstrated areas of recent and old myocardial infarction. There was thrombosis and complete occlusion of the left anterior descending and right coronary arteries, and the left main coronary artery demonstrated a 50 percent atherosclerotic narrowing. The histopathology demonstrated intimal proliferation, medial necrosis, fibrosis, and minimal mononuclear perivascular infiltration. Our sixth transplant patient was a 36-year-old male with end-stage rheumatic disease who had undergone two prior operations on the rheumatic mitral and aortic valves. He became a class IV heart failure patient from poor left ventricular contractility despite normal valve function. His transplant operation occurred on January II, 1973, with a heart from a 30-year-old male accident victim. There was a two-antigen HLA mismatch, but only one mild rejection episode, which was treated with an increase in steroids on' the eighth postoperative day. The patient subsequently returned to work and remained quite well, from a cardiac standpoint, for about 14 years. Recently, a routine examination revealed a decreased ejection fraction on gated cardiac blood pool scintigraphy (MUGA) scan, and coronary arteriograms demonstrated diffuse coronary disease with a significant obstruction in the proximal left anterior descending artery. The patient recently underwent transluminal angioplasty, with improvement in flow. Our tenth transplant patient was a 28-year-old female with end-stage idiopathic cardiomyopathy who received the heart of a 47-year-old male on November 21, 1974. She was treated once for acute rejection on the 41st postoperative day, diagnosed by biopsy, and again at 5 months. She was relatively well until 3 years after the operation, when signs of pulmonary congestion occurred. She was readmitted to the hospital but died suddenly soon after admission. The autopsy revealed a recent occlusion of the right coronary artery.
Accelerated Coronary Arteriosclerosis
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INCIDENCE The true incidence and the time of onset of clinically significant coronary artery obstruction in the cardiac allograft are difficult to determine for several reasons. These patients do not experience angina because of cardiac de nervation. Routine serial coronary angiography has usually not been undertaken, and sudden death has sometimes been the first indication. Thus, there is no precise method for determining exactly when the disease becomes manifest in each patient, and the criteria used for making the diagnosis vary. Several centers have accumulated adequate long-term experience to analyze the incidence of coronary artery obstruction. The Cape Town group reported that coronary atherosclerosis accounted for the majority of deaths following the first year of transplantation.' In 1982the Stanford transplant group reported coronary atherosclerosis as the cause of death in 14 of 131 patients (10.7 percent)." Of 85 I-year survivors, 21 had coronary angiographic evidence of atherosclerosis. A more recent report from the same group describes the number of patients free of coronary disease at I year to be 96 percent and at 5 years to be 57 percent.' In our. first retrospective analysis of 161 cardiac transplant recipients who survived for up to 14 years after transplantation, we used the criteria of absence of coronary disease at autopsy, negative exercise thallium or (MUGA) scan, and normal coronary arteriograrns to define the absence of significant coronary disease. Standard life table methods were employed in determining the following cumulative freedom from proven coronary disease: 99 percent at I year (11= 161), 96 percent at 2 years (11=65), 63 percent at 4 years (II = 11), and 50 percent at 5 years (11= 4). Thus it can be concluded that accelerated coronary atherosclerosis affects a high percentage of patients by the fifth year after transplantation and accounts for significant morbidity and mortality.
PATHOLOGY
Initial pathologic observations focused on the myocardial changes characterizing acute and chronic rejection. These early observations on experimental animals contain references to arterial and endothelial injury. Kosek et aI. compared the arterial changes in nonimmunosuppressed and immunosuppressed dogs. 2 .6-S Arterial necrosis was present only in untreated dogs with clinical acute rejection. In dogs who survived acute rejection episodes, acellular hyaline eosinophilic scleroprotein replaced arterial wall segments. Mural and adventitial monocyte, lymphocyte, and plasma cell exudates and fibrosis implied a more insidious process. All dogs who survived for more than 3 months had circumferential intimal thickening caused by dense cellular fibrous tissue with luminal narrowing (Fig. 2-1). These authors concluded that arterial intimal fibrosis typified chronic rejection. Alonso et aI. developed an experimental model in rabbit heterotopic cardiac allografts and found a synergistic effect between graft rejection and hypercholesterolemia in the development of coronary artery disease." Platelet aggregates and
Figure 2-1. Coronary arteries from a dog that survived for more than 3 months following cardiac transplantation. Note the intimal proliferation resulting in narrowing.
Figure 2-2. Left anterior descending coronary artery of a 31-year-old male who died of an acute myocardial infarction 18 months after cardiac transplantation. There is marked intracellular lipid accumulation, cholesterol clefts, and mononuclear infiltrate involving the intima and media. The lumen revealed the organizing thrombus responsible for the terminal anterior wall myocardial infarction. (From Caplan M, Hastillo A, Mohanakumart, et al: Immunologic Mechanisms in the atherosclerosis process. Cardiovasc Rev Rep 5:713-721, 1984. With permission.) 34
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Accelerated Coronary Arteriosclerosis
I
'
.
...
•• ,
"
,
. 'I,
••
L..-....1I.~L~'~ ~'i:tl: ~ • Flgure 2-3. Left anterior descending coronary artery of a 44-year-old male 2 years after cardiac transplantation with a documented serum lipid level consistent with type II hyperlipidemia. Note the marked intracellular lipid accumulation. the .proliferative coronary artery myointirnal cells. and the lymphocytes and plasma cytoid cells contributing to the process. The lumen reve als a thrombus. (From Hastillo A. Willis HE, Hess ML : The heart as a target organ of immune inj ury. CUIT Prob Cardiol 6:1-51, 1982. With permission.)
endothelial injury appeared to be early and continuing events in the development of accelerated graft atherosclerosis. Similar changes were reported by Laden'? and have been reported in pigs and primate cardiac allograft recipients. II Surgeons who performed the initial cardiac transplant trials began to recognize similar coronary arterial lesions1.12.13 in humans. These pathologic features in long-term human allografts have been described in some detail by Uys and Rose .14 . 15 These inve stigators described an "obliterative arteritis" manifested by a progressive proliferation of intimal cells , mainly fiberblasts . The thickened intima contained lipid deposits of various degrees and increased intercellular collagen. The large coronary artery branch lesions appeared quite similar in appearance to spontaneous coronary atherosclerosis, with abundant lipid deposition in the thickened intima . Additionally, most large, severely involved branches had signs of old thrombi with fibrous replacement and recanalization. We have found similar lesions in our own patients (Figs. 2-2 and 2-3). In addition to the arterial changes characteristic of spontaneous coronary atherosclerosis, a more proliferative arterial obliteration has been described.
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Figure 2-4. Left anterior descending coronary artery of a 12-year-old boy 11 months after cardiac transplantation. Note the marked intimal hyperplasia, the presence of cholesterol clefts, and the paucity of mononuclear cell infiltration. The patient had been maintained on an immunosuppressive protocol of cyclosporine plus prednisone. Palmer et aI. described coronary changes in a cardiac transplant recipient 11 months following transplantation. 16 The coronary arteries were characterized by myointimal cell proliferation, intimal fibrosis, and an absence of lipid deposition. We (Fig. 2-4) and others'? have seen this form of coronary artery change in the pediatric cardiac transplant recipient. Whether this form of accelerated atherosclerosis represents a unique type of disease or is simply a variation of the lesio~ more typical of spontaneous atherosclerosis remains to be determined.
PATHOGENESIS
There are many unanswered questions concerning the pathogenesis of the coronary artery obstructive disease which occurs in transplanted human hearts (Table 2-1). No single institution has a large enough series of long survivors to make a convincing analysis of the many potential predisposing factors. The two most logical incriminating mechanisms are, first, the immune response of the host to the antigenicity of the graft and, second, the existence in the recipient of genetic or acquired serum characteristics which predispose to the development of vascular atherosclerosis. The immune response of the host was early suspected as a major pathogenic factor when coronary artery lesions were seen in mongrel dog heart transplants in
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Table 2-1 Factors in the Pathogenesis of Accelerated Coronary Atherosclerosis Probable factors Immune response Acute and/or chronic Humoral and/or cell mediated Histocompatibility match Hyperlipidemia Type of maintenance immunosuppression Cyclosporine-induced hypertension Diabetes mellitus Possible factors Donor age Duration of ischemia Use of potassium cardioplegia Recipient obesity Smoking Recipient gender Original cardiac diagnosis
the absence of atherogenesis. 13 Further evidence of an immune response in the pathogenesis is that similar progressive changes are found in the vascular endothelium of renal and liver allografts. 1&-20 Obviously the vascular endothelium of the graft is the first level of contact between the immune responses of the host, both cellular and humoral, and the transplanted organ. The histology of acute, cell-mediated rejection does indeed show injury to endothelial cells as one of its early manifestations, often leading to interstitial edema and hemorrhage. And yet, clinical studies to date have failed to show a clear-cut association between the early onset, severity, or frequency of acute rejection and the later development of occlusive coronary disease in the graft. Indeed, it is not uncommon for patients who demonstrate little or no early rejection by current diagnostic techniques to succumb later from severe coronary obstructive lesions. Thus it must be assumed that the responsible immune mechanisms may differ from the classic first-set, cell-mediated response and may in fact consist of repeated or protracted contact between the humoral antibody and the target endothelium of the graft. The precise type of antibody responsible for such injury has not been identified although its existence is strongly suspected. Ce rilli et al. have shown the existence of a vascular endothelial cell autoantibody (anti-VEC) in patients with peripheral vascular atherosclerotic disease.?' The antigen system seems to be shared by both vascular endothelium and peripheral blood monocytes. The presence of this autoantibody was also demonstrated retrospectively in four patients who had a negative pretransplant lymphocyte crossmatch, but nonetheless were thought to have manifested hyperacute rejection of their cardiac transplants.F Whether this or other types of
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Barnhart, et al.
autoantibodies have a causative role in the later development of severe occlusive disease is yet to be determined. In an attempt to determine whether cardiac transplant recipients develop antibodies to endothelial antigens, we have tested pre- and posttransplant sera from 20 recipients, including 10 who developed severe coronary disease and 10 who did not, against a panel of five arteries by immunohistological methods. All sera were absorbed with platelets to remove anti-major histocompatibility complex (anti-MHC) class I antibodies, and the screening was done using the immunoperoxidase method. None of the sera reacted with the small panel of endothelial tissue, suggesting that the development of anti-(VEC) antibodies is not common. This study is very preliminary and has several limitations, such as the small panel of endothelial tissues and the possibility that the test system is not appropriate to define the antigen in question. We have, however, obtained suggestive evidence that the development of B-cell reactive antibodies may playa role in the pathogenesis of graft coronary atherosclerosis." The presence of cytotoxic B-cell antibodies combined with hyperlipidemia was a predictor of early myocardial infarction and/or sudden death. Histologically, the disease was characterized by severe atherosclerosis, with lymphocytes directed against MHC class I or II organ-specific antigens of endothelium that may not only damage the intima but may also increase the expression of both MHC class II and/or endothelial antigens due to increased amounts of interleukins and/or interferons in the local area. Such exposure may not only enhance killing by T cells but may also account for the production and possible accumulation of antibodies within the area. If the incidence or severity of graft arterial disease is at least in part a result of the host immune responses, the degree of histoincompatibility should have an unfavorable influence. A report by the Stanford group! using multivariate analysis revealed a strong positive association between incompatibility at the HLA-A2 and -A3 loci and the development of coronary obstructive disease. There is increasing evidence that hyperlipidemia plays a significant role in the development of graft coronary atherosclerosis. In addition to the immunologic factors noted in the Stanford study" when serum triglyceride levels were greater than 280 mg/Ioo ml at 1 year, there was a strong correlation with the development of transplant arteriosclerosis, and on multivariate analysis it remained a strong independent variable. It appears that patients treated with cyclosporine and prednisone maintenance immunosuppression have a higher incidence of postoperative hypercholesterolemia than prior patients who were treated with imuran and prednisone." Moreover, if the patients develop diabetes mellitus, there are further increases in both the cholesterol and the cholesterol: high-density lipoprotein (ct:Hdl) ratio. In our patients, the mean cholesterol level in patients who have developed evidence of coronary artery disease by their second anniversary following transplantation is consistently higher than the level in patients who have not developed evidence of coronary artery disease by their fifth anniversary (Fig. 2-5). The inverse relation is true when the mean Hdllevel is analyzed (Fig. 2-6). Further studies are in progress to better define the relationship between cyclosporine and the development of hyperlipidemia.
Accelerated Coronary Arteriosclerosis
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11 t
- - 2ljr CAD - 0 - 5 ljr non-CAD
a n
151>+---+---+--+--+--+--+--+---+---+-~
-2(1
0
*Y.Iths
Figure 2-5. Comparison of mean cholesterol (chol) levels in cardiac transplant recipients who had evidence of coronary artery disease (CAD) at the second anniversary of surgery versus patients who had no evidence of CAD at the fifth anniversary. Cyclosporine-induced hypertension has emerged as a major clinical problem for the cardiac transplant recipient." This form of hypertension is particularly resistant to treatment and in most instances requires multiple drugs for control." Whatever the mechanism, the presence of this refractory hypertension wiII probably have an impact on the acceleration of the atherosclerotic process within the cardiac allograft. A deeper understanding of the mechanisms of cyclosporine-
11 t
- - 2ljt CAD - 0 - 5 ljt non-CAD
i
n
-20
0
co
40
60
eo
100
120
140
160
190
IIIOnths
Figure 2-6. Comparison of mean Hdl levels in cardiac transplant recipients who had evidence of coronary artery disease (CAD) at the second anniversary of surgery versus patients who had no evidence of CAD at the fifth anniversary. Note the inverse relation compared to Figure 2-4.
Barnhart, et al.
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induced hypertension and its treatment is needed for better control of this risk factor. A salutary effect of cyclosporine immunosuppression is the reduction or elimination of maintenance steroids. This may reduce the incidence or severity of coronary disease in the graft, but this desired effect remains to be confirmed. An immunosuppressive protocol with low or no steroids will reduce the incidence of diabetes," and this reduction should have a beneficial effect on the development of accelerated coronary disease. Other potential risk factors in the pathogenesis of accelerated obstructive coronary disease in the transplanted heart should be subjected to further multivariate analysis. These factors include the age of the donor, duration of ischemic time, use of potassium cardioplegia, recipient obesity, smoking, gender of the recipient, and the original cardiac diagnosis. Thus, it is apparent that the multiplicity of factors, both immune and nonimmune, in the donor-recipient combination together with the great variability in management protocols requires a very large cohort of long-surviving patients to sort out those factors which have a strong independent correlation with graft coronary disease. It is likely that only multicenter data collection will allow a sufficiently extensive analysis to provide highly predictive information on pathogenesis ..a nd its modification.
DETECTION AND TREATMENT The precise time when graft coronary artery disease becomes significant may be difficult to identify due often to the insidious nature of its presentation. Since the transplanted heart is denervated, the patient will not manifest myocardial ischemia by experiencing angina pectoris. The clinical presentation may include incipient congestive heart failure due to multiple small myocardial infarcts or sudden death due to acute coronary occlusion without prior warning symptoms. In an effort to detect the onset of significant coronary disease, we employ the examinations listed in Table 2-2 at specified intervals. Holter monitoring may Table 2-2 Diagnostic Studies Performed Every 6 Months by the Medical College of Virginia Transplant Program for Detection of Coronary Artery Disease in Cardiac Transplant Recipients Holter monitoring MUGA scan Lipid profile Total cholesterol Hdl Triglycerides Thallium stress test If any of the above are suggestive. coronary angiography
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Figure 2-7. Coronary angiogram of a 51-year-old male 15 months after cardiac transplantation. There is extensive, diffuse involvement of all major coronary arteries and their secondary and tertiary branches, with no proximal, discrete lesions present. (From Hastillo A, Hess ML, Lower RR: Cardiac transplantation: Expectations and limitations. Mod Con Cardiovasc Dis 50 (March), 1981. With permission.) detect subclinical arrhythmias. Romhilt et aI. documented an association of complex premature ventricular contractions with the occurrence of graft atherosclerosis." A decrease in the ejection fraction on MUGA scan may signify ventricular dysfunction due to myocardial ischemia and/or infarction. An abnormal lipid profile may increase the likelihood of developing graft atherosclerosis; a Ct:Hdl ratio of more than 5 is particularly ominous.'? The thallium stress test has helped to detect ischemic myocardium before actual infarction occurs," although a negative test does not completely rule out coronary disease. Our five patients who have had coronary angioplasty were recognized because of this test. Endomyocardial biopsy can rarely diagnose accelerated graft atherosclerosis. 16,32 When evidence of developing coronary disease is provided by any of the above diagnostic studies, coronary angiography is performed. The coronary angiographic characteristics may differ from those of spontaneous coronary atherosclerosis. Proximal vessel disease is the hallmark of spontaneous atherosclerosis. The lesions in accelerated coronary artery disease tend to result in a more diffuse concentric narrowing and involve the more distal coronary arteries (Figs. 2-7 and 2-8). Angiography of the epicardial coronary arteries can show normal results despite severe intramyocardial atherosclerotic narrowing resulting in multiple diffuse microinfarcts.P We have found proximal vessel disease in only 5 of 12 coronary angiograrns in contrast to distal small-vessel disease in II of 12
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Figure 2-8. Coronary angiogram of the left system in the patient presented in Figure 2-2. There is diffuse tubular involvement of the left anterior descending system. Total' occlusion of the circumflex system had resulted in the electrocardiographic diagnosis of true posterior wall myocardial infarction, with the only symptom being the presentation of heart failure. (From Caplan M, Hastillo A, Mohanakumar T, et al: Immunologic mechanisms in the atherosclerosis process. Cardiovasc. Rev Rep 5:713-721, 1984. With permission.) coronary angiograms performed more than 4 years following cardiac transplantation. 34 In a much larger Stanford series of coronary angiography of cardiac transplant recipients, the coronary disease in the transplant patients appeared to be a mixture of typical coronary atherosclerosis and unique transplant-related progressive distal obliterative disease without collateral developrnent.P If coronary arteriography confirms the presence of significant epicardial proximal coronary artery disease, percutaneous transluminal coronary angioplasty may be considered. 36 •37 This technique has been applied to five of our patients (Figs. 2-9 and 2-10). Three have undergone dilatation of the left anterior descending artery, and the remaining two have undergone multivessel dilatation. Both procedures have increased the lumen diameter angiographically, but given the underlying pathology, this therapy should be considered only as providing temporary benefit. Pharmacologic intervention in the control of accelerated coronary artery disease has been disappointing. An early study from the Stanford transplant group suggested that coumadin and antiplatelet agents might reduce the incidence of graft atherosclerosis.P although more recent reports have discounted any beneficial effect of these agents. 39 •40 Since it appears that hyperlipidemia plays an important role in at least the acceleration of the disease, dietary manipulation and
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Figure 2-9. Coronary angiogram of a 52-year-old male with documented hypercholesterolemia 4 years after cardiac transplantation. Note the abrupt termination of the left anterior descending coronary artery and the severe, diffuse involvement of the first diagonal. There is a critical 95 percent proximal left anterior descending lesion. (From Hastillo A, Cowley MJ, Vetrovec G, et al: Serial coronary angioplasty for atherosclerosis following heart transplantation. J Heart Transplant 4:192-195, 1985. With permission.) the use of lipid-lowering agents should be considered in the medical management of these patients. Progressive atherosclerosis results in decreasing left ventricular function. The final treatment alternative is cardiac retransplantation, which is being required with increasing frequency. Although some success has been reported." the long-term results seem less favorable than those of the initial transplantation." One must balance the present scarcity of donor organs with the potential improvement in a patient's long-term outlook when considering cardiac retransplantation. Thus, the timing of retransplantation is a difficult decision, particularly in the patient who may have diffuse coronary disease and deteriorating left ventricular function, but only minimal or moderate disability. In general, we consider retransplantation only in patients who reach a stage similar to that for which the initial transplantation is done.
COMMENT Late mortality due to accelerated coronary artery disease remains a major problem in the field of cardiac transplantation. The chance of surviving for more than 5 years following cardiac transplantation free of coronary disease is about 50
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Barnhart, et al.
Figure 2-10. One-year follow-up of the patient presented in Figure 2-9. There is continued patency of the proximal left anterior descending lesion that had undergone percutaneous transluminal coronary angioplasty. There does appear to be progression of the atherosclerotic process in both the native and septal perforators of the left anterior descending coronary artery. (From Hastillo A, Cowley MJ, Vetrovec G, et al: Serial coronary angioplasty for atherosclerosis following heart transplantation. J Heart Transplant 4:192-195, 1985. With permission.) percent. Modifications have been made in the care of cardiac transplant patients so that early postoperative morbidity and mortality have decreased. What is not known is whether these modifications will have a favorable or an unfavorable effect on the development of accelerated coronary atherosclerosis. For instance, what role different types of maintenance immunosuppression play in the progression of graft atherosclerosis has yet to be determined. Our present knowledge of possible predisposing factors should lead us to focus more closely on potential therapeutic interventions. If adequate control of serum lipids and hypertension is achieved and accelerated coronary artery disease continues to be a major deterrent to long-term survival, improving immunologic control will be the major hope for preventing it. This will require more precise knowledge of what antigen systems are involved and how they might be manipulated. Additionally, histocompatibility matching may become extremely important, thus altering our present procurement techniques. In conclusion, accelerated coronary artery disease in cardiac transplantation has been recognized since the initial experimental and human trials. Many of the
Accelerated Coronary Arteriosclerosis
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issues of initial management have been resolved, resulting in low early morbidity and mortality. We must now make further refinements in the care affecting late survival. Through experimental and clinical research efforts, both on an individual and an interinstitutional basis, answers must be found to the questions concerning accelerated coronary atherosclerosis in cardiac transplant recipients. REFERENCES \. Thomson JG: Production of severe atheroma in a transplanted human heart. Lancet 2:1088,1969 2. Kosek JC, Hurley EJ, Lower RR: Histopathology of orthotopic canine cardiac homograft. Lab Invest 19:97, 1968 3. Cooper DKC, Novitsky D, Hassoulas J, et al: Heart transplantation: The South African experience. Heart Transplant 2:78, 1982 4. Pennock JL, Oyer PE. Reitz BA, et al: Cardiac transplantation in perspective for the future. J Thorac Cardiovasc Surg 83: 168, 1982 5. Zusman DR, Stinson EB. Oyer PE, et al: Determinants of accelerated graft atherosclerosis (AGAS) in conventional and cyclosporine treated heart transplant recipients. Heart Transplant 4:587, 1985 6. Kosek JC, Hurley EJ. Sewell DH, et al: Histopathology of orthotopic canine cardiac homografts arid its clinical correlation. Transplant Proc 1:311, 1969 7. Kosek JC, Chartrand C, Hurley EJ, et al: Arteries in canine cardiac homografts. Ultrastructure during acute rejection. Lab Invest 21:328, 1969 8. Lower RR, Kosek JC, Kemp VE, et al: Rejection of the cardiac transplant. Am J CardioI24:492, 1969 9. Alonso DR, Storek PK. Minick R: Studies on the pathogenesis of atheroarteriosclerosis induced in rabbit cardiac allografts by the synergy of graft rejection and hypercholesterolemia. Am J Pathol 87:415, 1977 10. Laden AMK: Experimental atherosclerosis in rat and rabbit cardiac allografts. Arch PathoI93:240, 1972 I \. Lurie KG, Billingham ME, Jamieson SW, et al: Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model. Transplantation 31:41, 1981 12. Bieber CP, Stinson EB, Shumway NE. et al: Cardiac transplantation in man. Cardiac allograft pathology. Circulation 41:753, 1970 13. Kosek JC, Bieber C. Lower RR: Heart graft arteriosclerosis. Transplant Proc 3:512, 1971 14. Uys CJ, Rose AG: Pathologic findings in long-term cardiac transplants. Arch Pathol Lab Med 108:112,1984 15. Uys CJ, Rose AG: Cardiac transplantation: Aspects of the pathology. Pathol Ann 17:147,1983 16. Palmer DC, Tsai CC, Roodman ST, et al: Heart graft arteriosclerosis. An ominous finding on endomyocardial biopsy. Transplantation 39:385, 1985 17. Fricker FJ, Griffith BP, Hardesty RL. et al: Experience with heart transplantation in children. Pediatrics 79:138, 1987 18. Ende N. Currier CB. Johnson KH, et al: Unusual vascular findings in transplanted kidneys. Human PathoI 13:272. 1982 19. Snover DC, Freese KD, Sharp HL. et al: Liver allograft rejection. Am J Surg Pathol 11:1, 1987 20. Snover DC, Sibley RK. Freese DK. et al: Orthotopic liver transplantation. HepatoJogy 4:1212, 1984
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21. Cerilli J, Brasile L, Karmody A: Role of the vascular endothelial cell system in the etiology of atherosclerosis. Ann Surg 202:329, 1985 22. Brasile L, Zerbe T, Rabin B, et al: Identification of the antibody to vascular endothelial cells in patients undergoing cardiac transplantation. Transplantation 40:672, 1985 23. Hess ML, Hastillo A, Mohanakurnar T, et al: Accelerated atherosclerosis in cardiac transplantation; Role of cytotoxic B-cell antibodies and hyperlipidemia. Circulation 68:94, 1983 24. Bieber CP, Hunt SA, Schwinn DA, et al: Complications in long-term survivors of cardiac transplantation. Transplant Proc 13:207, 1981 25. Eich D, Hastillo A, Thompson JA, et al: Hyper-cholesterolemia in long-term survivors of cardiac transplantation. J Heart Transplant 5:377, 1986 26. Barnhart GR, Hastillo A, Goldman MH, et al: A prospective randomized trial of pretransfusionlazathioprine/prednisone versus cyclosporine/prednisone immunosuppression in cardiac transplant recipients: Preliminary results. Circulation 72:227, 1985 27. Thqrnpson ME, Shapiro AP, Johnsen A, et al: The contrasting effects of cyclosporin-A and azathioprine on arterial blood pressure and renal function following cardiac transplantation. Int J Cardiol 11:219, 1986 28. Katz M, Barnhart GR, Szentpetery S, et al: Are steroids essential for successful maintenance immunosuppression in cardiac transplantation? J Heart Transplant 5:395, 1986 29. Romhilt DW, Doyle M, Sagar KB, et al: Prevalence and significance of arrhythmias in long-term survivors of cardiac transplantation. Circulation 66:219, 1982 30. Caplan M, Hastillo A, Mohanakurnar T, et al: Immunologic mechanisms in the atherosclerosis process. Cardiovasc Rev Rep 5:713, 1984 31. McKillop JH, Goris ML: Thallium-201 myocardial imaging in patients with previous cardiac transplantation. Clin Radiol 32:447, 1981 32. Chomette G, Auriol M, Delcourt A, et al: Human cardiac transplants. Diagnosis of rejection by endomyocardial biopsy. Virchows Arch 407:295, 1985 33. Mason JW, Strefling A: Small vessel disease of the heart resulting in myocardial necrosis and death despite angiographically normal coronary arteries. Am J Cardiol 44:171,1979 34. Newton M, Vetrovec G, Hastillo A, et al: Coronary angiographic characteristics of chronic cardiac transplant rejection. Circulation 70:174, 1984 . 35. Gao SZ, Alderman E, Schroeder J, et al: Accelerated coronary vascular disease in the heart transplant patient: Coronary arteriographic findings. JACC 9:149A, 1987 36. Hastillo A, Cowley MJ, Vetrovec G, et al: Serial coronary angioplasty for atherosclerosis following heart transplantation. Heart Transplant 4:192, 1985 37. Wohlgelernter D, Stevenson LW, Brunken R: Reversal of ischemic myocardial dysfunction by PTCA in a cardiac transplant patient. Am Heart J 112:837, 1986 38. Griepp RB, Stinson EB, Bieber CP, et al: Control of graft arteriosclerosis in human heart transplant recipients. Surgery 81:262, 1977 39. Nitkin RS, Hunt SA, Schroeder JS: Accelerated atherosclerosis in a cardiac transplant patient. JACC 6:243, 1985 40. Gao SZ, Schroeder JS, Hunt SA, et al: Retransplantation for severe accelerated coronary vascular disease in heart transplant. JACC 9:29A, 1987. 41. Copeland JG, Griepp RB, Bieber CP, et al: Successful retransplantation of the human heart. J Thorac Cardiovasc Surg 73:242, 1977
2 Accelerated Coronary Arteriosclerosis in Cardiac Transplant Recipients
The premature development of coronary artery obstructive disease in patients after cardiac transplantation currently ranks as the leading cause of death in those who survive the first postoperative year. This accelerated form of atherosclerosis or arteriosclerosis was noted by several observers within a few years after the start of clinical heart transplantation. The second patient transplanted by the Capetown group in 1968, Dr. Philip Blaiberg, received much media attention as the longest survivor until his death at 19 months. The autopsy showed a striking degree of coronary atherosclerosis despite the fact that the donor heart had been obtained from a 24-year-old male with presumably normal coronary arteries.' This complication of cardiac transplantation, which often caused the sudden death of patients who had survived the rigors of the early posttransplant course, undoubtedly influenced some groups to discontinue their heart transplant programs in the 1970s. Even before human trials were initiated, coronary obstructive lesions were noted in dogs which lived for several months after cardiac transplantatioru? this finding was recognized as a potential detriment to prolonged survival. The coronary obstructions in dogs were especially noteworthy since atherogenesis was obviously not a factor. The inescapable conclusion was that these obstructions were the result of chronic immune injury to the vascular endothelium. In the early years of clinical cardiac transplantation, our attention was focused primarily on improving methods of immunosuppression to avoid or treat early rejection and to minimize the risk of infection. With progress in these areas, early survival improved and patients achieved more rapid rehabilitation. The procedure then became much more widely accepted, and the number of patients transplanted rapidly increased. Consequently, many more surviving patients were observed to develop coronary artery disease in their grafts. This problem has TRANSPLANTATION REVIEWS, VOLUME1 ISBN 0-8089-1884·2
© 1987 by Grune & Stratton, Inc.
All rights reserved.
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become the major detriment to long-term survival. Considerations of accelerated graft arteriosclerosis which we will address in this review include factors which may predispose to its development, theories of pathogenesis, methods for diagnosis, and treatment options.
CLINICAL OBSERVATIONS
Three of our earliest transplant patients are illustrative of the problem. The second patient transplanted at the Medical ColIege of Virginia in 1968 was a 43-year-old male with end-stage coronary artery disease consisting of chronic congestive heart failure from multiple myocardial infarctions. He received the heart of a 17-year-old donor. No human leukocyte antigen (HLA) mismatch was identified. His course was relatively benign, with two early rejection episodes identified and treated with pulses of methylprednisolone. Maintenance therapy after the first year included azathioprine, 175 rng/day, and prednisone, 20 mg/daily. He returned to an active life and was the world's longest surviving patient until his rather sudden death 6.5 years after the transplant. At autopsy the left ventricle and septum demonstrated areas of recent and old myocardial infarction. There was thrombosis and complete occlusion of the left anterior descending and right coronary arteries, and the left main coronary artery demonstrated a 50 percent atherosclerotic narrowing. The histopathology demonstrated intimal proliferation, medial necrosis, fibrosis, and minimal mononuclear perivascular infiltration. Our sixth transplant patient was a 36-year-old male with end-stage rheumatic disease who had undergone two prior operations on the rheumatic mitral and aortic valves. He became a class IV heart failure patient from poor left ventricular contractility despite normal valve function. His transplant operation occurred on January II, 1973, with a heart from a 30-year-old male accident victim. There was a two-antigen HLA mismatch, but only one mild rejection episode, which was treated with an increase in steroids on' the eighth postoperative day. The patient subsequently returned to work and remained quite well, from a cardiac standpoint, for about 14 years. Recently, a routine examination revealed a decreased ejection fraction on gated cardiac blood pool scintigraphy (MUGA) scan, and coronary arteriograms demonstrated diffuse coronary disease with a significant obstruction in the proximal left anterior descending artery. The patient recently underwent transluminal angioplasty, with improvement in flow. Our tenth transplant patient was a 28-year-old female with end-stage idiopathic cardiomyopathy who received the heart of a 47-year-old male on November 21, 1974. She was treated once for acute rejection on the 41st postoperative day, diagnosed by biopsy, and again at 5 months. She was relatively well until 3 years after the operation, when signs of pulmonary congestion occurred. She was readmitted to the hospital but died suddenly soon after admission. The autopsy revealed a recent occlusion of the right coronary artery.
Accelerated Coronary Arteriosclerosis
33
INCIDENCE The true incidence and the time of onset of clinically significant coronary artery obstruction in the cardiac allograft are difficult to determine for several reasons. These patients do not experience angina because of cardiac de nervation. Routine serial coronary angiography has usually not been undertaken, and sudden death has sometimes been the first indication. Thus, there is no precise method for determining exactly when the disease becomes manifest in each patient, and the criteria used for making the diagnosis vary. Several centers have accumulated adequate long-term experience to analyze the incidence of coronary artery obstruction. The Cape Town group reported that coronary atherosclerosis accounted for the majority of deaths following the first year of transplantation.' In 1982the Stanford transplant group reported coronary atherosclerosis as the cause of death in 14 of 131 patients (10.7 percent)." Of 85 I-year survivors, 21 had coronary angiographic evidence of atherosclerosis. A more recent report from the same group describes the number of patients free of coronary disease at I year to be 96 percent and at 5 years to be 57 percent.' In our. first retrospective analysis of 161 cardiac transplant recipients who survived for up to 14 years after transplantation, we used the criteria of absence of coronary disease at autopsy, negative exercise thallium or (MUGA) scan, and normal coronary arteriograrns to define the absence of significant coronary disease. Standard life table methods were employed in determining the following cumulative freedom from proven coronary disease: 99 percent at I year (11= 161), 96 percent at 2 years (11=65), 63 percent at 4 years (II = 11), and 50 percent at 5 years (11= 4). Thus it can be concluded that accelerated coronary atherosclerosis affects a high percentage of patients by the fifth year after transplantation and accounts for significant morbidity and mortality.
PATHOLOGY
Initial pathologic observations focused on the myocardial changes characterizing acute and chronic rejection. These early observations on experimental animals contain references to arterial and endothelial injury. Kosek et aI. compared the arterial changes in nonimmunosuppressed and immunosuppressed dogs. 2 .6-S Arterial necrosis was present only in untreated dogs with clinical acute rejection. In dogs who survived acute rejection episodes, acellular hyaline eosinophilic scleroprotein replaced arterial wall segments. Mural and adventitial monocyte, lymphocyte, and plasma cell exudates and fibrosis implied a more insidious process. All dogs who survived for more than 3 months had circumferential intimal thickening caused by dense cellular fibrous tissue with luminal narrowing (Fig. 2-1). These authors concluded that arterial intimal fibrosis typified chronic rejection. Alonso et aI. developed an experimental model in rabbit heterotopic cardiac allografts and found a synergistic effect between graft rejection and hypercholesterolemia in the development of coronary artery disease." Platelet aggregates and
Figure 2-1. Coronary arteries from a dog that survived for more than 3 months following cardiac transplantation. Note the intimal proliferation resulting in narrowing.
Figure 2-2. Left anterior descending coronary artery of a 31-year-old male who died of an acute myocardial infarction 18 months after cardiac transplantation. There is marked intracellular lipid accumulation, cholesterol clefts, and mononuclear infiltrate involving the intima and media. The lumen revealed the organizing thrombus responsible for the terminal anterior wall myocardial infarction. (From Caplan M, Hastillo A, Mohanakumart, et al: Immunologic Mechanisms in the atherosclerosis process. Cardiovasc Rev Rep 5:713-721, 1984. With permission.) 34
35
Accelerated Coronary Arteriosclerosis
I
'
.
...
•• ,
"
,
. 'I,
••
L..-....1I.~L~'~ ~'i:tl: ~ • Flgure 2-3. Left anterior descending coronary artery of a 44-year-old male 2 years after cardiac transplantation with a documented serum lipid level consistent with type II hyperlipidemia. Note the marked intracellular lipid accumulation. the .proliferative coronary artery myointirnal cells. and the lymphocytes and plasma cytoid cells contributing to the process. The lumen reve als a thrombus. (From Hastillo A. Willis HE, Hess ML : The heart as a target organ of immune inj ury. CUIT Prob Cardiol 6:1-51, 1982. With permission.)
endothelial injury appeared to be early and continuing events in the development of accelerated graft atherosclerosis. Similar changes were reported by Laden'? and have been reported in pigs and primate cardiac allograft recipients. II Surgeons who performed the initial cardiac transplant trials began to recognize similar coronary arterial lesions1.12.13 in humans. These pathologic features in long-term human allografts have been described in some detail by Uys and Rose .14 . 15 These inve stigators described an "obliterative arteritis" manifested by a progressive proliferation of intimal cells , mainly fiberblasts . The thickened intima contained lipid deposits of various degrees and increased intercellular collagen. The large coronary artery branch lesions appeared quite similar in appearance to spontaneous coronary atherosclerosis, with abundant lipid deposition in the thickened intima . Additionally, most large, severely involved branches had signs of old thrombi with fibrous replacement and recanalization. We have found similar lesions in our own patients (Figs. 2-2 and 2-3). In addition to the arterial changes characteristic of spontaneous coronary atherosclerosis, a more proliferative arterial obliteration has been described.
36
Barnhart, et al.
Figure 2-4. Left anterior descending coronary artery of a 12-year-old boy 11 months after cardiac transplantation. Note the marked intimal hyperplasia, the presence of cholesterol clefts, and the paucity of mononuclear cell infiltration. The patient had been maintained on an immunosuppressive protocol of cyclosporine plus prednisone. Palmer et aI. described coronary changes in a cardiac transplant recipient 11 months following transplantation. 16 The coronary arteries were characterized by myointimal cell proliferation, intimal fibrosis, and an absence of lipid deposition. We (Fig. 2-4) and others'? have seen this form of coronary artery change in the pediatric cardiac transplant recipient. Whether this form of accelerated atherosclerosis represents a unique type of disease or is simply a variation of the lesio~ more typical of spontaneous atherosclerosis remains to be determined.
PATHOGENESIS
There are many unanswered questions concerning the pathogenesis of the coronary artery obstructive disease which occurs in transplanted human hearts (Table 2-1). No single institution has a large enough series of long survivors to make a convincing analysis of the many potential predisposing factors. The two most logical incriminating mechanisms are, first, the immune response of the host to the antigenicity of the graft and, second, the existence in the recipient of genetic or acquired serum characteristics which predispose to the development of vascular atherosclerosis. The immune response of the host was early suspected as a major pathogenic factor when coronary artery lesions were seen in mongrel dog heart transplants in
Accelerated Coronary Arteriosclerosis
37
Table 2-1 Factors in the Pathogenesis of Accelerated Coronary Atherosclerosis Probable factors Immune response Acute and/or chronic Humoral and/or cell mediated Histocompatibility match Hyperlipidemia Type of maintenance immunosuppression Cyclosporine-induced hypertension Diabetes mellitus Possible factors Donor age Duration of ischemia Use of potassium cardioplegia Recipient obesity Smoking Recipient gender Original cardiac diagnosis
the absence of atherogenesis. 13 Further evidence of an immune response in the pathogenesis is that similar progressive changes are found in the vascular endothelium of renal and liver allografts. 1&-20 Obviously the vascular endothelium of the graft is the first level of contact between the immune responses of the host, both cellular and humoral, and the transplanted organ. The histology of acute, cell-mediated rejection does indeed show injury to endothelial cells as one of its early manifestations, often leading to interstitial edema and hemorrhage. And yet, clinical studies to date have failed to show a clear-cut association between the early onset, severity, or frequency of acute rejection and the later development of occlusive coronary disease in the graft. Indeed, it is not uncommon for patients who demonstrate little or no early rejection by current diagnostic techniques to succumb later from severe coronary obstructive lesions. Thus it must be assumed that the responsible immune mechanisms may differ from the classic first-set, cell-mediated response and may in fact consist of repeated or protracted contact between the humoral antibody and the target endothelium of the graft. The precise type of antibody responsible for such injury has not been identified although its existence is strongly suspected. Ce rilli et al. have shown the existence of a vascular endothelial cell autoantibody (anti-VEC) in patients with peripheral vascular atherosclerotic disease.?' The antigen system seems to be shared by both vascular endothelium and peripheral blood monocytes. The presence of this autoantibody was also demonstrated retrospectively in four patients who had a negative pretransplant lymphocyte crossmatch, but nonetheless were thought to have manifested hyperacute rejection of their cardiac transplants.F Whether this or other types of
38
Barnhart, et al.
autoantibodies have a causative role in the later development of severe occlusive disease is yet to be determined. In an attempt to determine whether cardiac transplant recipients develop antibodies to endothelial antigens, we have tested pre- and posttransplant sera from 20 recipients, including 10 who developed severe coronary disease and 10 who did not, against a panel of five arteries by immunohistological methods. All sera were absorbed with platelets to remove anti-major histocompatibility complex (anti-MHC) class I antibodies, and the screening was done using the immunoperoxidase method. None of the sera reacted with the small panel of endothelial tissue, suggesting that the development of anti-(VEC) antibodies is not common. This study is very preliminary and has several limitations, such as the small panel of endothelial tissues and the possibility that the test system is not appropriate to define the antigen in question. We have, however, obtained suggestive evidence that the development of B-cell reactive antibodies may playa role in the pathogenesis of graft coronary atherosclerosis." The presence of cytotoxic B-cell antibodies combined with hyperlipidemia was a predictor of early myocardial infarction and/or sudden death. Histologically, the disease was characterized by severe atherosclerosis, with lymphocytes directed against MHC class I or II organ-specific antigens of endothelium that may not only damage the intima but may also increase the expression of both MHC class II and/or endothelial antigens due to increased amounts of interleukins and/or interferons in the local area. Such exposure may not only enhance killing by T cells but may also account for the production and possible accumulation of antibodies within the area. If the incidence or severity of graft arterial disease is at least in part a result of the host immune responses, the degree of histoincompatibility should have an unfavorable influence. A report by the Stanford group! using multivariate analysis revealed a strong positive association between incompatibility at the HLA-A2 and -A3 loci and the development of coronary obstructive disease. There is increasing evidence that hyperlipidemia plays a significant role in the development of graft coronary atherosclerosis. In addition to the immunologic factors noted in the Stanford study" when serum triglyceride levels were greater than 280 mg/Ioo ml at 1 year, there was a strong correlation with the development of transplant arteriosclerosis, and on multivariate analysis it remained a strong independent variable. It appears that patients treated with cyclosporine and prednisone maintenance immunosuppression have a higher incidence of postoperative hypercholesterolemia than prior patients who were treated with imuran and prednisone." Moreover, if the patients develop diabetes mellitus, there are further increases in both the cholesterol and the cholesterol: high-density lipoprotein (ct:Hdl) ratio. In our patients, the mean cholesterol level in patients who have developed evidence of coronary artery disease by their second anniversary following transplantation is consistently higher than the level in patients who have not developed evidence of coronary artery disease by their fifth anniversary (Fig. 2-5). The inverse relation is true when the mean Hdllevel is analyzed (Fig. 2-6). Further studies are in progress to better define the relationship between cyclosporine and the development of hyperlipidemia.
Accelerated Coronary Arteriosclerosis
39
11 t
- - 2ljr CAD - 0 - 5 ljr non-CAD
a n
151>+---+---+--+--+--+--+--+---+---+-~
-2(1
0
*Y.Iths
Figure 2-5. Comparison of mean cholesterol (chol) levels in cardiac transplant recipients who had evidence of coronary artery disease (CAD) at the second anniversary of surgery versus patients who had no evidence of CAD at the fifth anniversary. Cyclosporine-induced hypertension has emerged as a major clinical problem for the cardiac transplant recipient." This form of hypertension is particularly resistant to treatment and in most instances requires multiple drugs for control." Whatever the mechanism, the presence of this refractory hypertension wiII probably have an impact on the acceleration of the atherosclerotic process within the cardiac allograft. A deeper understanding of the mechanisms of cyclosporine-
11 t
- - 2ljt CAD - 0 - 5 ljt non-CAD
i
n
-20
0
co
40
60
eo
100
120
140
160
190
IIIOnths
Figure 2-6. Comparison of mean Hdl levels in cardiac transplant recipients who had evidence of coronary artery disease (CAD) at the second anniversary of surgery versus patients who had no evidence of CAD at the fifth anniversary. Note the inverse relation compared to Figure 2-4.
Barnhart, et al.
40
induced hypertension and its treatment is needed for better control of this risk factor. A salutary effect of cyclosporine immunosuppression is the reduction or elimination of maintenance steroids. This may reduce the incidence or severity of coronary disease in the graft, but this desired effect remains to be confirmed. An immunosuppressive protocol with low or no steroids will reduce the incidence of diabetes," and this reduction should have a beneficial effect on the development of accelerated coronary disease. Other potential risk factors in the pathogenesis of accelerated obstructive coronary disease in the transplanted heart should be subjected to further multivariate analysis. These factors include the age of the donor, duration of ischemic time, use of potassium cardioplegia, recipient obesity, smoking, gender of the recipient, and the original cardiac diagnosis. Thus, it is apparent that the multiplicity of factors, both immune and nonimmune, in the donor-recipient combination together with the great variability in management protocols requires a very large cohort of long-surviving patients to sort out those factors which have a strong independent correlation with graft coronary disease. It is likely that only multicenter data collection will allow a sufficiently extensive analysis to provide highly predictive information on pathogenesis ..a nd its modification.
DETECTION AND TREATMENT The precise time when graft coronary artery disease becomes significant may be difficult to identify due often to the insidious nature of its presentation. Since the transplanted heart is denervated, the patient will not manifest myocardial ischemia by experiencing angina pectoris. The clinical presentation may include incipient congestive heart failure due to multiple small myocardial infarcts or sudden death due to acute coronary occlusion without prior warning symptoms. In an effort to detect the onset of significant coronary disease, we employ the examinations listed in Table 2-2 at specified intervals. Holter monitoring may Table 2-2 Diagnostic Studies Performed Every 6 Months by the Medical College of Virginia Transplant Program for Detection of Coronary Artery Disease in Cardiac Transplant Recipients Holter monitoring MUGA scan Lipid profile Total cholesterol Hdl Triglycerides Thallium stress test If any of the above are suggestive. coronary angiography
Accelerated Coronary Arteriosclerosis
41
Figure 2-7. Coronary angiogram of a 51-year-old male 15 months after cardiac transplantation. There is extensive, diffuse involvement of all major coronary arteries and their secondary and tertiary branches, with no proximal, discrete lesions present. (From Hastillo A, Hess ML, Lower RR: Cardiac transplantation: Expectations and limitations. Mod Con Cardiovasc Dis 50 (March), 1981. With permission.) detect subclinical arrhythmias. Romhilt et aI. documented an association of complex premature ventricular contractions with the occurrence of graft atherosclerosis." A decrease in the ejection fraction on MUGA scan may signify ventricular dysfunction due to myocardial ischemia and/or infarction. An abnormal lipid profile may increase the likelihood of developing graft atherosclerosis; a Ct:Hdl ratio of more than 5 is particularly ominous.'? The thallium stress test has helped to detect ischemic myocardium before actual infarction occurs," although a negative test does not completely rule out coronary disease. Our five patients who have had coronary angioplasty were recognized because of this test. Endomyocardial biopsy can rarely diagnose accelerated graft atherosclerosis. 16,32 When evidence of developing coronary disease is provided by any of the above diagnostic studies, coronary angiography is performed. The coronary angiographic characteristics may differ from those of spontaneous coronary atherosclerosis. Proximal vessel disease is the hallmark of spontaneous atherosclerosis. The lesions in accelerated coronary artery disease tend to result in a more diffuse concentric narrowing and involve the more distal coronary arteries (Figs. 2-7 and 2-8). Angiography of the epicardial coronary arteries can show normal results despite severe intramyocardial atherosclerotic narrowing resulting in multiple diffuse microinfarcts.P We have found proximal vessel disease in only 5 of 12 coronary angiograrns in contrast to distal small-vessel disease in II of 12
42
Barnhart, et al.
Figure 2-8. Coronary angiogram of the left system in the patient presented in Figure 2-2. There is diffuse tubular involvement of the left anterior descending system. Total' occlusion of the circumflex system had resulted in the electrocardiographic diagnosis of true posterior wall myocardial infarction, with the only symptom being the presentation of heart failure. (From Caplan M, Hastillo A, Mohanakumar T, et al: Immunologic mechanisms in the atherosclerosis process. Cardiovasc. Rev Rep 5:713-721, 1984. With permission.) coronary angiograms performed more than 4 years following cardiac transplantation. 34 In a much larger Stanford series of coronary angiography of cardiac transplant recipients, the coronary disease in the transplant patients appeared to be a mixture of typical coronary atherosclerosis and unique transplant-related progressive distal obliterative disease without collateral developrnent.P If coronary arteriography confirms the presence of significant epicardial proximal coronary artery disease, percutaneous transluminal coronary angioplasty may be considered. 36 •37 This technique has been applied to five of our patients (Figs. 2-9 and 2-10). Three have undergone dilatation of the left anterior descending artery, and the remaining two have undergone multivessel dilatation. Both procedures have increased the lumen diameter angiographically, but given the underlying pathology, this therapy should be considered only as providing temporary benefit. Pharmacologic intervention in the control of accelerated coronary artery disease has been disappointing. An early study from the Stanford transplant group suggested that coumadin and antiplatelet agents might reduce the incidence of graft atherosclerosis.P although more recent reports have discounted any beneficial effect of these agents. 39 •40 Since it appears that hyperlipidemia plays an important role in at least the acceleration of the disease, dietary manipulation and
Accelerated Coronary Arteriosclerosis
43
Figure 2-9. Coronary angiogram of a 52-year-old male with documented hypercholesterolemia 4 years after cardiac transplantation. Note the abrupt termination of the left anterior descending coronary artery and the severe, diffuse involvement of the first diagonal. There is a critical 95 percent proximal left anterior descending lesion. (From Hastillo A, Cowley MJ, Vetrovec G, et al: Serial coronary angioplasty for atherosclerosis following heart transplantation. J Heart Transplant 4:192-195, 1985. With permission.) the use of lipid-lowering agents should be considered in the medical management of these patients. Progressive atherosclerosis results in decreasing left ventricular function. The final treatment alternative is cardiac retransplantation, which is being required with increasing frequency. Although some success has been reported." the long-term results seem less favorable than those of the initial transplantation." One must balance the present scarcity of donor organs with the potential improvement in a patient's long-term outlook when considering cardiac retransplantation. Thus, the timing of retransplantation is a difficult decision, particularly in the patient who may have diffuse coronary disease and deteriorating left ventricular function, but only minimal or moderate disability. In general, we consider retransplantation only in patients who reach a stage similar to that for which the initial transplantation is done.
COMMENT Late mortality due to accelerated coronary artery disease remains a major problem in the field of cardiac transplantation. The chance of surviving for more than 5 years following cardiac transplantation free of coronary disease is about 50
44
Barnhart, et al.
Figure 2-10. One-year follow-up of the patient presented in Figure 2-9. There is continued patency of the proximal left anterior descending lesion that had undergone percutaneous transluminal coronary angioplasty. There does appear to be progression of the atherosclerotic process in both the native and septal perforators of the left anterior descending coronary artery. (From Hastillo A, Cowley MJ, Vetrovec G, et al: Serial coronary angioplasty for atherosclerosis following heart transplantation. J Heart Transplant 4:192-195, 1985. With permission.) percent. Modifications have been made in the care of cardiac transplant patients so that early postoperative morbidity and mortality have decreased. What is not known is whether these modifications will have a favorable or an unfavorable effect on the development of accelerated coronary atherosclerosis. For instance, what role different types of maintenance immunosuppression play in the progression of graft atherosclerosis has yet to be determined. Our present knowledge of possible predisposing factors should lead us to focus more closely on potential therapeutic interventions. If adequate control of serum lipids and hypertension is achieved and accelerated coronary artery disease continues to be a major deterrent to long-term survival, improving immunologic control will be the major hope for preventing it. This will require more precise knowledge of what antigen systems are involved and how they might be manipulated. Additionally, histocompatibility matching may become extremely important, thus altering our present procurement techniques. In conclusion, accelerated coronary artery disease in cardiac transplantation has been recognized since the initial experimental and human trials. Many of the
Accelerated Coronary Arteriosclerosis
45
issues of initial management have been resolved, resulting in low early morbidity and mortality. We must now make further refinements in the care affecting late survival. Through experimental and clinical research efforts, both on an individual and an interinstitutional basis, answers must be found to the questions concerning accelerated coronary atherosclerosis in cardiac transplant recipients. REFERENCES \. Thomson JG: Production of severe atheroma in a transplanted human heart. Lancet 2:1088,1969 2. Kosek JC, Hurley EJ, Lower RR: Histopathology of orthotopic canine cardiac homograft. Lab Invest 19:97, 1968 3. Cooper DKC, Novitsky D, Hassoulas J, et al: Heart transplantation: The South African experience. Heart Transplant 2:78, 1982 4. Pennock JL, Oyer PE. Reitz BA, et al: Cardiac transplantation in perspective for the future. J Thorac Cardiovasc Surg 83: 168, 1982 5. Zusman DR, Stinson EB. Oyer PE, et al: Determinants of accelerated graft atherosclerosis (AGAS) in conventional and cyclosporine treated heart transplant recipients. Heart Transplant 4:587, 1985 6. Kosek JC, Hurley EJ. Sewell DH, et al: Histopathology of orthotopic canine cardiac homografts arid its clinical correlation. Transplant Proc 1:311, 1969 7. Kosek JC, Chartrand C, Hurley EJ, et al: Arteries in canine cardiac homografts. Ultrastructure during acute rejection. Lab Invest 21:328, 1969 8. Lower RR, Kosek JC, Kemp VE, et al: Rejection of the cardiac transplant. Am J CardioI24:492, 1969 9. Alonso DR, Storek PK. Minick R: Studies on the pathogenesis of atheroarteriosclerosis induced in rabbit cardiac allografts by the synergy of graft rejection and hypercholesterolemia. Am J Pathol 87:415, 1977 10. Laden AMK: Experimental atherosclerosis in rat and rabbit cardiac allografts. Arch PathoI93:240, 1972 I \. Lurie KG, Billingham ME, Jamieson SW, et al: Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model. Transplantation 31:41, 1981 12. Bieber CP, Stinson EB, Shumway NE. et al: Cardiac transplantation in man. Cardiac allograft pathology. Circulation 41:753, 1970 13. Kosek JC, Bieber C. Lower RR: Heart graft arteriosclerosis. Transplant Proc 3:512, 1971 14. Uys CJ, Rose AG: Pathologic findings in long-term cardiac transplants. Arch Pathol Lab Med 108:112,1984 15. Uys CJ, Rose AG: Cardiac transplantation: Aspects of the pathology. Pathol Ann 17:147,1983 16. Palmer DC, Tsai CC, Roodman ST, et al: Heart graft arteriosclerosis. An ominous finding on endomyocardial biopsy. Transplantation 39:385, 1985 17. Fricker FJ, Griffith BP, Hardesty RL. et al: Experience with heart transplantation in children. Pediatrics 79:138, 1987 18. Ende N. Currier CB. Johnson KH, et al: Unusual vascular findings in transplanted kidneys. Human PathoI 13:272. 1982 19. Snover DC, Freese KD, Sharp HL. et al: Liver allograft rejection. Am J Surg Pathol 11:1, 1987 20. Snover DC, Sibley RK. Freese DK. et al: Orthotopic liver transplantation. HepatoJogy 4:1212, 1984
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21. Cerilli J, Brasile L, Karmody A: Role of the vascular endothelial cell system in the etiology of atherosclerosis. Ann Surg 202:329, 1985 22. Brasile L, Zerbe T, Rabin B, et al: Identification of the antibody to vascular endothelial cells in patients undergoing cardiac transplantation. Transplantation 40:672, 1985 23. Hess ML, Hastillo A, Mohanakurnar T, et al: Accelerated atherosclerosis in cardiac transplantation; Role of cytotoxic B-cell antibodies and hyperlipidemia. Circulation 68:94, 1983 24. Bieber CP, Hunt SA, Schwinn DA, et al: Complications in long-term survivors of cardiac transplantation. Transplant Proc 13:207, 1981 25. Eich D, Hastillo A, Thompson JA, et al: Hyper-cholesterolemia in long-term survivors of cardiac transplantation. J Heart Transplant 5:377, 1986 26. Barnhart GR, Hastillo A, Goldman MH, et al: A prospective randomized trial of pretransfusionlazathioprine/prednisone versus cyclosporine/prednisone immunosuppression in cardiac transplant recipients: Preliminary results. Circulation 72:227, 1985 27. Thqrnpson ME, Shapiro AP, Johnsen A, et al: The contrasting effects of cyclosporin-A and azathioprine on arterial blood pressure and renal function following cardiac transplantation. Int J Cardiol 11:219, 1986 28. Katz M, Barnhart GR, Szentpetery S, et al: Are steroids essential for successful maintenance immunosuppression in cardiac transplantation? J Heart Transplant 5:395, 1986 29. Romhilt DW, Doyle M, Sagar KB, et al: Prevalence and significance of arrhythmias in long-term survivors of cardiac transplantation. Circulation 66:219, 1982 30. Caplan M, Hastillo A, Mohanakurnar T, et al: Immunologic mechanisms in the atherosclerosis process. Cardiovasc Rev Rep 5:713, 1984 31. McKillop JH, Goris ML: Thallium-201 myocardial imaging in patients with previous cardiac transplantation. Clin Radiol 32:447, 1981 32. Chomette G, Auriol M, Delcourt A, et al: Human cardiac transplants. Diagnosis of rejection by endomyocardial biopsy. Virchows Arch 407:295, 1985 33. Mason JW, Strefling A: Small vessel disease of the heart resulting in myocardial necrosis and death despite angiographically normal coronary arteries. Am J Cardiol 44:171,1979 34. Newton M, Vetrovec G, Hastillo A, et al: Coronary angiographic characteristics of chronic cardiac transplant rejection. Circulation 70:174, 1984 . 35. Gao SZ, Alderman E, Schroeder J, et al: Accelerated coronary vascular disease in the heart transplant patient: Coronary arteriographic findings. JACC 9:149A, 1987 36. Hastillo A, Cowley MJ, Vetrovec G, et al: Serial coronary angioplasty for atherosclerosis following heart transplantation. Heart Transplant 4:192, 1985 37. Wohlgelernter D, Stevenson LW, Brunken R: Reversal of ischemic myocardial dysfunction by PTCA in a cardiac transplant patient. Am Heart J 112:837, 1986 38. Griepp RB, Stinson EB, Bieber CP, et al: Control of graft arteriosclerosis in human heart transplant recipients. Surgery 81:262, 1977 39. Nitkin RS, Hunt SA, Schroeder JS: Accelerated atherosclerosis in a cardiac transplant patient. JACC 6:243, 1985 40. Gao SZ, Schroeder JS, Hunt SA, et al: Retransplantation for severe accelerated coronary vascular disease in heart transplant. JACC 9:29A, 1987. 41. Copeland JG, Griepp RB, Bieber CP, et al: Successful retransplantation of the human heart. J Thorac Cardiovasc Surg 73:242, 1977