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Accelerated coronary atherosclerosis in cardiac transplantation
Accelerated Coronary Atherosclerosis in Cardiac Transplantation David O. Taylor, Hassan M. Ibrahim) DavidR. Tolman) andMichael L. Hess
r thotopic heart transplantation has become a
O standard treatment for severe, irreversible heart failure. The survival rate after cardiac transplantation according to the latest International Society of Heart Transplantation Registry (1990) is 81% after I year" This figure has been attributed to better supportive care, better immunosuppression with the introduction ofcyclosporine in 1981, and the improvement in the diagnosis and treatment of rejection and infection. This spectacular success in the short-term is shadowed by the development of accelerated coronary artery disease in long-term survivors, making it the most common cause for both late death and retransplantation. In this article we will discuss the pathology, current theories related to etiologies and risk factors, clinical presentations, and possible treatment options for this accelerated allograft atherosclerosis.
Pathology Johnson et af from Stanford University, recently reviewed their pathological experience with 61 human cardiac allografts and divided the findings into 5 morphological categories. The first category consisted of 7 grafts surviving I day to 6.57 months (mean, 2.2 months), and having no evidence of intimal thickening. The second category consisted of 29 grafts having fibrous intimal hyperplasia that was limited to the proximal and middle segments of the epicardial arteries. It was found in grafts as early as I week and as late as 53 months, but 83% of the transplanted hearts studied survived less than I year. Foam cells were rare and the internal elastic lamina was intact. The intimal hyperplasia was primarily
From The Cardiac Transplantation Program, The Medical College if Virginia, Departments if Surgf1)' and Medicin«, Virginia Commonuealth Unicersity, Richmond, J-:4. Supported in part by Grant-in-Aid Ko. RROoo65 from the National Institutes ifHealth totheClinical Research Center iftheMedical College if Virginia Hospitals, Address reprint requests to .lfichaelL Hess, MD, Box 281, .lfedical College ifVirginia, Richmond, J:'123298. CopJright e 1991!?J' WE. Saunders Company 0955·170:
due to smooth muscle cell proliferation. Luminal compromise was mild to moderate in most grafts, but 2 grafts had> 75% luminal narrowing. The third category consisted of a diffuse necrotizing vasculitis that was present in 4 grafts surviving 7 to 13 months. Intimal thickening was also noted in all 4 grafts, and 3 of these had moderate to severe myocardial rejection at the time of necropsy. The fourth category consisted of 12 grafts with "fibrofatty atheromatous plaques of proximal to middle regions of epicardial arteries only." The smaller arteries had relatively normal morphology and the lesions resembled those occurring in "native" atherosclerosis. The survival times ranged from 13 to 143 months (mean, 67.5). Earlier lesions typically had lipid-laden mononuclear cells found in a fibrotic intima, whereas older lesions had complex plaques with extracellular, as well as intracellular lipid deposition. Calcification occurred in all 4 hearts surviving more than 5 years. In addition, 91% of hearts surviving less than 5 years had concentric lesions whereas 64% of hearts surviving greater than 5 years had eccentric lesions. The fifth category consisted of9 allografts surviving 15 to 134 months (mean, 56 months) which demonstrated "diffuse fibrous intimal thickening with or without atheromatous plaques." The individual lesions were similar to other categories noted previously with the major difference being the diffuse distribution. Also, there was complete replacement of the media and adventitia with fibrous tissue in 4 of the 9 grafts. Five of the 9 grafts had thrombosis noted, usually in distal epicardial segments. It is possible that this pattern starts as a diffuse necrotizing vasculitis with medial necrosis that subsequently heals by scarring of the media and luminal narrowing due to chronic inflammation, intimal fibrosis, intramural hemorrhage, and thrombosis. There was I patient (3%) in the large vessel fibrointimal hyperplasia group, I patient (25%) in the necrotizing vasculitis group, 5 patients (50%) in the large vessel atheroma group, and 8 patients (89%) in the diffuse fibrointimal thickening and/or atheroma group who died or required retransplantation for the coronary vascular disease. Thus, histologically, cardiac allograft "arter-
Transplantation Recieus, Vol5, N03 (fu!J), 1991:pp 165-171
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opathy" encompasses a wide spectrum of disease that may represent different extremes of a single ongoing process, multiple interrelated processes, or, possibly,multiple independent processes.
Incidence The incidence of angiographic coronary artery disease in heart transplantation recipients was first reported by Bieber et al 3 to be 40% at 5 years after transplant. More recent data suggest that the incidence in the United States is essentially unchanged and is 6% to 18% at I year, 23% at 2 years, 46% at 3 years, and 48% at 4 years, 50% at 5 years, and 66% at 6 years after heart transplantation.t" However, the incidence of atherosclerosis at autopsy or necropsy is much higher. Gao et al9 at Stanford University reported a 72% incidence of fibrointimal thickening at 3 months after transplantation, a 94% incidence between 3 and 12 months, and a 100% incidence 1 year after transplantation. Interestingly, 100% of angiographically normal segments exhibited pathological evidence of coronary artery disease. Johnson et al'" reviewed detailed gross and histopathology in 10 allografts having coronal)' arteriography within 2 months of necropsy. The mean graft survival was 52 months (14 to 135 months) and the cause of death or retransplantation was coronary atherosclerosis in all cases, all angiographically "normal" segments had disease, primarily fibrointimal hyperplasia narrowing the lumen from 1% to 57%. Focal lesions consisted primarily of atheromatous lesions, and diffuse concentration narrowings consisted primarily of fibrointimal hyperplasia. Coronary angiography was insensitive for detecting early graft coronary disease and often underestimated the severity ofangiographically identified disease. Therefore, it is not a question of whether a patient "ill develop coronal)' allograft atherosclerosis, but rather what type and how severe.
Clinical Presentation and Diagnosis Because the cardiac allograft lacks innervation, the typical symptoms of myocardial ischemia do not occur, resulting in a syndrome of silent myocardial ischemia. Most commonly, patients present with progressive deterioration of exercise tolerance or a significant decrease in the left ventricular systolic function found on routine echocardiogram, radionuc1ide ventriculogram, or angiography. It is not uncommon for patients to present for the first time with a
full-blown picture of congestive heart failure, pulmo-
nal)' edema, sudden cardiac death, or malignant arrhythmias. The silent and rapid nature of this disease mandates aggressive surveillance to detect the earliest signs of allograft arteriosclerosis. The Medical College of Virginia has adopted a policy of obtaining a baseline coronal)' angiogram within 3 months of transplant, and yearly thereafter. The angiogram might show a variety of lesions (Figs 1 and 2) depending on the underlying pathology. Frequently, it is a mixture of typical atheromatous lesions found in naturally occurring atherosclerosis and a unique transplant-related progressive distal obliterative disease. Gao et al" classified these angiographic lesions into three categories. Type A is characterized by discrete or tubular stenosis of the type typically found in nontransplant angiograms. This t}pe constitutes 76% of the transplant angiographic lesions. Type B is characterized by diffuse concentric narrowing prominent in the middle to distal vessels with distal vessel obliteration or pruning. This t}pe constitutes 15% of transplant lesions and is rarely found in nontransplant disease. Type C is characterized by narrowed irregular distal branches with loss of small branches and squared offterminations that end abruptly. Type C constitutes 10% of transplant lesions. It is found predominantly in the terminal branch of segments and rarely found in nontransplant disease. Another major difference is the lack of collateral blood supply to occluded vessels. Seventy-six percent of occluded vessels in nontransplant patients had good collateral vessels present, but less than 10% of occluded vessels in transplant patients had good collaterals. In addition, occluded vessels in transplant patients are more likely to be occluded distally (49% v 3.5%) and less likely to be occluded proximately (43% v 72%). It should be emphasized that even though the coronal)' angiogram seems to be the best way for early detection of allograft arteriosclerosis, it is far from perfect in diagnosing early or advanced small vessel disease. TIle use of noninvasive methods for detecting allograft atherosclerosis has been disappointing. Exercise qualitative 2°'TI myocardial imaging has been shown to lack sensitivity and specificitybecause of the nature of this disease and the extensive involvement of small vcssels.f More recently however, Fitzpatrick et al," using exercise single-photon emission computed tomography (SPECT) 20lTI reported a sensitivity of82% and a specificity of'Bl% for detecting major epicardial stenoses (> 50%). Radionuclide ventriculography and echocardio-
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Figure 1. Selective coronary angiogram of the left coronary artery system in a man I year after retransplantation for severe, recurrent accelerated coronary atherosclerosis 4 years after the initial transplantation. Note the significant "pruning" of the distal, small epicardial vessels with what seems to be angiographically "normal" large epicardial vessels.
graphy are used routinely in follow-up studies to evaluate the overall systolic function of the heart and to assess the presence of regional wall motion abnormalitics. Unfortunately these findings arc late manifestations of advanced coronary arteriosclerosis, The true value of Holter monitoring in the surveillance for clinically significant graft coronary artery disease is uncertain. Romhilt et all! showed that the presence of complex ventricular ectopy was associated with higher incidence of coronary artery disease in patients on prednisone and azathioprine. Although coronal)' artery disease has been demonstrated on endomyocardial biopsy," it is not often observed, even in advanced disease, Coronal)' flow reserve determination and intracoronal)' ultrasound arc two promising investigational
tools that might open a new era in early detection and pathophysiology of graft arteriosclerosis, Extensive investigations arc currently underway exploring these methods.
Potential Etiology Until recently there has been a paucity of basic investigations into transplant-related accelerated coronal)' artery disease, but fortunately there is now a growing body of experimental data. It is agreed that the problem is significant, having a 50% 5-year incidence in cardiac transplantation, but the etiology, pathogenesis, and treatment of this disease remain elusive. The "chronic vascular rejection" theory is
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Figure 2. Selective coronary angiogram of the len coronary artery system in a patient 5 years after transplantation. Note the significant and diffuse involvement of both the large and small epicardial coronary art eries and the proximal "type AU lesion of the len anterior descending coronary artery associated with significant distal pruning and occlusion.
favored by most experts in the field as the basic underlying mechanism. TIle transplanted heart seems to express the two major histocompatibility antigen classes, class I (A,B,C) and class II (D-related), which are not expressed in the normal heart. Following transplantation there is a rapid expression of class I antigens, T'-lymphocyte activation, and cell-mediated rejection." Class II antigens are expressed 100 to 200 days posttransplant on the myocyte and endothelial cells, and are strongly associated with the emergence of the accelerated atherosclerotic process." Upon activation of this process, there is a capacity for type I and/or type II vascular injury by either the humoral or cell-mediated process. The immune-mediated vascular injury theory has been well supported for both
humoral and cellular mechanisms. Hess et al 18 demonstrated that the presence of cytotoxic B cellantibodies (which were directed against HLA-Dr antigens on vascular endothelium) predicted early myocardial infarction and sudden death in cardiac transplantation patients. This has been confirmed by Petrossian" and Suciu-Foca et al,20 who have demonstrated that the presence of anti-HlA antibodies in cardiac transplant recipients was associated with the development of coronary artery disease in the graft, and an increased mortality. Frist et al" demonstrated that HLA-Aand HLA-B mismatches were associated with lower survival. Multicenter data gathered by Opelz2"l also show that long-term survival is related to HLA matchingjust as in renal transplantation.
Atherosclerosis ill Cardiac Transplantation
The precise role of cellular immunity in the pathogenesis of graft arteriosclerosis is still unclear. The activated Tdymphocytes, which constitute a major proportion of cells in the atheromatous lesion, can release interleukin-2 (IL-2), which causes induction of structural changes in the endothelial cells, monocyte and platelet accumulation, and stimulation of smooth muscle cell proliferation and secretion of growth factors. In support of this hypothesis, investigators from Pittsburgh' found that the occurrence of2 or more rejection episodes was associated with more frequent graft arteriosclerosis, and investigators from Stanford" found that rejection frequency was a strong risk factor for the development of graft atherosclerosis in retransplant patients. Further support for the immune theory comes from the recent studies of Young et aV t who demonstrated that soluble IL-2 receptor levels measured in the first few weeks after transplantation correlated strongly with the development of graft atherosclerosis and late mortality. Because IL-2 is primarily secreted by activated T cells, soluble IL-2 receptor levels would be expected to be elevated in both T cell-mediated cellular rejection as well as T cell-initiated, B cellmediated humoral rejection. Young et af' found no correlation with IL-2 receptor levels and cellular rejection or cellular rejection and coronary atherosclerosis. Further evidence for humoral-mediated rejection comes from the observation that patients receiving combined heart-lung transplants also have accelerated coronary atherosclerosis in spite of the fact that cellular cardiac allograft rejection is rare." Hyperlipidemia is common after cardiac transplantation 26-28 and is a potential risk factor contributing to accelerated atherosclerosis. In addition to causing endothelial injury, hypercholesterolemia can also increase platelet adhesion and lipid accumulation. Gao et al 29 studied 132heart transplantation patients for the possible correlation between arteriosclerosis defined angiographically and multiple clinical and laboratory variables. They reported that only higher donor age and evaluated plasma triglycerides were significant predisposing factors for graft arteriosclerosis. No other indexes, including the number of HIA mismatch, level of maintenance steroids, fasting blood sugar, or cholesterol and its subfraction, were found to identify patients who develop transplant coronary arteriosclerosis. In a later study," examining retransplantation for accelerated atherosclerosis, total cholesterol and LDL-cholesterol were strong predictors of recurrent atherosclerosis. Bilodern et afo found that atherogenic dyslipopro-
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teinemia characterized by elevated LDL-TG, LDLAPO B, and decreased HDL are factors that playa significant role in the pathogenesis of allograft atherosclerosis. Hess et al 18 reported that hypercholesterolemia in patients after heart transplant was associated with higher rates of graft arteriosclerosis, early myocardial infarction, and death, especially in patients with cytotoxic B cell antibodies. Eich et al30 reported recently that total cholesterol levels 6 months posttransplant predicted early (less than 3 years) graft atherosclerosis. In their recent articles, Ip et al" strongly suggested that immunologic and platelet factors playa secondary role to hyperlipidemia in transplant-related atherosclerosis, citing evidence that hyperlipidemia may induce type I injury. For years, the rabbit has been an established model for the study of atherosclerosis. As early as 1977,Alonso" examined coronary atherosclerosis in the hypercholesterolemic rabbit model of heterotopic cardiac transplantation. In this model of endogenous immune injury, they clearly showed a progression of type II vascular injury, but both endothelial lesions and platelet interactions progressed to the final manifestation of accelerated atherosclerosis in the cardiac allograft. In a recent study of "native" atherosclerosis, Badimon et al33 demonstrated that homologous HDL-VHDL administered concomitantly with an atherogenic diet inhibited aortic fatty streak formation and lipid deposition. They have also shO\\1131 that HDL plasma fractions are able to induce regression of aortic fat streaks and lipid deposits. Using a rabbit model, Foegh et ae5-37 have reported that estradiol and angiopeptide protect against experimental cardiac transplant atherosclerosis in animals immunosuppressed with only cyclosporine. Unfortunately, no reference is made as to the degree of cell-mediated rejection, changes in lipid profiles, or the degree of stenosis in various portions of the coronary vascular' tree. Recently, growing evidence in support of the role of cytomegalovirus (C~IV) infection in the pathogenesis of graft arteriosclerosis has been mounting. 38-1O Grattan et al" studied 301 heart transplantion patients and found that graft arteriosclerosis was significantly more severe in those patients with posttransplant C~IV infections and that there were significantly more deaths caused by graft arteriosclerosis in this group. Vascular endothelial damage can occur during the procurement of the graft even with current methods of cardiac preservations." This "irnplanta-
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tion injury" may be responsible for the findings of Ryan et al." Early postoperative (10 to 44 days) endothelial function as tested by rcsponse to acetylcholine was impaired, but returned toward normal in a time-dependent manner. The same investigators" also have demonstrated that the endothelium is dysfunctional in a large portion of patients at 12 and 24 months. It is unclear if the late dysfunction represents residual early dysfunction or a separate insult to the endothelium (immune mechanism, lipids, or C1\IV). In addition, denervation of the heart can result in catecholamine depletion and glucose metabolism impairment that may predispose to endothelial injury." In summary, accelerated atherosclerosis associatcd with cardiac transplantation remains an important problem with a poorly understood association of multiple interacting phenomena including implantation injury, early and ongoing immune injury, hyperlipidemia, and viral-mediated injury (Table I). Intense investigation is ongoing to clarify the possible causes.
Prevention and Treatment Until the precise mechanisms responsible for the development of cardiac allograft atherosclerosis arc identified, the measures that need to be taken to prevent this disease "ill remain speculative. Even though chronic rejection must playa pivotal role in the pathogenesis of graft atherosclerosis, the introduction of cyclosporine with its potent suppressive effect on the cellular component of the immune system has not produced any signficant impact on the incidence of the disease. The role of humoral rejection on the pathogenesis of this disease should be emphasized and more selective immunosuppressive agents against humoral rejection need to be developed. Several of these new and unique immunosuppressive agents arc currently being investigated Table 1. Pathogenesis ofAccelerated Graft Atherosclerosis Probable Factors Humoral immune injury Cellular immune injury Hyperlipidemia Cytomegalovirus infection Possible Factors Ischemic endothelial implantation injury Denervation injury to the endothelium Hypertension Smoking
at different centers. A macrolide fungal byproduct, FK-506, completely inhibited cellular rejection but allowed severe graft coronal)' disease in a rat modeI.H,~6 Raparnycin, another macrolide immunosuppressant, prevented both cellular rejection and graft coronal)' disease in the same rat model.~5 RS-61443 (RS) is a derivative of myocophenolic acid and inhibits DNA synthesis of both T and B cells. In the rat model," RS decreased the incidence and severity of graft coronal)' disease and eliminated the graft coronal)' disease associated with FK-506. Perhaps the future of transplant immunosuppression will be a multiple drug combination aimed at specific and varied targets in the immune cascade, ie, T and B lymphocytes, platelets, macrophages, and cytokine production. Better immune monitoring may allow more selective immunotherapy because we currently rely primarily on the presence or absence of cell-mediated allograft rejection to dictate therapy. As noted previously, Young et af' have demonstrated that elevated soluble IL-2 receptor levels early after transplantation, irrespective ofcellular rejection, predicted graft atherosclerosis and survival, The same investigators" have also demonstrated that these receptor levels remain elevated chronically in the patients with graft atherosclerosis. Investigators at Cornell UniversityI9,20 and the Medical College of Virginia" have demonstrated similar results following anti-Hl.A antibodies. Perhaps more aggressive (or more tailored) therapy when these markers are elevated, regardless of endomyocardial biopsy scores, can lead to a decreased incidence of accelerated graft atherosclerosis, As noted previously, Frist et afl and Opelz" have demonstrated the importance of HLA matching in survival after cardiac transplantation and because the majority of late deaths involve graft coronal)' disease, it follows that graft coronal)' disease may be decreased by better HLA matching. However, until cardiac preservation can be maintained for greater than 18 to 24 hours, prospective HLA matching "ill not be feasible. Although it seems that C1\1V may playa role in the development of graft atherosclerosis, it remains to be seen ifaggressive treatment with the anti-C1\1V drug, DHI'G, "ill decrease the incidence of atherosclerosis. Perhaps once the viremia is clinically apparent and diagnosed, the damage has already been done. The focus should remain trying to prevent C1\1V infections with better donor-recipient C1\1V status matching and postoperative prophylactic
Atherosclerosis in Cardiac Transplantation
therapy for mismatches. The Stanford and Utah groupS39.~9 are currently conducting a prospective,
randomized, double-blind study evaluating the prophylactic use ofDHPG for 6 weeks after transplantation for all seronegative recipients of seropositive donors and all seropositive recipients. The initial results" regarding early Cl\IV infections are promising but the effect on coronal)' atherosclerosis "ill require several years of follow-up. Other centers have published preliminary data on a small group of patients showing the efficacyofDHPG50 and hyperimmune globulins plus acyclovir" in preventing Cl\IV infection early after cardiac transplant. High-dose acyclovir for 6 weeks after renal transplantation has also been shown to be beneficial in preventing Cl\IV infections.f Data derived from animal studies and early clinical trials53.59 suggest that calcium antagonists alter the morphology of established coronal)' artery disease and may prevent new disease. The Stanford group" has published an interim report on a prospective randomized study using diltiazem early after cardiac transplantation in 134 patients. Using quantative angiography, they found that the patients not receiving diltiazem had a mean decrease in vessel size from 2.40 ± 0.31 mm at baseline to 2.19 ± 0.30 mm at last evaluation and the diltiazem group remained unchanged from a baseline of 2.36 ± 0.27 mm to 2.37 ± 0.24 mm. Three patients from the control group developed overt multivessel disease and one patient from the diltiazem group developed mild single-vessel disease. A respective study at the Medical College ofVirginia and McGuire VA Hospital'" found similar results. Although a retrospective study, the group of 106 patients were evenly matched for pre transplant and posttransplant variables and were evenly divided with 50 patients receiving calcium antagonists and 56 receiving none. The percentage of patients with no angiographic coronary artery disease, at a mean of 24 months, was higher in the calcium antagonist group, 52% versus 27%. Diffuse concentric narrowing was lower in the treatment group, 34% versus 67%. Proximal left anterior descending diameter was also larger in the treatment group, 4.2 mm versus 3.9 mm. Discrete stenosis or multivessel disease was no different between the groups. These two studies would suggest that calcium channel blockers may have a primal)' mode of action by inhibiting the smooth muscle proliferation primarily responsible for the early posttransplant changes. As noted previously, the role of hyperlipidemia in
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accelerated atherosclerosis seems to be more than a casual one. Several animal studies have demonstrated that modulation of the lipoprotein-endothelial interface using agents such as DHEA,62 estradiol," and omega-3 fatty acids" retards the development of accelerated atherosclerosis in rabbit and rat models. Other agents directed primarily against smooth muscle proliferation have also been shown to decrease the incidence of angioplasty restenosis and allograft coronary disease in animal models. These include angiopeptin, a somatostatin analogue,m8 and heparin." Because platelets playa key .role in the atherosclerotic process of native coronary arteries, antiplatelet regimens, primarily dipyridamole and aspirin, have been used by several transplant centers. Even though the combination ofcyclesporine and dipyridamole was found to inhibit the accelerated atherosclerosis in the rat model'" this effect has not been demonstrated in humans. Once accelerated graft atherosclerosis is evident angiographically, long-term survival is dramatically influenced. \Vhen the process is severe and diffuse, it usually progresses rapidly. Medical therapy with antiischemia drugs has not been effective. Coronary artery bypass grafting is rarely used as the distal beds are typically severely diseased. Coronary angioplasty has been performed with moderate success at some centers for isolated epicardial stenosis as palliative therapy.66.59 A recent multicenter, retrospective study of 51 percutaneous transluminal coronary angioplasty (ITCA) procedures performed in 35 patients found a 93% primary angiographic success rate with I procedural death, I myocardial infarction, 3 groin hematomas, and I episode of acute renal failure." This compares favorably with primary angioplasty in native vessels; however, the incidence of restenosis seems to be higher and the progression of non dilated disease rapid. It should be noted that this angioplasty population represented less than 2% of the total transplanted patients at the various institutions, thus the patients were a very highly selected group. We have performed angioplasty on several patients for isolated discrete epicardial stenosis occurring from 4 to 12 years posttransplant and they are doing well up to 5 years post-ITCA. This subgroup likely represents the less aggressive, more "typical" atherosclerotic process. One concern about angioplasty in the transplanted coronary is the mechanical injury to the endothelium, intima, and media, which may further accelerate the process in the less severely involved vessel segments. In addition, not all discrete angiographic "stenosis" represent the typical atheroscle-
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rotic plaque. We have anecdotal experience with a transplantation patient undergoing PTCA of a proximal left anterior deccnding coronary lesion who suffered an acute infarction post procedure and subsequ ently died. The findings at autopsy showed severe and diffuse arteritis involved all the coronaries, epicardial as well as the sm all vessels. It should be stressed again that PTCA for accelerated graft atherosclerosis is a palliative treatment at best and needs prospective eva lua tion to fully assess the risks and benefits. Retransplantation remains , the most effective tr eatment for advanced accelerated atherosclerosis. Even though the operative mortality of retransplantation for graft atherosclerosis is similar to that of initial transplants, the l-year survival is only 55% and the incidence of recurrent graft atherosclerosis is
high." Our current approach to graft atherosclerosis can be summarized as follows. Initial immunosuppressive th erapy uses cyclosporine, azathioprine, and often corticosteroids. Even in those patients who require corticosteroids ea rly, an aggressive effort is made to wean them completely off, or to the lowest possible dose to prevent not ani)' the lipid abnormalities but the other well known steroid side effects. C~IV infections are treated aggressively with DHPG as are seronegative patients receiving seropositive hearts. Hyperlipidemia is treated aggressively with attempts to maintain total cholesterol levels below 220 to 240 mg/dL by primary use of diet, weight reduction, minimal prednisone doses, and low-dose lovastatin if needed. A special note of caution should be mentioned here about the safety and efficacy of the recently released hydroxymethylglutaryl coenZ)we A (H~IG-CoA) reductase inhibitor in patients re ceiving cyclosporine. Earl)' experience with higher doses of lovastatin was associated with several reported cases of rhabdomyalysis and acute renal failure caused by an interaction between the drug and cyclosporine." Patients taking lovastatin and cyclosporine have blood levels of the enzyme inhibitor that are up to 8 times the expected values." A number of centers have documented both the safety and efficacy of lower doses of Iovastatin in transplantation patients taking cyclosporine."?' \Ve currently start lovastatin at doses as low as 10 mg every other day and rarely exceed 20 mid. Serum creatine pho sphokinase (CPK) levels are measured initially and at 6- to 8-week intervals. The drug is stopped for any significant muscle complaints or elevated serum
CPK
Once accelerated graft atherosclerosis is evident angiographically, patients with severe, aggressive disease a re evaluated for possible retransplant. For patients with slowly developing disease, such as that not ed serially over 2 to 5 years, we may wait until left ventricular dysfunction or sever e and critical two- or three-vessel disease develops before listing for retransplant. Coronary angioplasty is reserved for patients with primarily epicardial dis ease and angiographically normal distal vessels who demonstrate ischemia by thallium scintigraphy in large anatomic distributions. PTCA is generally not performed for distal branch vessel disease or proximal major vessel lesions if t he distal vessel is also severely diseased.
Summary Accelerated atherosclerosis remains the single most important obstacle limiting the long-t erm success of ca rdiac transplantation. It occurs to different degrees in all long-term survivors and is the major cause of either their death or retransplantation procedures. Its etiology is multifactoral, including immune mechanisms, hyperlipidemia, viral interactions, and implantation injury. Active investigation is ongoing to try to unlock this complicated puzzle. Lessons learned from this model ofatherosclerosis will also be applicable to native atherosclerosis, vein graft atherosclerosis, and restenosis after intervcntional coronary artery procedures.
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graft coronary disease and graft infiltrating lymphocyte subset following rat heart transplantation comparison with cyclosporineA.] Heart Lung Transplant 1991, 10:175 Morris R, Rodriguez M, Murphy }'I, et al: Treatment of rat heart allograft recipients with RS-61443 (RS): Prevention of graft coronary disease (GCD) and effects of combined treatment with FK-506, rapamycin and cyclosporinc.] Heart Transplant 1991, 10:182 Young]B, Windsor 1'."1", Kleiman r\S, et al: Relationship of persistently elevated soluble interleukin-2 levels after heart transplant to allograft arteriopathy. ] Am Coli Cardiol 1991, 17:102A (abstr) Merigan T, Renlund D, Keay S, et al: A multicenter, randomizcd, double-blind, placebo controlled study of C~[V prophylaxis with intravenous ganciclovir(DIll'G) in cardiac transplantation.] Heart Lung Transplant 1991, 10:175A (abstr) Warner },I, Luthy A, Lanke A, et al: Docs gancyclovir prophylaxis prevent C~lV infection in heart transplant recipients. Eur Heart] 1990,2:12-16 Eisenmann D, Petzold T, Stegmann T: Prevention and therapy of cytomegalovirus (C~lV) disease in hcart transplant (H-TX) recipients byC~lVhyperimmuneglobulin plus acyclovir.] Heart Transplant 1990, 9:72A (abstr) Balfour HH, Chace BA, Stapleton ]T, et al: A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl] ~Ied 1989,320:1381 Henry PD: Atherosclerosis, calcium and calcium antagonist. Circulation 1985,72:456 Weinstein DB: Anti-atherogenic properties of calcium antagonists. Am] Cardiol1987, 59: 163B Sugano ~I, Noskashimay, Matsuhima T, et al: Suppression of atherosclerosis in cholesterol-fed rabbits by diltiazem injection.Arteriosclerosis 1986,6:237 Lichtlcn PR, Hugenholz PG, Rafllenbcul W, et al: Retardation of angiographic progression of coronary artery disease by nifedipine. Results of international nifedipine trial on antiatherosclerotic therapy (1;\"1"ACT). Lancet 1990,335: 1109 KoberG, Schneider W, Kaltenbach }'I: Can the progression of coronary sclerosis be influenced by calcium antagonist? ] Cardiovasc Pharmacol1989, 13:S2 (sup pI) Etingen OR, Hajjar DP: Calcium channel blockers enhance cholesteryl ester hydrolysis and decrease total cholesterol accumulation in human aortic tissue. Circ Res 1990,66: 185 Henry PD: Atherogenesis, calcium and calcium antagonists. Am]CardioI1990,66:3I Schroeder]S, Gao SZ, Alderman E1., et al: Diltiazem inhibits
61.
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development of early accelerated transplant coronary disease-An interim report. Circulation 1990, 82:IIl-257 (suppl Ill) Sheehan H, Vetrovec G, Graham S, et al: Calcium channel antagonists protect against the development of coronary artery disease following cardiac transplantation.] Am Coli Cardiol1991, 17:290A (abstr) Eich D~I, Johnson DE, Dworkin GH, et al: Inhibition of accelerated coronary atherosclerosis with dihydrocpiandersterone in the heterotopic rabbit model of cardiac transplantation. Circulation 1991, (in press) Sarris GE, Mitchell RS, Billingham }'IE, et al: Inhibition of accelerated cardiac allograft arteriosclerosis by fish oil. ] Thorac Cardiovasc Surg 1989, 97 :841 Clowes AW, Clowes }'I~I: Inhibition of smooth muscle cell proliferation by heparin molecules, Transplant Proc 1989, 21:3700 Lurie KG, Billingham }'IE,]amieson SW, et al: Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model. Transplantation 1981,31 :41 Vctrovcc GW, Cowley },U, Newton C~I, ct al: Application of percutaneous transluminal angioplasty in cardiac transplantation. Circulation 1988, 78:IIl-83 (suppllII) Hastillo A, Cowley M], Vetrovcc G, et al: Serial coronary angioplasty for atherosclerosis following heart transplantation.] Heart Transplant 1985,4:192 Swan ]W, Norell },I, Ilsley C, et al: Balloon angioplasty in cardiac transplant recipients. Eur Heart] 1990, 11:257 (suppl
H) 69. Wohlgelernter D, Stevenson LW, Brunken R: Reversal of ischemic myocardial dysfunction by ITCA in a cardiac transplant patient. Am Heart] 1986, 112:837 70. Halle A, DiSciascio G, Wilson R, et al: Coronary angioplasty in cardiac transplant patients: Results of a multicenter study.] Am Coli Cardiol1991, 17:103A (abstr) 71. Corpier C1.,]ones PH, Suki WN, ct al: Rhabdomyolysis and renal injurywith Lovastatin usc. Report of two cases in cardiac transplant recipients.]A.\1A 1988,260:239 72. Kobashigawa]A, Murphy FL, Stevenson LW, ct al: Low-dose Lovastatin safely lowers cholesterol after cardiac transplantation. Circulation 1990, 82:lV-28I (suppllV) 73. Heroux A, Thompson ]A, Katz S, ct al: Elimination of the Lovastatin-cyclosporine adverse interaction in heart transplant patients. Circulation 1989,80:11-6-1l (suppllI) 74. Miller LW, Noedcl N, Pennington DG, et al: Treatment of hypercholesterolemia in cardiac transplant recipients with Lovastatin.] Heart Transplant 1989,8: 105
r thotopic heart transplantation has become a
O standard treatment for severe, irreversible heart failure. The survival rate after cardiac transplantation according to the latest International Society of Heart Transplantation Registry (1990) is 81% after I year" This figure has been attributed to better supportive care, better immunosuppression with the introduction ofcyclosporine in 1981, and the improvement in the diagnosis and treatment of rejection and infection. This spectacular success in the short-term is shadowed by the development of accelerated coronary artery disease in long-term survivors, making it the most common cause for both late death and retransplantation. In this article we will discuss the pathology, current theories related to etiologies and risk factors, clinical presentations, and possible treatment options for this accelerated allograft atherosclerosis.
Pathology Johnson et af from Stanford University, recently reviewed their pathological experience with 61 human cardiac allografts and divided the findings into 5 morphological categories. The first category consisted of 7 grafts surviving I day to 6.57 months (mean, 2.2 months), and having no evidence of intimal thickening. The second category consisted of 29 grafts having fibrous intimal hyperplasia that was limited to the proximal and middle segments of the epicardial arteries. It was found in grafts as early as I week and as late as 53 months, but 83% of the transplanted hearts studied survived less than I year. Foam cells were rare and the internal elastic lamina was intact. The intimal hyperplasia was primarily
From The Cardiac Transplantation Program, The Medical College if Virginia, Departments if Surgf1)' and Medicin«, Virginia Commonuealth Unicersity, Richmond, J-:4. Supported in part by Grant-in-Aid Ko. RROoo65 from the National Institutes ifHealth totheClinical Research Center iftheMedical College if Virginia Hospitals, Address reprint requests to .lfichaelL Hess, MD, Box 281, .lfedical College ifVirginia, Richmond, J:'123298. CopJright e 1991!?J' WE. Saunders Company 0955·170:
due to smooth muscle cell proliferation. Luminal compromise was mild to moderate in most grafts, but 2 grafts had> 75% luminal narrowing. The third category consisted of a diffuse necrotizing vasculitis that was present in 4 grafts surviving 7 to 13 months. Intimal thickening was also noted in all 4 grafts, and 3 of these had moderate to severe myocardial rejection at the time of necropsy. The fourth category consisted of 12 grafts with "fibrofatty atheromatous plaques of proximal to middle regions of epicardial arteries only." The smaller arteries had relatively normal morphology and the lesions resembled those occurring in "native" atherosclerosis. The survival times ranged from 13 to 143 months (mean, 67.5). Earlier lesions typically had lipid-laden mononuclear cells found in a fibrotic intima, whereas older lesions had complex plaques with extracellular, as well as intracellular lipid deposition. Calcification occurred in all 4 hearts surviving more than 5 years. In addition, 91% of hearts surviving less than 5 years had concentric lesions whereas 64% of hearts surviving greater than 5 years had eccentric lesions. The fifth category consisted of9 allografts surviving 15 to 134 months (mean, 56 months) which demonstrated "diffuse fibrous intimal thickening with or without atheromatous plaques." The individual lesions were similar to other categories noted previously with the major difference being the diffuse distribution. Also, there was complete replacement of the media and adventitia with fibrous tissue in 4 of the 9 grafts. Five of the 9 grafts had thrombosis noted, usually in distal epicardial segments. It is possible that this pattern starts as a diffuse necrotizing vasculitis with medial necrosis that subsequently heals by scarring of the media and luminal narrowing due to chronic inflammation, intimal fibrosis, intramural hemorrhage, and thrombosis. There was I patient (3%) in the large vessel fibrointimal hyperplasia group, I patient (25%) in the necrotizing vasculitis group, 5 patients (50%) in the large vessel atheroma group, and 8 patients (89%) in the diffuse fibrointimal thickening and/or atheroma group who died or required retransplantation for the coronary vascular disease. Thus, histologically, cardiac allograft "arter-
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opathy" encompasses a wide spectrum of disease that may represent different extremes of a single ongoing process, multiple interrelated processes, or, possibly,multiple independent processes.
Incidence The incidence of angiographic coronary artery disease in heart transplantation recipients was first reported by Bieber et al 3 to be 40% at 5 years after transplant. More recent data suggest that the incidence in the United States is essentially unchanged and is 6% to 18% at I year, 23% at 2 years, 46% at 3 years, and 48% at 4 years, 50% at 5 years, and 66% at 6 years after heart transplantation.t" However, the incidence of atherosclerosis at autopsy or necropsy is much higher. Gao et al9 at Stanford University reported a 72% incidence of fibrointimal thickening at 3 months after transplantation, a 94% incidence between 3 and 12 months, and a 100% incidence 1 year after transplantation. Interestingly, 100% of angiographically normal segments exhibited pathological evidence of coronary artery disease. Johnson et al'" reviewed detailed gross and histopathology in 10 allografts having coronal)' arteriography within 2 months of necropsy. The mean graft survival was 52 months (14 to 135 months) and the cause of death or retransplantation was coronary atherosclerosis in all cases, all angiographically "normal" segments had disease, primarily fibrointimal hyperplasia narrowing the lumen from 1% to 57%. Focal lesions consisted primarily of atheromatous lesions, and diffuse concentration narrowings consisted primarily of fibrointimal hyperplasia. Coronary angiography was insensitive for detecting early graft coronary disease and often underestimated the severity ofangiographically identified disease. Therefore, it is not a question of whether a patient "ill develop coronal)' allograft atherosclerosis, but rather what type and how severe.
Clinical Presentation and Diagnosis Because the cardiac allograft lacks innervation, the typical symptoms of myocardial ischemia do not occur, resulting in a syndrome of silent myocardial ischemia. Most commonly, patients present with progressive deterioration of exercise tolerance or a significant decrease in the left ventricular systolic function found on routine echocardiogram, radionuc1ide ventriculogram, or angiography. It is not uncommon for patients to present for the first time with a
full-blown picture of congestive heart failure, pulmo-
nal)' edema, sudden cardiac death, or malignant arrhythmias. The silent and rapid nature of this disease mandates aggressive surveillance to detect the earliest signs of allograft arteriosclerosis. The Medical College of Virginia has adopted a policy of obtaining a baseline coronal)' angiogram within 3 months of transplant, and yearly thereafter. The angiogram might show a variety of lesions (Figs 1 and 2) depending on the underlying pathology. Frequently, it is a mixture of typical atheromatous lesions found in naturally occurring atherosclerosis and a unique transplant-related progressive distal obliterative disease. Gao et al" classified these angiographic lesions into three categories. Type A is characterized by discrete or tubular stenosis of the type typically found in nontransplant angiograms. This t}pe constitutes 76% of the transplant angiographic lesions. Type B is characterized by diffuse concentric narrowing prominent in the middle to distal vessels with distal vessel obliteration or pruning. This t}pe constitutes 15% of transplant lesions and is rarely found in nontransplant disease. Type C is characterized by narrowed irregular distal branches with loss of small branches and squared offterminations that end abruptly. Type C constitutes 10% of transplant lesions. It is found predominantly in the terminal branch of segments and rarely found in nontransplant disease. Another major difference is the lack of collateral blood supply to occluded vessels. Seventy-six percent of occluded vessels in nontransplant patients had good collateral vessels present, but less than 10% of occluded vessels in transplant patients had good collaterals. In addition, occluded vessels in transplant patients are more likely to be occluded distally (49% v 3.5%) and less likely to be occluded proximately (43% v 72%). It should be emphasized that even though the coronal)' angiogram seems to be the best way for early detection of allograft arteriosclerosis, it is far from perfect in diagnosing early or advanced small vessel disease. TIle use of noninvasive methods for detecting allograft atherosclerosis has been disappointing. Exercise qualitative 2°'TI myocardial imaging has been shown to lack sensitivity and specificitybecause of the nature of this disease and the extensive involvement of small vcssels.f More recently however, Fitzpatrick et al," using exercise single-photon emission computed tomography (SPECT) 20lTI reported a sensitivity of82% and a specificity of'Bl% for detecting major epicardial stenoses (> 50%). Radionuclide ventriculography and echocardio-
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Figure 1. Selective coronary angiogram of the left coronary artery system in a man I year after retransplantation for severe, recurrent accelerated coronary atherosclerosis 4 years after the initial transplantation. Note the significant "pruning" of the distal, small epicardial vessels with what seems to be angiographically "normal" large epicardial vessels.
graphy are used routinely in follow-up studies to evaluate the overall systolic function of the heart and to assess the presence of regional wall motion abnormalitics. Unfortunately these findings arc late manifestations of advanced coronary arteriosclerosis, The true value of Holter monitoring in the surveillance for clinically significant graft coronary artery disease is uncertain. Romhilt et all! showed that the presence of complex ventricular ectopy was associated with higher incidence of coronary artery disease in patients on prednisone and azathioprine. Although coronal)' artery disease has been demonstrated on endomyocardial biopsy," it is not often observed, even in advanced disease, Coronal)' flow reserve determination and intracoronal)' ultrasound arc two promising investigational
tools that might open a new era in early detection and pathophysiology of graft arteriosclerosis, Extensive investigations arc currently underway exploring these methods.
Potential Etiology Until recently there has been a paucity of basic investigations into transplant-related accelerated coronal)' artery disease, but fortunately there is now a growing body of experimental data. It is agreed that the problem is significant, having a 50% 5-year incidence in cardiac transplantation, but the etiology, pathogenesis, and treatment of this disease remain elusive. The "chronic vascular rejection" theory is
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Figure 2. Selective coronary angiogram of the len coronary artery system in a patient 5 years after transplantation. Note the significant and diffuse involvement of both the large and small epicardial coronary art eries and the proximal "type AU lesion of the len anterior descending coronary artery associated with significant distal pruning and occlusion.
favored by most experts in the field as the basic underlying mechanism. TIle transplanted heart seems to express the two major histocompatibility antigen classes, class I (A,B,C) and class II (D-related), which are not expressed in the normal heart. Following transplantation there is a rapid expression of class I antigens, T'-lymphocyte activation, and cell-mediated rejection." Class II antigens are expressed 100 to 200 days posttransplant on the myocyte and endothelial cells, and are strongly associated with the emergence of the accelerated atherosclerotic process." Upon activation of this process, there is a capacity for type I and/or type II vascular injury by either the humoral or cell-mediated process. The immune-mediated vascular injury theory has been well supported for both
humoral and cellular mechanisms. Hess et al 18 demonstrated that the presence of cytotoxic B cellantibodies (which were directed against HLA-Dr antigens on vascular endothelium) predicted early myocardial infarction and sudden death in cardiac transplantation patients. This has been confirmed by Petrossian" and Suciu-Foca et al,20 who have demonstrated that the presence of anti-HlA antibodies in cardiac transplant recipients was associated with the development of coronary artery disease in the graft, and an increased mortality. Frist et al" demonstrated that HLA-Aand HLA-B mismatches were associated with lower survival. Multicenter data gathered by Opelz2"l also show that long-term survival is related to HLA matchingjust as in renal transplantation.
Atherosclerosis ill Cardiac Transplantation
The precise role of cellular immunity in the pathogenesis of graft arteriosclerosis is still unclear. The activated Tdymphocytes, which constitute a major proportion of cells in the atheromatous lesion, can release interleukin-2 (IL-2), which causes induction of structural changes in the endothelial cells, monocyte and platelet accumulation, and stimulation of smooth muscle cell proliferation and secretion of growth factors. In support of this hypothesis, investigators from Pittsburgh' found that the occurrence of2 or more rejection episodes was associated with more frequent graft arteriosclerosis, and investigators from Stanford" found that rejection frequency was a strong risk factor for the development of graft atherosclerosis in retransplant patients. Further support for the immune theory comes from the recent studies of Young et aV t who demonstrated that soluble IL-2 receptor levels measured in the first few weeks after transplantation correlated strongly with the development of graft atherosclerosis and late mortality. Because IL-2 is primarily secreted by activated T cells, soluble IL-2 receptor levels would be expected to be elevated in both T cell-mediated cellular rejection as well as T cell-initiated, B cellmediated humoral rejection. Young et af' found no correlation with IL-2 receptor levels and cellular rejection or cellular rejection and coronary atherosclerosis. Further evidence for humoral-mediated rejection comes from the observation that patients receiving combined heart-lung transplants also have accelerated coronary atherosclerosis in spite of the fact that cellular cardiac allograft rejection is rare." Hyperlipidemia is common after cardiac transplantation 26-28 and is a potential risk factor contributing to accelerated atherosclerosis. In addition to causing endothelial injury, hypercholesterolemia can also increase platelet adhesion and lipid accumulation. Gao et al 29 studied 132heart transplantation patients for the possible correlation between arteriosclerosis defined angiographically and multiple clinical and laboratory variables. They reported that only higher donor age and evaluated plasma triglycerides were significant predisposing factors for graft arteriosclerosis. No other indexes, including the number of HIA mismatch, level of maintenance steroids, fasting blood sugar, or cholesterol and its subfraction, were found to identify patients who develop transplant coronary arteriosclerosis. In a later study," examining retransplantation for accelerated atherosclerosis, total cholesterol and LDL-cholesterol were strong predictors of recurrent atherosclerosis. Bilodern et afo found that atherogenic dyslipopro-
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teinemia characterized by elevated LDL-TG, LDLAPO B, and decreased HDL are factors that playa significant role in the pathogenesis of allograft atherosclerosis. Hess et al 18 reported that hypercholesterolemia in patients after heart transplant was associated with higher rates of graft arteriosclerosis, early myocardial infarction, and death, especially in patients with cytotoxic B cell antibodies. Eich et al30 reported recently that total cholesterol levels 6 months posttransplant predicted early (less than 3 years) graft atherosclerosis. In their recent articles, Ip et al" strongly suggested that immunologic and platelet factors playa secondary role to hyperlipidemia in transplant-related atherosclerosis, citing evidence that hyperlipidemia may induce type I injury. For years, the rabbit has been an established model for the study of atherosclerosis. As early as 1977,Alonso" examined coronary atherosclerosis in the hypercholesterolemic rabbit model of heterotopic cardiac transplantation. In this model of endogenous immune injury, they clearly showed a progression of type II vascular injury, but both endothelial lesions and platelet interactions progressed to the final manifestation of accelerated atherosclerosis in the cardiac allograft. In a recent study of "native" atherosclerosis, Badimon et al33 demonstrated that homologous HDL-VHDL administered concomitantly with an atherogenic diet inhibited aortic fatty streak formation and lipid deposition. They have also shO\\1131 that HDL plasma fractions are able to induce regression of aortic fat streaks and lipid deposits. Using a rabbit model, Foegh et ae5-37 have reported that estradiol and angiopeptide protect against experimental cardiac transplant atherosclerosis in animals immunosuppressed with only cyclosporine. Unfortunately, no reference is made as to the degree of cell-mediated rejection, changes in lipid profiles, or the degree of stenosis in various portions of the coronary vascular' tree. Recently, growing evidence in support of the role of cytomegalovirus (C~IV) infection in the pathogenesis of graft arteriosclerosis has been mounting. 38-1O Grattan et al" studied 301 heart transplantion patients and found that graft arteriosclerosis was significantly more severe in those patients with posttransplant C~IV infections and that there were significantly more deaths caused by graft arteriosclerosis in this group. Vascular endothelial damage can occur during the procurement of the graft even with current methods of cardiac preservations." This "irnplanta-
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tion injury" may be responsible for the findings of Ryan et al." Early postoperative (10 to 44 days) endothelial function as tested by rcsponse to acetylcholine was impaired, but returned toward normal in a time-dependent manner. The same investigators" also have demonstrated that the endothelium is dysfunctional in a large portion of patients at 12 and 24 months. It is unclear if the late dysfunction represents residual early dysfunction or a separate insult to the endothelium (immune mechanism, lipids, or C1\IV). In addition, denervation of the heart can result in catecholamine depletion and glucose metabolism impairment that may predispose to endothelial injury." In summary, accelerated atherosclerosis associatcd with cardiac transplantation remains an important problem with a poorly understood association of multiple interacting phenomena including implantation injury, early and ongoing immune injury, hyperlipidemia, and viral-mediated injury (Table I). Intense investigation is ongoing to clarify the possible causes.
Prevention and Treatment Until the precise mechanisms responsible for the development of cardiac allograft atherosclerosis arc identified, the measures that need to be taken to prevent this disease "ill remain speculative. Even though chronic rejection must playa pivotal role in the pathogenesis of graft atherosclerosis, the introduction of cyclosporine with its potent suppressive effect on the cellular component of the immune system has not produced any signficant impact on the incidence of the disease. The role of humoral rejection on the pathogenesis of this disease should be emphasized and more selective immunosuppressive agents against humoral rejection need to be developed. Several of these new and unique immunosuppressive agents arc currently being investigated Table 1. Pathogenesis ofAccelerated Graft Atherosclerosis Probable Factors Humoral immune injury Cellular immune injury Hyperlipidemia Cytomegalovirus infection Possible Factors Ischemic endothelial implantation injury Denervation injury to the endothelium Hypertension Smoking
at different centers. A macrolide fungal byproduct, FK-506, completely inhibited cellular rejection but allowed severe graft coronal)' disease in a rat modeI.H,~6 Raparnycin, another macrolide immunosuppressant, prevented both cellular rejection and graft coronal)' disease in the same rat model.~5 RS-61443 (RS) is a derivative of myocophenolic acid and inhibits DNA synthesis of both T and B cells. In the rat model," RS decreased the incidence and severity of graft coronal)' disease and eliminated the graft coronal)' disease associated with FK-506. Perhaps the future of transplant immunosuppression will be a multiple drug combination aimed at specific and varied targets in the immune cascade, ie, T and B lymphocytes, platelets, macrophages, and cytokine production. Better immune monitoring may allow more selective immunotherapy because we currently rely primarily on the presence or absence of cell-mediated allograft rejection to dictate therapy. As noted previously, Young et af' have demonstrated that elevated soluble IL-2 receptor levels early after transplantation, irrespective ofcellular rejection, predicted graft atherosclerosis and survival, The same investigators" have also demonstrated that these receptor levels remain elevated chronically in the patients with graft atherosclerosis. Investigators at Cornell UniversityI9,20 and the Medical College of Virginia" have demonstrated similar results following anti-Hl.A antibodies. Perhaps more aggressive (or more tailored) therapy when these markers are elevated, regardless of endomyocardial biopsy scores, can lead to a decreased incidence of accelerated graft atherosclerosis, As noted previously, Frist et afl and Opelz" have demonstrated the importance of HLA matching in survival after cardiac transplantation and because the majority of late deaths involve graft coronal)' disease, it follows that graft coronal)' disease may be decreased by better HLA matching. However, until cardiac preservation can be maintained for greater than 18 to 24 hours, prospective HLA matching "ill not be feasible. Although it seems that C1\1V may playa role in the development of graft atherosclerosis, it remains to be seen ifaggressive treatment with the anti-C1\1V drug, DHI'G, "ill decrease the incidence of atherosclerosis. Perhaps once the viremia is clinically apparent and diagnosed, the damage has already been done. The focus should remain trying to prevent C1\1V infections with better donor-recipient C1\1V status matching and postoperative prophylactic
Atherosclerosis in Cardiac Transplantation
therapy for mismatches. The Stanford and Utah groupS39.~9 are currently conducting a prospective,
randomized, double-blind study evaluating the prophylactic use ofDHPG for 6 weeks after transplantation for all seronegative recipients of seropositive donors and all seropositive recipients. The initial results" regarding early Cl\IV infections are promising but the effect on coronal)' atherosclerosis "ill require several years of follow-up. Other centers have published preliminary data on a small group of patients showing the efficacyofDHPG50 and hyperimmune globulins plus acyclovir" in preventing Cl\IV infection early after cardiac transplant. High-dose acyclovir for 6 weeks after renal transplantation has also been shown to be beneficial in preventing Cl\IV infections.f Data derived from animal studies and early clinical trials53.59 suggest that calcium antagonists alter the morphology of established coronal)' artery disease and may prevent new disease. The Stanford group" has published an interim report on a prospective randomized study using diltiazem early after cardiac transplantation in 134 patients. Using quantative angiography, they found that the patients not receiving diltiazem had a mean decrease in vessel size from 2.40 ± 0.31 mm at baseline to 2.19 ± 0.30 mm at last evaluation and the diltiazem group remained unchanged from a baseline of 2.36 ± 0.27 mm to 2.37 ± 0.24 mm. Three patients from the control group developed overt multivessel disease and one patient from the diltiazem group developed mild single-vessel disease. A respective study at the Medical College ofVirginia and McGuire VA Hospital'" found similar results. Although a retrospective study, the group of 106 patients were evenly matched for pre transplant and posttransplant variables and were evenly divided with 50 patients receiving calcium antagonists and 56 receiving none. The percentage of patients with no angiographic coronary artery disease, at a mean of 24 months, was higher in the calcium antagonist group, 52% versus 27%. Diffuse concentric narrowing was lower in the treatment group, 34% versus 67%. Proximal left anterior descending diameter was also larger in the treatment group, 4.2 mm versus 3.9 mm. Discrete stenosis or multivessel disease was no different between the groups. These two studies would suggest that calcium channel blockers may have a primal)' mode of action by inhibiting the smooth muscle proliferation primarily responsible for the early posttransplant changes. As noted previously, the role of hyperlipidemia in
171
accelerated atherosclerosis seems to be more than a casual one. Several animal studies have demonstrated that modulation of the lipoprotein-endothelial interface using agents such as DHEA,62 estradiol," and omega-3 fatty acids" retards the development of accelerated atherosclerosis in rabbit and rat models. Other agents directed primarily against smooth muscle proliferation have also been shown to decrease the incidence of angioplasty restenosis and allograft coronary disease in animal models. These include angiopeptin, a somatostatin analogue,m8 and heparin." Because platelets playa key .role in the atherosclerotic process of native coronary arteries, antiplatelet regimens, primarily dipyridamole and aspirin, have been used by several transplant centers. Even though the combination ofcyclesporine and dipyridamole was found to inhibit the accelerated atherosclerosis in the rat model'" this effect has not been demonstrated in humans. Once accelerated graft atherosclerosis is evident angiographically, long-term survival is dramatically influenced. \Vhen the process is severe and diffuse, it usually progresses rapidly. Medical therapy with antiischemia drugs has not been effective. Coronary artery bypass grafting is rarely used as the distal beds are typically severely diseased. Coronary angioplasty has been performed with moderate success at some centers for isolated epicardial stenosis as palliative therapy.66.59 A recent multicenter, retrospective study of 51 percutaneous transluminal coronary angioplasty (ITCA) procedures performed in 35 patients found a 93% primary angiographic success rate with I procedural death, I myocardial infarction, 3 groin hematomas, and I episode of acute renal failure." This compares favorably with primary angioplasty in native vessels; however, the incidence of restenosis seems to be higher and the progression of non dilated disease rapid. It should be noted that this angioplasty population represented less than 2% of the total transplanted patients at the various institutions, thus the patients were a very highly selected group. We have performed angioplasty on several patients for isolated discrete epicardial stenosis occurring from 4 to 12 years posttransplant and they are doing well up to 5 years post-ITCA. This subgroup likely represents the less aggressive, more "typical" atherosclerotic process. One concern about angioplasty in the transplanted coronary is the mechanical injury to the endothelium, intima, and media, which may further accelerate the process in the less severely involved vessel segments. In addition, not all discrete angiographic "stenosis" represent the typical atheroscle-
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rotic plaque. We have anecdotal experience with a transplantation patient undergoing PTCA of a proximal left anterior deccnding coronary lesion who suffered an acute infarction post procedure and subsequ ently died. The findings at autopsy showed severe and diffuse arteritis involved all the coronaries, epicardial as well as the sm all vessels. It should be stressed again that PTCA for accelerated graft atherosclerosis is a palliative treatment at best and needs prospective eva lua tion to fully assess the risks and benefits. Retransplantation remains , the most effective tr eatment for advanced accelerated atherosclerosis. Even though the operative mortality of retransplantation for graft atherosclerosis is similar to that of initial transplants, the l-year survival is only 55% and the incidence of recurrent graft atherosclerosis is
high." Our current approach to graft atherosclerosis can be summarized as follows. Initial immunosuppressive th erapy uses cyclosporine, azathioprine, and often corticosteroids. Even in those patients who require corticosteroids ea rly, an aggressive effort is made to wean them completely off, or to the lowest possible dose to prevent not ani)' the lipid abnormalities but the other well known steroid side effects. C~IV infections are treated aggressively with DHPG as are seronegative patients receiving seropositive hearts. Hyperlipidemia is treated aggressively with attempts to maintain total cholesterol levels below 220 to 240 mg/dL by primary use of diet, weight reduction, minimal prednisone doses, and low-dose lovastatin if needed. A special note of caution should be mentioned here about the safety and efficacy of the recently released hydroxymethylglutaryl coenZ)we A (H~IG-CoA) reductase inhibitor in patients re ceiving cyclosporine. Earl)' experience with higher doses of lovastatin was associated with several reported cases of rhabdomyalysis and acute renal failure caused by an interaction between the drug and cyclosporine." Patients taking lovastatin and cyclosporine have blood levels of the enzyme inhibitor that are up to 8 times the expected values." A number of centers have documented both the safety and efficacy of lower doses of Iovastatin in transplantation patients taking cyclosporine."?' \Ve currently start lovastatin at doses as low as 10 mg every other day and rarely exceed 20 mid. Serum creatine pho sphokinase (CPK) levels are measured initially and at 6- to 8-week intervals. The drug is stopped for any significant muscle complaints or elevated serum
CPK
Once accelerated graft atherosclerosis is evident angiographically, patients with severe, aggressive disease a re evaluated for possible retransplant. For patients with slowly developing disease, such as that not ed serially over 2 to 5 years, we may wait until left ventricular dysfunction or sever e and critical two- or three-vessel disease develops before listing for retransplant. Coronary angioplasty is reserved for patients with primarily epicardial dis ease and angiographically normal distal vessels who demonstrate ischemia by thallium scintigraphy in large anatomic distributions. PTCA is generally not performed for distal branch vessel disease or proximal major vessel lesions if t he distal vessel is also severely diseased.
Summary Accelerated atherosclerosis remains the single most important obstacle limiting the long-t erm success of ca rdiac transplantation. It occurs to different degrees in all long-term survivors and is the major cause of either their death or retransplantation procedures. Its etiology is multifactoral, including immune mechanisms, hyperlipidemia, viral interactions, and implantation injury. Active investigation is ongoing to try to unlock this complicated puzzle. Lessons learned from this model ofatherosclerosis will also be applicable to native atherosclerosis, vein graft atherosclerosis, and restenosis after intervcntional coronary artery procedures.
References I.
Kriclt]~I,
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Aiherosclaosis in Cardiac Transplantation
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