Targeting nonalloimmune-dependent pathways

ELSEVIER

Targeting Nonalloimmune-DependentPathways J.A. K o b a s h i g a w a

RANSPLANT coronary artery disease (TCAD) is one of the leading causes of mortality among long-term cardiac transplant recipients. It occurs in 5% to 10% of heart transplant recipients each year; therefore, up to 50% of all heart transplant patients have angiographically confirmed atherosclerosis within 5 years after transplantation. J Numerous immune and nonimmune risk factors are associated with the development of TCAD. Nonalloimmunedependent pathways of TCAD and specific approaches and therapies will be reviewed here. Many nonalloimmune risk factors have been associated with the development of TCAD. These include hyperlipidemia, recipient age and gender, obe'.dty, pretransplant diagnosis, and donor ischemic time. 2'3 Figure 1 summarizes factors involved in the development of TCAD. The central event appears to be endothelial-cell injury. This may occur early as a result of procurement and reperfusion, both of which may cause ischemia to the endothelial cell. Other factors appear to have effects over long periods after transplantation. One of the most controversial relationships of TCAD has been with cholesterol. In a review by Johnson, 2 three studies had statistically significant correlations between elevated cholesterol and the develop~aent of TCAD; in two other studies, there was a trend that did not reach statistical significance, and in two others, no correlation was found. Similar experience has been seen with high triglyceride levels. A multicenter study using intravascular ultrasound reported an association of higher triglyceride levels with increasing intimal thickness. 4 Other nonimmune risk factors pre,4ously reported to be associated with TCAD include donor age, preoperative etiologies, donor or recipient gender, gender mismatch, and recipient age. These were not found to be associated with increased intimal thickness in the mu[ticenter intravascular ultrasound study; however, obesity, defined as body-mass index of at least 29 kg/m 2, was associated with increasing intimal thickness, although the precise reasons are not clear. 5

T

APPROACHES AND THERAPIES

The current treatment options for TCAD include modification of risk factors, medical therapies and strategies, revascularization procedures, and retransplantation. In © 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

Transplantation Proceedings, 29 (Suppl 8A), 47S-50S (1997)

general, treatment of clinically relevant or severe TCAD has not been satisfactory. Modification of Risk Factors The modification of risk factors includes the treatment of

hypertension, hyperlipidemia, obesity, and diabetes; promotion of exercise programs; and abstinence from smoking. Although modification of risk factors in native coronary artery disease has been found to be beneficial, there are questions as to the applicability of these results to heart transplant patients. Recent single-center studies have demonstrated that primary prevention with calcium-channel blockers or lipidlowering agents may be beneficial. The control of hypertension with calcium-channel blockers may hold promise for altering the natural history, of TCAD by their potential influence on the development of intimal proliferation. Schroeder et al r' randomly assigned 106 heart transplant patients to receive either diltiazem or no calcium-channel blocker immediately after transplantation and assessed these patients by quantitative coronary angiography at 1 and 2 years posttransplant. The patient cohort treated with diltiazem was less likely to demonstrate a significant change in follow-up angiograms when compared with baseline values, whereas patients left untreated showed a slight decline in their coronary artery luminal diameters, by approximately 0.2 ram. ~ At 5-year follow-up, there was a significant difference in freedom from death and angiographic TCAD (56% in the diltiazem group vs 30% in the control group). 7 A major limitation of this study was the use of angiography, as one cannot sufficiently control for variations in vascular tone. In addition, coronary angiography is relatively insensitive in detecting early intimal thickening. Atkinson et al s reported that the calcium-channel blocker amlodipine could significantly decrease narrowing in the coronary arteries of the rat heterotopic transplant model as evaluated by digitized morphometry. Smoothmuscle cell migration and proliferation may involve calcium-dependent mechanisms. Calcium-channel blockade has been reported to stabilize endothelial function and inhibit From the University of California School of Medicine, UCLA Heart Transplant Program, Los Angeles, California, USA. Address reprint requests to Jon A. Kobashigawa, MD, 100 UCLA Medical Plaza, Suite 630, Los Angeles, CA 90095-6988. 0041-1345/97/$17.00 PII S0041-1345(97)00856-7 47S

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KOBASHIGAWA Acute rejection

Cyclosporine/Corticosteroids

Ische rnic time Fig 1. Proposed mechanisms in the development of cardiac transplant vasculopathy. Endothelial cell injury has been proposed as the event that initially triggers proliferation of smoothmuscle cells and macrophages. Hyperlipidemia may not be directly involved in endothelial injury but may play a secondary role in the development of the

disease.

~. Endothelial cell injury

Reperf~sion

Viruses (CMV)

..,mllmmmlm.~

Hyperlipidemia Donor age

Hypertension

platelet aggregation, with a decrease in the release of platelet-derived growth factors. 9 Therefore, use of calciumchannel blockers may decrease the development of intimal thickening. Hypercholesterolemia is common after cardiac transplantation; many studies have associated it with the development of TCAD. 2 In an autopsy study, McManus et alm carried out morphometric, immunohistochemical, ultrastructural, and biochemical assessments in 23 explanted allografts and donor-age-matched coronary artery controls. Mean total cholesterol, esterified cholesterol, and free cholesterol content in the transplant arteriopathic coronary arteries were more than 10-fold higher than in comparable native coronary artery segments. Extent of lipids in the arterial walls was highly correlated with digitized percent of luminal narrowing. The authors concluded that lipid accumulation is an important early and per~,.istent phenomenon in the development of TCAD. m A study at our institution evaluated the use of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in primary prevention of hyperlipidemia in heart transplant recipients. ~ Ninety-seven patients were randomized to pravastatin or no H M G - C o A reductase inhibitor within 2 weeks after transplantation. Twelve months after transplantation, the pravastatin group had significantly lower mean cholesterol levels than the control group (193 + 36 vs 248 _+ 49 mg/dL), less frequent cardiac reject:ion accompanied by hemodynamic compromise (3 vs 14 patients), better survival (94% vs 78%), and a lower incidence of TCAD as determined by angiography and autopsy (3 v~ 10 patients)] 1 In a subgroup of study patients, intravascu[ar ultrasound measurements at baseline and 1 year after transplantation showed significantly less progression ot intimal thickness in the pravastatin group than in the control group (P = .002). In another subgroup of patients, the cytotoxicity of natural killer cells was significantly lower in the pravastatin group than in the control group (9.8% vs 22.2% specific lysis).tJ This stud), suggests that pravastatin may decrease TCAD not only as a result of cholesterol lowering but also by

J Intimal hyperplasia (allograft vasculopathy)

exerting an additional immunosuppressive effect. The inhibition of natural killer cells by other H M G - C o A reductase inhibitors has also been demonstrated in vitro. ~2 Several investigators have reported significant lipid reduction using simvastatin in cardiac transplant recipients. Wenke et aP 3 randomly allocated 70 heart transplant patients immediately after transplantation to simvastatin 5 to 20 mg/d (n = 37) or to no simvastatin (n = 33). After 24 months, low-density-lipoprotein cholesterol levels were 110 mg/dL and 150 mg/dL in the simvastatin and control groups, respectively (P < .001). No benefit in rejection or survival was noted. The use of low-density-lipoprotein-cholesterol apheresis in combination with diet and pravastatin 10 mg/d has demonstrated regression in TCAD. Larger trials of this interesting lipid-lowering strategy are in progress. ~4 The effects of diabetes control, weight reduction, promotion of exercise, and abstinence from smoking have not been studied in heart transplant patients with respect to the development of TCAD. Benefits to nontransplant patients, however, would suggest a similar advantage for heart transplant recipients.

Other Medical Therapies/Strategies Therapeutic modalities in the treatment of TCAD are aimed at the proposed underlying mechanisms. Table 1 lists the areas of interest where treatment has been targeted. The somatostatin analog angiopeptin has been demonstrated to have an inhibitory effect on proliferation of smooth-muscle cells in experimental studies] 5 Other experimental data have shown that angiopeptin inhibits the release of insulinlike growth factor, which may inhibit proliferation of smooth-muscle cells after vascular injury. Wahlers et al ~6 studied 54 heart transplant patients who received angiopeptin injections and found similar survival and angiographic coronary atherosclerosis when they compared these patients with historical controls. A prospective, randomized trial is currently underway. Photopheresis is a new therapeutic strategy, that appears

TARGETING NONALLOIMMUNE-DEPENDENT PATHWAYS Table 1. Therapeutic Modalities to Treat Cardiac-AIIograft Vasculopathy Antiproliferative agents Angiopeptin Low-molecular-weight heparin Antimetabolites Methotrexate Antithrombotic agents Hirulog Antithrombin III Monoclonal antibodies Growth factors Adhesion molecules Cytokines

Antihypertensive agents Calciu-n-channel blockers Angiotensin-converting-enzyme inhibitors New immunosuppressive agents Use of pqotopheresis

Lipid-lowering agents HMG-CoA reductase inhibitors

to modulate the immune response. Patients are administered 8-methoxy-psoralen, and their white blood cells are subsequently removed via apheresis techniques. The psoralen-bound white blood cells are then irradiated with ultraviolet light and subsequently reinfused into the patient. It is postulated that this causes a host autoregulatory T-cell response that may have a beneficial ,effect on the development of intimal thickness. In a ra:ldomized trial of 23 cardiac transplant recipients, photopheresis was found via intravascular ultrasound to reduce irttimal thickening. 17 A larger multicenter study is currently in progress. Photopheresis may be a promising technique; however, it is expensive and time-consuming (patients receive photopheresis for 4 hours during 2 consecutive days and have this procedure performed at least once monthly for the first year) and therefore may have limited use. An impaired anticoagulant pathway has been associated with the development of TCAD. Azig et al is have demonstrated in the rat heterotopic heart model that rats treated with cyclosporine plus low-molecular-weight heparin have reduced frequency and severity for TCAD and less parenchymal rejection. Studies in cardiac transplant patients are currently underway. Research interest in antithrombotic agents has also evolved. Studies of hirulog and antithrombin III have demonstrated the impre:~sive inhibitory activities of these agents in the period after coronary angioplasty. Experience with heart transplant patients has not yet been reported. Antimetabolites such as methotrexate have been used empirically by many transplant physicians to treat patients with TCAD. The rationale is to add r~lore immunosuppression in the belief that TCAD is, in part, immune-mediated. There have been no randomized trials using methotrexate in patients who develop TCAD, however. Most anecdotal experiences do not show clear benefit. Animal studies have suggested a benefit of captopril, an angiotensin-converting-enzyme inhibitor, in TCAD. 19 In the rat heterotopic heart transplant model, Kobayashi et al 2° demonstrated that rats treated with captopril had a lower incidence of cellular and vascular rejection, minimal intimal proliferation, and reduced smooth-muscle cell pro-

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liferation. It is suggested that captopril may mediate this vascular response through a paracrine renin-angiotensin mechanism or a suppressive effect on platelet-activating factor. Medical therapies and strategies to prevent and treat TCAD are progressing as the mechanisms surrounding the development of this disease process become clear. Whatever the agent or modality used to treat this complication, one needs to start the intervention at the time of transplantation. The mechanisms of TCAD appear to start at that time, with both immune and nonimmune factors involved in its pathogenesis. It is likely that a combination of therapies will be necessary to prevent this complication effectively by combating the effects of ischemia during preservation and by decreasing the continuous immune response to the donor heart. Revascularization Procedures

Medical therapy to treat TCAD has been inadequate; therefore, palliative coronary revascularization has been attempted. A multicenter experience reported by Halle et a121 described revascularization procedures in heart transplant recipients. From 13 cardiac transplant programs, 66 patients underwent coronary angioplasty. Angiographic success (-<50% residual stenosis) occurred in 153 (94%) of 162 lesions. Forty patients (61%) are alive without retransplantation at 19 --- 14 (mean ~ standard deviation) months after angioplasty. Angiographic restenosis occurred in 42 (55%) of 76 lesions at 8 + 5 months after angioplasty. On the angiogram, the presence of distal arteriopathy was a marker for adverse allograft survival. Twenty-two of 39 patients (56%) with angiographic distal arteriopathy had subsequent death or retransplantation compared with 4 of 22 patients (18%) with no angiographic distal arteriopathy. Eleven patients from this multicenter study underwent directional coronary atherectomy. Angiographic success occurred in 9 (82%) of 11 lesions. Nine patients are alive without retransplantation at 7 -+ 4 months after atherectomy. 21 In the same study, coronary artery bypass surgery (CABS) was performed in 12 patients who developed TCAD after heart transplantation. This limited experience with CABS in the treatment of TCAD reflects the infrequency of focal proximal and midvessel coronary stenoses with suitable distal targets for anastomoses. Of the 12 patients undergoing CABS after heart transplantation, four patients died perioperatively and there was one late death. Seven patients are alive without retransplant 9 + 7 months after operation. 21 Although carefully selected transplant recipients with significant coronary artery disease may benefit from CABS in lieu of retransplantation, the immediate procedural outcomes appear worse than those after CABS for severe native atherosclerosis. The reasons for this may be the extent of coronary artery disease in heart transplant patients. Diffuse disease of the microcirculation may fail to provide adequate myocardial perfusion during and after cardiopulmonary bypass.

,%0S metransulant;atio~ i

Survival rate, of paticnls ~d:t0:, rctr~t~splan[atiol~ have bccn lov~er than for patierlts ttn(lcr~olrl~ transManlati~m for the first time. Tile International Sociclv Ior l-{[eart and I,ung Transplantation t~,egistry reports that patients undergoing rctransplantation within the firs1 (i morths after original transplant have a 1-year survival of 3it(~: and a 2-year survival of 33ff~,. One- and 2-year survival of patients undergoing retransplantation after the first 6 months are 59% and 54%, respectively. 22 These numbers are in con* trust to those for prima W heart transplant patients, who have an overall I-year smwival of 76% and a 2-year survival of 72%. Smith et a123 reported on the Stanford University experience with retransplantation. RetransMant 1-, 5-, and 10-year survival rates are 55%, 33%, and 22%, respectively; however, the 1-year actuarial survival of patients who underwent retransplantation for TCAE~ was 69 + 10%, which approaches the 1-year survival of primary, heart transplant patients. This study also showed that patients having second heart transplants do not have an increased risk of developing T C A D in the second donor heart. The actuarial freedom from T C A D in the entire heart-retransplantation population at 5 years was 89 + 7%, and, for patients who underwent retransplantation for TCAD, the actuarial freedom from this disease process in the retransplanted heart at 5 years Was 91 _+ 9%. 23 This suggests that heart transplant patients who develop se,:ere T C A D may be suitable candidates for retransplantation, although there is much ethical controversy regarding retransplantation because of the scarcity of donor hearts. SUMMARY

Medical therapy to treat and prevent this major complication has progressed slowly. The early use of diltiazem, pravastatin, or photopheresis has had reported efficacy in slowing the development of T C A D but not in preventing its development. Current ongoing multicenter studies with mycophenolate mofetil, angiopeptin, and other agents may hold promise for the future. It is clear that whatever intervention is applied, it must be sta::ted at the time of transplantation, as the cascade of events of T C A D begins at the time of surgery. Revascularization procedures, including angioplasty and CABS, have proven to be palliative and not applicable to all patients with TCAD. Currently, retranspiantation remains the only viable treatment for patients w: th severe transplant

KOBASH!GAWA

~as~td~puth)'. t ~ r t-I:,1icI'tt~ tmdcFgoing rclr',tnsplnnt~ltion tor scwqc T ( A I ) . survival alld tht: dc',cloplnClll u'd"T ( ' : \ I ) i n the scco[id dnilor houri appc:~r acccptaldc conlparcd to ~utcolncs for patients undergoing primary heart transpkmlation. The ethical dilemma surrounding heart rctransplantation, ht~wcvcr, is considerable because {~f the scarcity of donor organs. REFERENCES

1. Gao SZ, Schrocder JS, Alderman EL, et al: Circulation 80:100:1989 2. Johnson MR: J Iteart Lung Transplant 11:Sl24, 1992 3. Winters GL, Kendall TJ, Radio SJ. el al: J Heart Transplant 9:364, 1990 4. Vatantine HA: J Heart Lung Transplant 14:$234, 1995 5. ttauptman PJ, Davis SF, Miller L, et al: J Heart Lung Transplant 14:$238, 1995 6. Schroeder JS, Gao S-Z, Alderman EL, et al: N Engl J Med 328:164, 1993 7. Schroedcr JS, Gao S-Z, Alderman EL, et al: J Am Coll Cardiol: 231A, 1994 8. Atkinson JB, Wudel JH, Hoff SJ, et al: J Heart Lung Transplant 12:1036, 1993 9. Betz E, Weiss HD, Heinle H, et al: J Cardiovasc Pharmacol 18(suppl 10):$71, 1991 10. McManus BM, Horley IO, Wilson JE, et al: Am J Pathol 147:293, 1995 11. Kobashigawa JA, Katznelson S, Laks H, et al: N Engl J Med 333:621, 1995 12. Cutts JL, Scallen TJ, Watson J, et al: J Cell Physiol 139:550, 1989 13. Wenke K, Thiery J, Meiser B, et al: Z Kardiol 84:130, 1995 14. Park J-W, Vermeltfoort M, Braun P, et al: Atherosclerosis 115:1, 1995 15. Foegh ML: J Heart Lung Transplant 11:$28, 1992 16. Wahlers T, Mtigge A, Oppelt P, et al: J Heart Lung Transplant 14:143, 1995 17. Barr ML, Berger eL, Wiederman JG, et al: J Heart Lung Transplant 12:$85, 1993 18. Aziz S, Tada Y, Gordon D, et al: J Heart Lung Transplant 12:634, 1993 19. Mehra MR, Ventura HO, Smart FW, et al: J Heart Lung Transplant 14:$246, 1995 20. Kobayashi J, Crawford SE, Backer eL, et al: Circulation 88:286, 1993 21. Halle AA III, DiSciascio G, Massin EK, et al: J Am Coil Cardiol 26:120, 1995 22. Hosenpud JD, Novick R J, Breen TJ, et al: J Heart Lung Transplant 14:805, 1995 23. Smith JA, Ribakove GH, Hunt SA, et al: J Heart Lung Transplant 14:832, 1995