Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 1997;96:2069-2077

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weis, M.
Right arrow Articles by von Scheidt, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weis, M.
Right arrow Articles by von Scheidt, W.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Heart Transplantation
*Vascular Diseases

(Circulation. 1997;96:2069-2077.)
© 1997 American Heart Association, Inc.

Articles

Cardiac Allograft Vasculopathy

A Review

Michael Weis, MD; ; Wolfgang von Scheidt, MD

From Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, University of Munich, Germany.

Correspondence to Dr Michael Weis, Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, University of Munich, Marchioninistraße 15, 81377 Munich, Germany. E-mail Micha.Weis{at}t-online.de


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowPathological Characteristics
 down arrowPathophysiology/Immunopathology
 down arrowAlloantigen Independent Risk...
 down arrowDiagnosis
 down arrowProphylaxis and Therapy
 down arrowSummary and Conclusion
 down arrowReferences
 
Abstract Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins. CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV. Apoptosis and loss of functional vascular remodeling have to be considered as important mediators of clinically relevant CAV. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help prevent chronic rejection in clinical transplantation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and antiproliferative drugs may slow progression of CAV by various effects. Methods to augment endogenous nitric oxide bioavailability as well as newer immunosuppressive regimens may be protective. Balloon angioplasty has a limited role in the treatment of focal lesions. Experiences with coronary stenting, coronary artery bypass grafting, and transmyocardial laser revascularization are limited. Retransplantation has a worse outcome than initial transplantation.


Key Words: transplantation • vasculopathy • coronary disease • endothelium


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowPathological Characteristics
 down arrowPathophysiology/Immunopathology
 down arrowAlloantigen Independent Risk...
 down arrowDiagnosis
 down arrowProphylaxis and Therapy
 down arrowSummary and Conclusion
 down arrowReferences
 
Cardiac allograft vasculopathy remains a troublesome long-term complication of heart transplantation and is the major cause of death in patients surviving 1 year after transplantation.1 It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramyocardial and epicardial coronary arteries and veins.2 Although the disease selectively involves the vascular bed of the allograft, including the donor aortic segment, all other native vessels throughout the body are spared. Rapid or fulminant development of CAV within 1 year portends a poor prognosis for major clinical events.3 Although there is evidence of partial reinnervation of the cardiac allografts, most heart transplant recipients cannot experience typical anginal pain associated with myocardial ischemia or infarction. The first clinical manifestations, therefore, are often ventricular arrhythmias, congestive heart failure, or sudden death. At 1, 2, and 4 years, the actuarial likelihood of any angiographically visible CAV is 11%, 22%, and 45%, respectively, as demonstrated in a multi-institutional study.4 Intimal thickening is detectable with ICUS in up to 75% of patients at year 1.5 With the development of animal models of CAV, the use of ICUS, and pharmacological testing of coronary vasomotor function, new insights into the pathogenesis, functional and morphological patterns, and progression of CAV are possible. This article evaluates the pathological characteristics, immunopathology, pathophysiology, diagnosis, and treatment options, as well as future directions of CAV research.


*    Pathological Characteristics
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Pathological Characteristics
down arrowPathophysiology/Immunopathology
 down arrowAlloantigen Independent Risk...
 down arrowDiagnosis
 down arrowProphylaxis and Therapy
 down arrowSummary and Conclusion
 down arrowReferences
 
The histological changes that characterize CAV are not uniform. Pathological examination of coronary arteries from human cardiac allografts has shown a broad spectrum of abnormalities, ranging from concentric fibrous intimal thickening to complicated atherosclerotic plaques that bear a close resemblance to spontaneous atherosclerosis.6 It has been demonstrated that early intimal proliferation progresses with time and with subsequent increases in lipid deposits and calcification of the coronary vessel.2 Atheromas and diffuse intracellular and extracellular accumulation of lipids in both intimal and medial walls are frequent occurrences.7 The internal elastic lamina remains almost intact except for small breaks.2 A time-dependent spectrum of histopathological changes has been described.8 Early after transplantation, diffuse fibrous intimal thickening or a vasculitis predominates. Late after transplantation, focal atherosclerotic plaques, diffuse intimal thickening, or a mixture of both is found. The smaller branches are often occluded before the larger epicardial arteries, resulting in small, stellate infarcts.9 Despite exuberant intimal proliferation, the media of the vessel is rarely thickened and sometimes becomes narrower than in normal conditions.10 The cellular infiltrate of intimal proliferative lesions consists of modified smooth muscle cells, macrophages/monocytes, and T lymphocytes.10


*    Pathophysiology/Immunopathology
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowPathological Characteristics
 *Pathophysiology/Immunopathology
down arrowAlloantigen Independent Risk...
 down arrowDiagnosis
 down arrowProphylaxis and Therapy
 down arrowSummary and Conclusion
 down arrowReferences
 
Although the exact pathogenesis of CAV remains to be established, several lines of data suggest that it is primarily an immune-mediated disease. Limitation of the proliferative vascular disease to the allograft arterial and venous tree, the often diffuse nature of allograft vascular involvement, the development of CAV in cardiac allografts of animal models with some histocompatibility mismatch, and the lack of development in isografts support the immunologic hypothesis of CAV development. Several experimental models suggest that immunologic mechanisms operating in a milieu of nonimmunologic risk factors constitute the principal stimuli that result in progressive myointimal hyperplasia. The initial event of CAV is probably a subclinical graft coronary endothelial injury. The endothelial cell is the major determinant of vessel wall function. It normally inhibits thrombus formation and leukocyte adhesion, regulates vasomotor function, and inhibits vascular smooth muscle cell proliferation. Damage to the endothelium could alter any or all of these functions, predisposing the artery to inflammation, thrombosis, vasoconstriction, and vascular smooth muscle cell growth.11 After human cardiac transplantation, humoral or more important cellular responses to HLA antigens and vascular endothelial cell antigens are potential sources of endothelial damage. CD4 lymphocyte–induced upregulation of MHC class II antigens on endothelial cells (subsequent to MHC-I antigen detection by CD8 lymphocytes) elicits a cellular immune response.12 The role of MHC donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. However, HLA class I or class II mismatching was not found to be associated with posttransplant coronary atherosclerosis in a large, single-center study.13 The ability to produce CAV in animals transplanted with an MHC-identical graft and, more recently, to document the occurrence of allograft rejection in genetically engineered animals lacking MHC genes should spur further investigations of other allograft-specific antigens, distinct from those of the MHC, which may play an important role in the development of CAV.14 Irrespective of the initial specific immune-mediated injury, the cascade of events that follows appears to be a physiologically nonspecific inflammatory response.15 It is important to note that activated lymphocytes secrete interferon-{gamma}, which stimulates production of ICAM-1.16 The involvement of adhesion molecules plays a crucial role in regulating the interaction of inflammatory cells with cells in the vascular wall because the adherence of leukocytes to vascular endothelium is a prerequisite for transmigration. Expression of vascular adhesion molecules (VCAM-1, ICAM-1, and ELAM-1) on endothelial cells and medial smooth muscle cells in cardiac transplant patients has been observed,17 and early ICAM-1 expression could be correlated to early development of angiographically visible CAV.18 The intercellular network, via macrophages, T lymphocytes, endothelial cells, and smooth muscle cells, generates a variety of stimulatory cytokines (IL-1, IL-2, IL-6, and tumor necrosis factor-{alpha}) and growth factors (PDGF, IGF-I, FGF, HBGF, EGF, GM-CSF, and TGF-ß) that promote the development of the chronic allograft lesion.15 Thus, at the end of the "endothelial injury process," chronic inflammation elicits a repair response that causes the production of a connective tissue matrix19 and the migration and proliferation of vascular wall smooth muscle cells that compromise the vascular lumen. Recently apoptosis, a genetically encoded cell-death program, has been proposed to be involved in human coronary atherosclerosis, especially during restenosis.20 Dong et al21 demonstrated a pathological evidence for Fas-mediated apoptotic cytotoxicity in CAV. Nitric oxide has the capacity to influence apoptosis22 and is induced during cardiac allograft rejection.23 Moreover, induction of inducible nitric oxide synthase was associated with CAV in a rat cardiac allograft transplant model.24 Conceivably, there is a possible link between nitric oxide–mediated apoptosis in smooth muscle cells and transplant intimal thickening.

However, the development of clinically evident CAV depends on the interplay between the lesion-formation response of the allograft to injury versus the adaptive process of vascular remodeling.25 The expansion of the intimal lesion eventually overcomes the capacity of the vessel to undergo compensatory enlargement remodeling such that the plaque creates a vessel stenosis. Indeed, the pathogenesis of clinically relevant CAV may be due in part to the possible lack of compensatory dilation (enlargement) of the vessel wall over time.26 Intriguingly, dilated angiopathy, a specific subtype of CAV,27 might be an example of overcompensating positive remodeling.


*    Alloantigen Independent Risk Factors
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowPathological Characteristics
 up arrowPathophysiology/Immunopathology
 *Alloantigen Independent Risk...
down arrowDiagnosis
 down arrowProphylaxis and Therapy
 down arrowSummary and Conclusion
 down arrowReferences
 
Several nonimmunologic mechanisms could contribute to the progression of CAV. These include recipient characteristics (age, sex, obesity, hypertension, hyperlipidemia, insulin resistance, and CMV infection) and donor characteristics (age, sex, preexisting coronary disease, and donor ischemic time).28 29 30 Preliminary insights from a multicenter ICUS study31 indicated that there is no apparent association between the progression of intimal thickening and multiple nonimmune factors, including donor and recipient characteristics (recipient or donor age and sex, sex mismatch, pretransplant diagnosis, ischemic time, posttransplant hypertension, body mass index, and CMV infection).

Metabolic Risk Factors
Glucose intolerance and insulin resistance, hypercholesterolemia, hypertriglyceridemia, and low HDL cell surface levels occur in 50% to 80% of patients after cardiac transplantation.32 In vitro studies33 have shown that LDL cholesterol, particularly its oxidized derivatives, is injurious to the endothelium. Hypercholesterolemia can impair endothelium-dependent vasorelaxation via oxidative inactivation of nitric oxide, and the damaged endothelium is a source of excess superoxide anion. A close relation between abnormalities in lipids and coronary artery endothelial dysfunction has been demonstrated in patients with atherosclerosis, but not after human heart transplantation.34 35 However, in a multicenter ICUS study,36 an insignificant trend with triglyceride level and an inverse relationship between HDL cholesterol level and intimal thickening was observed. Intimal thickening was more pronounced in those patients with higher LDL/HDL cholesterol ratios. The high-triglyceride/low-HDL cholesterol levels associated with atherosclerosis are well described, particularly in patients who demonstrate the syndrome of insulin resistance.37 Indeed, Valantine et al38 demonstrated that glucose intolerance and insulin resistance, frequently observed after heart transplantation, were strong predictors of intravascularly visible CAV.

CMV
Human CMV has been associated with CAV.39 The endothelium is a common target for CMV infection, and the immediate early gene of human CMV can code for a protein that has sequence homology and immunologic cross-reactivity with a domain of HLA-DR.40 Preliminary data from Briggs et al41 provide information regarding virally induced molecular events that may serve to promote host mononuclear adhesion, activation, and transendothelial migration within the allograft vasculature. Additionally, the CMV-induced blockage of the regulatory role of p53,42 a protein that inhibits proliferation of smooth muscle cells and apoptosis, might accelerate the progression of CAV.43 Cytokines associated with CMV infection, as well as virus-related factors such as dysregulation of cellular lipid metabolism, may also increase endothelial damage and vasculopathic changes. However, Gulizia et al44 recently observed that the presence of the human CMV genome is not associated with the nature or extent of CAV. Thus, additional pathological and molecular work is needed to determine whether or how CMV infection may be involved pathogenically in CAV.

Ischemia-Reperfusion Injury
The role of ischemia and reperfusion has to be considered as an early, transient (but important) cofactor of endothelial injury45 46 after transplantation. Presumably, beginning from an activation of the microvascular endothelium, free oxygen radicals lead to a subsequent activation of passing host leukocytes and macrophages. Activated cells release oxygen radicals and other aggressive mediators, such as proteases, cytokines, and eicosanoids, which chemotactically attract host leukocytes. Thus, postischemic reperfusion injury in total represents the result of network interactions mediated by a large variety of oxidative molecules and aggressive mediators. The primary endothelial injury is transferred to interstitial injury.47


*    Diagnosis
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowPathological Characteristics
 up arrowPathophysiology/Immunopathology
 up arrowAlloantigen Independent Risk...
 *Diagnosis
down arrowProphylaxis and Therapy
 down arrowSummary and Conclusion
 down arrowReferences
 
Noninvasive Screening
Noninvasive screening tests such as exercise electrocardiography, thallium scintigraphy, exercise radionuclide ventriculography, and ambulatory electrocardiography are generally not sensitive or specific enough to be considered reliable screening tests.48 Conflicting data have been reported concerning the accuracy of stress echocardiography in diagnosing CAV.49 50

Coronary Angiography
Although coronary angiography may be specific in the diagnosis of CAV, it has been shown to underestimate the presence of disease and therefore has not proven to be a sensitive method of diagnosis. The insensitivity of coronary angiography in the diagnosis of CAV, except for significant focal stenoses, has been demonstrated by histopathologic studies51 and by comparison with ICUS.52 This may result from the fact that severe intimal thickening may be compensated by vessel-enlarging remodeling. Additionally, in the rare case of homogeneous intimal proliferation, a reference vessel segment, required to detect luminal narrowing, may be missing. Although no correlation between the severity of CAV and left ventricular ejection fraction is detectable,53 the development of significant epicardial coronary stenoses does convey a poor prognosis with a high degree of specificity.54 It is likely that angiographic luminal irregularities indicate a change not only in the volume but also in the character of the plaque mass.

ICUS
More recently, ICUS has been investigated as an imaging modality in the coronary arteries of heart transplant recipients. This technique allows a reproducible look at both actual lumen diameter and the appearance and thickness of the intima and media. An intravascular ultrasound study in 132 patients 1 to 9 years after transplantation detected atherosclerosis in >80% of patients, with proximal segments most frequently (focally) involved.55 Diffuse and circumferential atherosclerosis was more common in mid and distal segments. Tuzcu et al56 described unequivocal atherosclerosis in 56% of recipients studied within 1 month after transplantation, representing donor-transmitted disease. These intravascular studies suggest that CAV has a dual origin, with many donor-transmitted early, focal, noncircumferential plaques in proximal segments. The diffuse, concentric pattern observed in distal segments likely represents the result of an overlapping immune-mediated vessel injury. Botas et al57 noted that preexistent donor coronary disease does not accelerate the progression of CAV within the first few years after transplantation. Importantly, the first prospectively collected, multicenter, intravascular study database of 299 heart transplant recipients5 indicated that the most rapid rate of progression of intimal thickening occurs during the first year after the transplant procedure (intimal thickness at baseline was 190±18 µm, and this thickness increased to 300±26 µm), followed by slow but inexorable progression over time. The presence of moderate to severe intimal thickening by ICUS is predictive of the future development of angiographically apparent CAV.58 Moreover, in a recent study that assessed the clinical predictive value of ICUS, Mehra et al59 demonstrated that cardiac transplant recipients with severe intimal thickening were 10-fold more likely to suffer cardiac events than those without severe hyperplasia. Because many heart transplant recipients with severe intimal thickening remain free of clinical morbid events, additional studies must consider the importance of the quality and not merely the quantity of intimal proliferation, as well as compensatory remodeling, in determining prediction of morbid cardiac events. The question of whether ICUS is superior to angiography with respect to direct therapeutic consequences (except for studies evaluating antiproliferative strategies) remains unanswered. Standardization of the quantification of intimal thickening by ICUS and the definition of pathological intimal thickness are continuing problems that must be solved.

Epicardial Endothelial Function
The consequence of epicardial endothelial dysfunction, frequently observed in cardiac transplant patients,60 61 is still unclear. The existence of coronary segments with functioning endothelium indicates that the latter is not diffusely disturbed in all cardiac transplant recipients and that possibly the endothelial function is not irreversibly lost.62 It is recognized that the anticoagulant factors synthesized by a well-functioning endothelium play an important role in determining the local homeostatic equilibrium and that deficient fibrinolysis plays a role in the development of CAV.63 Nitric oxide as an antimitogenic, antiproliferative substance with antioxidative effects is clearly involved in the accelerated process of intimal thickening.64 Recently, Davis et al65 demonstrated that early endothelial dysfunction (15±3 days after transplantation) predicts the development of intravascular ultrasound–visible CAV at 1 year after heart transplantation. Preliminary data from Yeung et al66 suggest that early evidence of endothelial dysfunction may predict an adverse clinical outcome.

Intracoronary Doppler Flow Velocity Measurement
Coronary blood flow measurement is an established functional parameter to assess the integrity of the microcirculation. Usually, intracoronary Doppler flow is used to assess the resistance bed of the coronary microcirculation. Microvascular disease leads to a diminishment in coronary flow reserve (ratio of hyperemic to resting blood flow velocities). Coronary flow reserve after cardiac transplantation was found to be preserved in the first 2 years after cardiac transplantation,67 68 but conflicting results have been reported concerning the long-term follow-up even in the absence of flow-limiting epicardial stenoses.35 67 68 69 A reduced coronary flow reserve during follow-up might be attributed to structural changes of the myocardium as a consequence of subclinical rejection episodes and the development of left ventricular hypertrophy, or it may represent a manifestation of CAV that affects microvascular vessels. To date, the prevalence, nature (endothelium dependent and/or independent), and consequences of coronary microvascular dysfunction are not well defined. In a recent study from Weis et al,70 microvascular vessel disease (detected as reduced endothelium-independent coronary flow reserve) was associated with a subsequent reduction in left ventricular ejection fraction during a 2-year follow-up. Thus, the impaired coronary flow reserve may lead to chronic, repetitive left ventricular subendocardial ischemia and resultant impairment of left ventricular function.71

Importantly, Clausell et al72 demonstrated that there is no correlation between microvascular and epicardial vessel disease, suggesting discordant distribution patterns of CAV. We73 investigated epicardial and microvascular vasodilator function in 110 cardiac transplant recipients (1 to 160 months after transplantation) and could not find any correlation between epicardial and microvascular endothelial function nor any correlation between vasomotor function and epicardial intimal hyperplasia. Differences in pathobiology and rate of progression of disease, as well as antigen heterogeneity, in the large and small arteries may account for the heterogeneous presentation.


*    Prophylaxis and Therapy
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowPathological Characteristics
 up arrowPathophysiology/Immunopathology
 up arrowAlloantigen Independent Risk...
 up arrowDiagnosis
 *Prophylaxis and Therapy
down arrowSummary and Conclusion
 down arrowReferences
 
A preliminary study by Schroeder et al74 randomly (not blinded or placebo controlled) assigned 116 consecutive patients to receive either diltiazem or no calcium entry blocker and assessed this cohort by baseline and annual angiograms at 1 and 2 years thereafter. The patients treated with diltiazem were less likely to demonstrate a significant change in their follow-up angiogram and had a significantly better survival rate. Calcium antagonists facilitate the effects of endothelium-derived relaxing factors in vascular smooth muscle, and they also inhibit the vasoconstrictive effects of endothelin and cyclooxygenase contracting factors and thus may have protective cardiovascular properties.75 However, diltiazem failed to suppress intimal proliferation in a rat allograft coronary disease model.76 A case-control study by Mehra et al77 in 32 consecutive posttransplant patients demonstrated that patients treated either with calcium entry blockers or with ACE inhibitors have a lesser degree of intimal proliferation in the first year after transplantation. A salutary effect of ACE inhibitors on CAV was confirmed in a Lewis-to–Fisher 344 rat heterotopic transplant model.78 Kobayashi et al78 demonstrated that animals in the captopril group showed minimal intimal proliferation and reduced smooth muscle cell proliferation for up to 3 months of follow-up. Importantly, ACE inhibitors not only prevent the formation of angiotensin II, a potent vasoconstrictor with proliferative properties, but also augment the local vascular concentrations of bradykinin and in turn the activation of the L-arginine–nitric oxide pathway.79 ACE inhibitors have been shown to retard the vascular remodeling process within the renal microcirculation that promotes diabetic nephropathy and eventual kidney failure.80 Thus, one may speculate that vasodilators are effective in part because of flow-induced remodeling. Recently, von der Leyen et al81 demonstrated the impact of in vivo gene transfer of the nitric oxide synthase gene, which effectively inhibited intimal lesion formation in a rat carotid balloon-injury model. The local delivery of nitric oxide donors, especially as stable nitrosothiol compounds, may have therapeutic benefit in inhibiting the proliferation of smooth muscle cells. Even supplementation of L-arginine, the precursor of nitric oxide, could represent a novel therapeutic strategy to maintain normal endothelial function after cardiac transplantation.82 In a rabbit cardiac allograft model, L-arginine feeding reduced coronary artery myointimal hyperplasia by attenuating the mitogenic response of vascular cells to IGF-I and IL-6.83 Thus, strategies to augment endogenous nitric oxide–generating capacity and/or to inhibit the deleterious effects of free oxygen radicals on nitric oxide efficacy (bioavailability) may prove to be protective against endothelial dysfunction and development of CAV. Inhibitors of HMG-CoA reductase have been associated with a reduced incidence of severe rejection episodes and reduced progression of CAV.29 84 HMG-CoA reductase inhibitors may slow the progression of CAV by immunomodulatory effects independent of cholesterol reduction.84 85 86 87 88 Moreover, simvastatin inhibits growth factor–induced cell proliferation and modulates platelet thromboxane-A2 biosynthesis.89 Angiopeptin, an octapeptide analogue of somatostatin, was found to have immunosuppressive properties, most probably due to inhibition of IGF-I and reduction of MHC class II, T lymphocyte, macrophage, and ICAM-1 expression.90 In a rabbit heterotopic heart transplant model, angiopeptin has been shown to attenuate myointimal hyperplasia.91 Preliminary results from a prospective, randomized, double-blind, placebo-controlled clinical trial indicated that treatment with angiopeptin for 14 days after heart transplantation and as an adjunct treatment during rejection episodes significantly reduced intimal proliferation within a follow-up time of 32 months.92 Because of the early and sustained presence of T cells and macrophages in vascular lesions, Russell et al93 have used CTLA4Ig, a fusion protein that blocks the CD28-B7 costimulatory T-cell activation pathway, in a rat heterotopic cardiac transplantation model. Grafts from long-term (>120 days) survivors treated with the fusion protein showed significant reductions in the frequency and severity of arteriosclerosis compared with cyclosporine A–treated rats. Thus, strategies for blocking T-cell costimulation may help prevent chronic rejection in clinical transplantation.

Clinical and Experimental Immunosuppressive Drugs
Using a predictive model for adverse cardiac events from CAV in a cohort of 163 consecutive heart transplant recipients, Mehra et al94 detected a prognostic impact of immunosuppression and cellular rejection on CAV. Whereas a higher daily cyclosporine dose was found to be protective for adverse cardiac events, greater prednisone consumption was substantially deleterious. Tacrolimus (FK 506), a new macrolide immunosuppressant agent, appears to exert its effects through a molecular mechanism of action similar to that of cyclosporine but has been thought to be more potent, presumably by inhibiting cytokine synthesis by T cells infiltrating the allograft.95 Meiser et al96 compared FK 506 to cyclosporine in a rat cardiac allograft vascular model. Allografted hearts from rats treated with FK 506 showed a worse grade of CAV than did grafted hearts from rats treated with cyclosporine. These results could be confirmed by Arai et al.97 In contrast, Wu et al98 have described the inhibition of rat heart allograft arteriosclerosis by FK 506 in recipients of syngeneic grafts. The intermediate-term results from a prospective trial99 of FK 506 in clinical heart transplantation demonstrated no significant difference in actuarial freedom from angiographically visible CAV at 4 years between patients treated with FK 506 (n=80) and cyclosporine (n=80). Mycophenolate mofetil, an antimetabolite derived from mycophenolic acid, was shown to prolong cardiac allograft survival, induce donor-specific tolerance, and reverse ongoing acute cellular rejection in rodent and primate models.95 Gregory et al100 demonstrated a regression in arterial thickening and endothelial replacement by mycophenolate mofetil using a balloon-catheter–induced arterial-injury model in rats. Thus, the direct antiproliferative action on smooth muscle cells by mycophenolate mofetil in vivo may retard the development of CAV. However, mycophenolate mofetil increased tumor necrosis factor-{alpha}–induced expression of vascular cell adhesion molecules on cultured human venous endothelial cells101 and thus may have deleterious effects. 15-Deoxyspergualin, an agent that directly suppresses macrophage function, including the expression of HLA-DR antigens, appeared to be superior to cyclosporine for preventing the development of CAV in a rat heterotopic heart transplantation model.102 In a rat aortic allograft model of chronic graft rejection, 15-deoxyspergualin was shown to partially inhibit all parameters of graft vascular disease, apparently through immune-mediated mechanisms.103 Rapamycin and leflunomide interfere with signals transduced by cytokines and growth factors and thus interrupt the proliferation of a variety of cells, including B cells, fibroblasts, and smooth muscle cells.104 105 It is noteworthy that both these agents are able to reverse arterial thickening in a rat model of transplant vasculopathy (Lewis to Fisher 344). Leflunomide was associated with significant downregulation of circulating anti-donor antibodies.105 Recently, Gregory et al100 demonstrated that rapamycin can also inhibit vascular lesion formation after balloon injury, presumably by blocking cell-cycle progression.106 These studies suggest that the coordinated blockade of cellular processes common to the immune response and vascular lesion formation may have particular clinical efficacy in preventing CAV.

Revascularization Procedures
Coronary artery revascularization in heart transplant recipients, by use of PTCA,107 108 directional coronary atherectomy,109 or coronary artery bypass graft surgery,110 has been performed in selected patients as palliative therapy to decrease ischemia-related morbidity and mortality. Although helpful in the short-term setting, the long-term results are disappointing, most probably because of the rapid and diffuse nature of the disease. Recently, 13 medical centers retrospectively analyzed their complete experience with different revascularization procedures.111 Sixty-six patients underwent coronary angioplasty. Angiographic success (<50% residual stenoses) occurred in 153 of 162 lesions. Forty patients (61%) were alive without retransplantation at 19±14 months after angioplasty. Two patients sustained periprocedural myocardial infarction and died. Angiographic restenosis occurred in 42 (55%) of 76 lesions at 8±5 months after angioplasty. Angiographic distal arteriopathy adversely affected allograft survival. Thus, balloon angioplasty has comparable primary success rates but is characterized by a high restenosis rate and progression of CAV in non-PTCA segments, thus limiting the long-term benefit. There is a growing number of patients who have symptomatic, diffuse CAV that is not amenable to mechanical intervention and maximal medical therapy. Preliminary data suggest evidence of clinical efficacy in relieving anginal symptoms and improving myocardial perfusion by transmyocardial laser revascularization in 12 heart transplant recipients,112 but long-term results are needed.

Retransplantation
Repeat cardiac transplantation has been performed, but survival after retransplantation is shorter than after the initial transplantation.113 114 115 This increased mortality occurs predominantly during the early posttransplant period and is due in part to a more frequent requirement for preoperative mechanical assistance, a higher level of HLA sensitization, and more frequent surgical complications.114 A shorter interval between transplants and rejection as the cause of allograft failure are predictors of increased mortality. Infection, rejection, and development of CAV probably do not occur more frequently after repeat transplantation, whereas the incidence of malignancy is double that observed in primary transplant recipients.114 In view of the limited donor supply, a number of centers no longer recommend retransplantation. The individual clinician must balance the therapeutic obligation to the transplant recipient with the current limitations in the supply of organs.


*    Summary and Conclusion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowPathological Characteristics
 up arrowPathophysiology/Immunopathology
 up arrowAlloantigen Independent Risk...
 up arrowDiagnosis
 up arrowProphylaxis and Therapy
 *Summary and Conclusion
down arrowReferences
 
CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors. The obstructive vascular lesion characteristics of CAV are thought to progress through repetitive endothelial injury followed by repair response. T lymphocytes, macrophages, and neutrophils migrate to the subendothelial area via the activity of endothelial adhesion molecules and, in turn, elaborate various cytokines and growth factors that cause progression of the process. The role of donor-recipient MHC differences in the pathogenesis of CAV has not yet been completely elucidated, and experimental models within species (such as pigs) that, like humans, express MHC class II on the endothelium could be useful.

ICUS studies demonstrate a resemblance to conventional atherosclerosis as evidenced by eccentric rather than concentric lesions, branch vessel location, and a large intravessel and intervessel variability in type and extent of disease in a given patient. The diffuse, concentric pattern observed in distal segments likely represents the result of the process of the response to endothelial injury. Because many heart transplant recipients with severe intimal thickening remain free of clinical morbid events, additional studies should consider the importance of the quality and not merely the quantity of intimal proliferation in determining the occurrence of morbid cardiac events. Additionally, the lack of a correlation between microvascular and epicardial vessel disease suggests different subtypes of CAV. Differences in pathobiology and the rate of progression of disease in the large and small arteries may account for the heterogeneous presentation. Apoptosis and loss of functional vascular remodeling must be considered as important mediators of clinically relevant CAV in the future. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help to prevent long-term rejection in clinical transplantation. HMG-CoA reductase inhibitors and antiproliferative drugs may slow the progression of CAV by different immunologic and nonimmunologic effects. Methods to augment endogenous nitric oxide metabolism capacity (by use of ACE inhibitors, L-arginine, or antioxidants) may be protective against endothelial injury. The central role of immunosuppressive drugs in the natural history of CAV is obvious. Newer immunosuppressive drugs may emerge that will be shown to be protective of (or even deleterious for) the development of CAV, making randomized clinical trials using ICUS necessary. Revascularization procedures have an established but very limited role in the setting of significant focal lesions. Retransplantation is associated with an increased mortality and is discussed controversially in the face of organ shortage. With a better understanding of the causes of CAV and the development of specific treatment options to halt or prevent this form of vascular disease, the lifetime of allografts may be extended in most recipients.


*    Selected Abbreviations and Acronyms
 
CAV = cardiac allograft vasculopathy
CMV = cytomegalovirus
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A
ICAM-1 = intercellular adhesion molecule-1
ICUS = intracoronary ultrasound
IGF = insulin-like growth factor
IL = interleukin
MHC = major histocompatibility complex
PTCA = percutaneous transluminal coronary angioplasty


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowPathological Characteristics
 up arrowPathophysiology/Immunopathology
 up arrowAlloantigen Independent Risk...
 up arrowDiagnosis
 up arrowProphylaxis and Therapy
 up arrowSummary and Conclusion
 *References
 

  1. Kaye MP. The Registry of the International Society for Heart and Lung Transplantation: Tenth Official Report—1993. J Heart Lung Transplant. 1993;12:541-548.[Medline] [Order article via Infotrieve]
  2. Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant. 1992;11:S38-S44.[Medline] [Order article via Infotrieve]
  3. Gao SZ, Hunt SA, Schroeder JS, Alderman E, Hill IR, Stinson EB. Does rapidity of development of transplant coronary artery disease portend a worse prognosis? J Heart Lung Transplant. 1994;13:1119-1124.[Medline] [Order article via Infotrieve]
  4. Costanzo MR, Naftel DC, Pritzker MR, Hellman JK, Boehmer JP, Brozena SC, Dec WG, Ventura HO, Kirklin JK, Bourge RC, Miller LW. Heart transplant coronary artery disease detected by angiography: a multi-institutional study. J Heart Lung Transplant. 1996;15:S39. Abstract.
  5. Yeung AC, Davis SF, Hauptmann PJ, Kobashigawa JA, Miller LW, Valantine HA, Ventura HO, Wiedermann J, Wilensky R. Incidence and progression of transplant coronary artery disease over 1 year: results of a multicenter trial with use of intravascular ultrasound. J Heart Lung Transplant. 1995;14:S215-S220.[Medline] [Order article via Infotrieve]
  6. Pucci AM, Forbes RDC, Billingham ME. Pathologic features in long-term cardiac allograft. J Heart Transplant. 1990;9:339-345.[Medline] [Order article via Infotrieve]
  7. McManus BM, Horley KJ, Wilson JE, Malcom GT, Kendall TJ, Miles RR, Winters GL, Costanzo MR, Miller LL, Radio SJ. Prominence of coronary arterial wall lipids in human heart allografts. Am J Pathol. 1995;147:293-308.[Abstract]
  8. Johnson DE, Gao SZ, Schroeder JS, DeCampli WM, Billingham ME. The spectrum of coronary artery pathologic findings in human cardiac allografts. J Heart Transplant. 1989;8:349-359.[Medline] [Order article via Infotrieve]
  9. Neish AS, Loh E, Schoen FJ. Myocardial changes in cardiac transplant-associated coronary arteriosclerosis: potential for timely diagnosis. J Am Coll Cardiol. 1992;19:586-592.[Abstract]
  10. Billingham ME. Pathology of graft vascular disease after heart and heart-lung transplantation and its relationship to obliterative bronchiolitis. Transplant Proc. 1995;27:2013-2016.[Medline] [Order article via Infotrieve]
  11. Treasure CB, Alexander RW. Relevance of vascular biology to the ischemic syndromes of coronary atherosclerosis. Cardiovasc Drugs Ther. 1995;9:13-19.
  12. Libby P, Swanson SJ, Tanaka H. Immunopathology of coronary arteriosclerosis in transplanted hearts. J Heart Lung Transplant. 1992;11:5-6.
  13. Smith JD, Pomerance A, Burke M, Yacoub M, Rose ML. Effect of HLA matching on graft function and long-term survival after cardiac transplantation: results of a large single center study. J Heart Lung Transplant. 1995;14(part 2):S40. Abstract.
  14. Crisp SJ, Dunn MJ, Rose ML, Barbir M, Yacoub MA. Antiendothelial antibodies after heart transplantation: the accelerating factor in transplant-associated coronary artery disease. J Heart Lung Transplant. 1994;13:1381-1392.
  15. Duquesnoy RJ, Demetris AJ. Immunopathology of cardiac transplant rejection. Curr Opin Cardiol. 1995;10:193-206.[Medline] [Order article via Infotrieve]
  16. Hayry P, Renkonen R, Leszczynski D, Mattila P, Tiisala S, Halltunnen J, Turunen JP, Partanen T, Rinta K. Local events in graft rejection. Transplant Proc. 1989;21:3716-3720.[Medline] [Order article via Infotrieve]
  17. Ardehali A, Laks H, Drinkwater DC, Ziv E, Drake TA. Vascular cell adhesion molecule-1 is induced on vascular endothelial and medial smooth muscle cells in experimental cardiac allograft vasculopathy. Circulation. 1995;92:450-456.[Abstract/Free Full Text]
  18. Labarrere CA, Pitts D, Nelson DR, Faulk WP. Coronary artery disease in cardiac allografts: association with arteriolar endothelial HLA-DR and ICAM-1 antigens. Transplant Proc. 1995;27:1939-1940.[Medline] [Order article via Infotrieve]
  19. Rabinovitch M, Molossi S, Clausell N. Cytokine-mediated fibronectin production and transendothelial migration of lymphocytes in the mechanism of cardiac allograft vascular disease: efficacy of novel therapeutic approaches. J Heart Lung Transplant. 1995;14:S116-S123.[Medline] [Order article via Infotrieve]
  20. Isner JM, Kearney M, Bortman S, Passeri J. Apoptosis in human atherosclerosis and restenosis. Circulation. 1995;91:2703-2711.[Abstract/Free Full Text]
  21. Dong C, Wilson JE, Winters GL, McManus BM. Human transplant coronary artery disease: pathological evidence for Fas-mediated apoptotic cytotoxicity in allograft arteriopathy. Lab Invest. 1996;74:921-931.[Medline] [Order article via Infotrieve]
  22. Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive substances regulate vascular smooth muscle cell apoptosis. Circ Res. 1996;79:748-756.[Abstract/Free Full Text]
  23. Szabolcs M, Mitchler RE, Yang Y, Aji W, Roy D, Athan E, Sciacca RR, Minanov OP, Cannon PJ. Apoptosis of cardiac myocytes during cardiac allograft rejection: relation to induction of nitric oxide synthase. Circulation. 1996;94:1665-1673.[Abstract/Free Full Text]
  24. Russell ME, Wallace AF, Wyner LR, Newell JB, Karnoswky MJ. Upregulation and modulation of inducible nitric oxide synthase in rat cardiac allografts with chronic rejection and transplant arterioscleroses. Circulation. 1995;92:457-464.[Abstract/Free Full Text]
  25. Gibbons GH. The pathogenesis of graft vascular disease: implications of vascular remodeling. J Heart Lung Transplant. 1995;14:S149-S158.[Medline] [Order article via Infotrieve]
  26. Lim TT, Botas J, Liang DH, Schroeder JS, Oesterle SN, Popp RL, Yeung AC. Does compensatory dilation occur in heart transplant recipients with progressive coronary artery disease? Serial studies using intravascular ultrasound. Circulation. 1994;90(part 2):3439. Abstract.
  27. von Scheidt W, Erdmann E. Dilated angiopathy: a specific subtype of allograft coronary artery disease. J Heart Lung Transplant. 1991;10:698-703.[Medline] [Order article via Infotrieve]
  28. Johnson MR. Transplant coronary disease: nonimmunologic risk factors. J Heart Lung Transplant. 1992;11:S124-S132.[Medline] [Order article via Infotrieve]
  29. Escobar A, Ventura HO, Stapleton DD, Mehra MR, Ramee SR, Collins TC, Jain SP, White CJ. Cardiac allograft vasculopathy assessed by intravascular ultrasonography and nonimmunologic risk factors. Am J Cardiol. 1994;74:1042-1046.[Medline] [Order article via Infotrieve]
  30. Gao SZ, Hunt SA, Schroeder JS, Alderman EL, Hill IR, Stinson EB. Early development of accelerated graft coronary artery disease: risk factors and course. J Am Coll Cardiol. 1996;28:673-679.[Abstract]
  31. Hauptmann PJ, Davis SF, Miller L, Yeung AC. The role of nonimmune risk factors in the development and progression of graft arteriosclerosis: preliminary insights from a multicenter intravascular ultrasound study. J Heart Lung Transplant. 1995;14:S238-S242.[Medline] [Order article via Infotrieve]
  32. Kemma MS, Valantine HA, Hunt SA, Schroeder JS, Chen Y-D, Reaven GM. Metabolic risk factors for atherosclerosis in heart transplant recipients. Am Heart J. 1994;128:68-72.[Medline] [Order article via Infotrieve]
  33. Kugiyama K, Kerns SA, Morrisett JD, Robbers R, Henry PD. Impairment of endothelium dependent arterial relaxation of arterial smooth muscle by lysolecithin in modified low density lipoproteins. Nature. 1990;344:160-162.[Medline] [Order article via Infotrieve]
  34. Seiler C, Hess OM, Buechi M, Suter TM, Krayenbuehl HP. Influence of serum cholesterol and other coronary risk factors on vasomotion of angiographically normal coronary arteries. Circulation. 1993;88:2139-2148.[Abstract/Free Full Text]
  35. Hartmann A, Weis M, Olbrich HG, Cieslinski G, Schacherer C, Burger W, Beyersdorf F, Schräder R. Endothelium-dependent and endothelium-independent vasomotion in large coronary arteries and in the microcirculation after cardiac transplantation. Eur Heart J. 1994;15:1486-1493.[Abstract/Free Full Text]
  36. Valantine HA. Role of lipids in allograft vascular disease: a multicenter study of intimal thickening detected by intravascular ultrasound. J Heart Lung Transplant. 1995;14:S234-S237.[Medline] [Order article via Infotrieve]
  37. Tenkanen L, Pietila K, Manninen V, Manttari M. The triglyceride issue revisited: findings from the Helsinki Heart Study. Arch Intern Med. 1994;154:2712-2720.
  38. Valantine HA, Rickenbacher P, Kemma M. Metabolic abnormalities characteristic of syndrome X and microvascular coronary artery disease are associated with cardiac allograft vascular disease. Circulation. In press.
  39. Grattan MT, Moreno-Cabral CE, Stames VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA. 1989;261:3561-3566.[Abstract]
  40. Fujinami RS, Nelson JA, Walker L, Oldstone MB. Sequence homology and immunologic cross-reactivity of human cytomegalovirus with human leukocyte antigen-DR ß-chain: a means for graft rejection and immunosuppression. J Virol. 1988;62:100-105.[Abstract/Free Full Text]
  41. Briggs B, Vook N, Knight D, Sedmak D. Molecular mechanisms of adhesion molecule modulation by human cytomegalovirus. Transplant Proc. In press.
  42. Seir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE. Potential role of human cytomegalovirus and p52 interaction in coronary restenosis. Science. 1994;165:391-394.
  43. Costanzo MR. Heart transplantation. Curr Opin Cardiol. 1995;10:155-158. Editorial.[Medline] [Order article via Infotrieve]
  44. Gulizia JM, Kandolf R, Kendall TJ, Thieszen SL, Wilson JE, Radio SJ, Costanzo MR, Winters GL, Miller LL, McManus BM. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts. Am J Pathol. 1995;147:461-475.[Abstract]
  45. Ardehali A, Laks H, Drinkwater DC, Kato NS, Permut LC, Grant PW, Aharon AS, Drake TA. Expression of major histocompatibility antigens and vascular adhesion molecules on human cardiac allografts preserved in University of Wisconsin solution. J Heart Lung Transplant. 1993;12:1044-1052.[Medline] [Order article via Infotrieve]
  46. Day JD, Rayburn BK, Gaudin PB, Baldwin WM III, Lowenstein CJ, Kasper EK, Baugham KL, Baumgartner WA, Hutchins GM, Hruban RH. Cardiac allograft vasculopathy: the central role of ischemia-induced endothelial cell injury. J Heart Lung Transplant. 1995;14:S142-S149.[Medline] [Order article via Infotrieve]
  47. Land W, Messmer K. The impact of ischemic/reperfusion injury on specific and non-specific early and late chronic events after organ transplantation. Transplant Rev. 1996;10:108-127.
  48. Smart FW, Ballantyne CM, Cocanougher B, Farmer JA, Sekela ME, Noon GP, Young JB. Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplantation. Am J Cardiol. 1991;67:243-247.[Medline] [Order article via Infotrieve]
  49. Akosah KO, Mohanty PK, Funai JT, Jesse RL, Minisi AJ, Crandall CW, Kirchberg D, Guerraty A, Salter D. Noninvasive detection of transplant coronary artery disease by dobutamine stress echocardiography. J Heart Lung Transplant. 1994;13:1024-1038.[Medline] [Order article via Infotrieve]
  50. Cohn JM, Wilensky RL, O'Donnell JA, Bourdillon PDV, Dilon JC, Feigenbaum H. Exercise echocardiography, angiography, and intracoronary ultrasound after cardiac transplantation. Am J Cardiol. 1996;77:1216-1219.[Medline] [Order article via Infotrieve]
  51. Johnson DE, Aldermann EL, Schroeder JS, Silvermann JF, Hunt SA, De Campli WM, Stinson EB, Billingham M. Transplant coronary artery disease: histopathological correlations with angiographic morphology. J Am Coll Cardiol. 1991;17:449-457.[Abstract]
  52. St. Goar FG, Pinto FJ, Aldermann EL, Valantine HA, Schroeder JS, Gao SZ, Stinson EB, Popp RL. Intracoronary ultrasound in cardiac transplant recipients: in vivo evidence of angiographically silent intimal thickening. Circulation. 1992;85:979-987.[Abstract/Free Full Text]
  53. von Scheidt W, Ziegler U, Kemkes BM, Erdmann E. Heart transplantation: hemodynamics over a five-year period. J Heart Lung Transplant. 1991;10:342-350.[Medline] [Order article via Infotrieve]
  54. Keogh AM, Valantine HA, Hunt SA, Schroeder JS, McIntosh N, Oyer PE, Stinson EB. Impact of proximal or midvessel discrete coronary artery stenoses on survival after heart transplantation. J Heart Lung Transplant. 1992;11:892-901.[Medline] [Order article via Infotrieve]
  55. Tuzcu EM, De Franco AC, Goormastic M, Hobbs RE, Rincon G, Bott-Silverman C, McCarthy P, Stewart R, Mayer E, Nissen SE. Dichotomous pattern of coronary atherosclerosis 1 to 9 years after transplantation: insights from systematic intravascular ultrasound imaging. J Am Coll Cardiol. 1996;27:839-846.[Abstract]
  56. Tuzcu EM, Hobbs RE, Rincon G, Bott-Silverman C, de Franco AC, Robinson K, McCarthy PM, Stewart RW, Guyer S, Nissen SE. Occult and frequent transmission of atherosclerotic coronary disease with cardiac transplantation: insights from intravascular ultrasound. Circulation. 1995;91:1706-1713.[Abstract/Free Full Text]
  57. Botas J, Pinto FJ, Chenzbraun A, Liang D, Schroeder JS, Oesterle SN, Alderman EL, Popp RL, Yeung AC. Influence of preexistent donor coronary artery disease on the progression of transplant vasculopathy: an intravascular ultrasound study. Circulation. 1995;92:1126-1132.[Abstract/Free Full Text]
  58. Rickenbacher PR, Pinto FJ, Lewis NP, Hunt SA, Aldermann EL, Schroeder JS, Stinson EB, Brown BW, Valantine HA. Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation. Circulation. 1995;92:3445-3452.[Abstract/Free Full Text]
  59. Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TJ, Ramee SR. Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy. J Heart Lung Transplant. 1995;14:632-639.[Medline] [Order article via Infotrieve]
  60. Fish RD, Nabel EG, Selwyn AP, Ludmer PL, Mudge GH, Kirsshenbaum JM, Schoen FJ, Alexander RW, Ganz P. Response of coronary arteries of transplant patients to acetylcholine. J Clin Invest. 1988;81:21-31.
  61. Hartmann A, Mazzilli N, Weis M, Olbrich HG, Burger W, Satter P. Time course of endothelial function in epicardial conduit coronary arteries and in the microcirculation in the long-term follow-up after cardiac transplantation. Int J Cardiol. 1996;53:127-136.[Medline] [Order article via Infotrieve]
  62. Weis M, Hartmann A, Marzzilli N, Olbrich HG, Burger W, Satter P. Variations of segmental endothelium dependent and endothelium independent vasomotor tone in the long term follow up after cardiac transplantation (qualitative changes in endothelial function). J Am Coll Cardiol. 1995;2:430A. Abstract.
  63. Labarrere CA, Pitts D, Nelson DR, Faulk WP. Vascular tissue activator and the development of coronary artery disease in heart-transplant recipients. N Engl J Med. 1995;333:1111-1116.[Abstract/Free Full Text]
  64. Wennmalm A. Endothelial nitric oxide and cardiovascular disease. J Intern Med. 1994;235:317-327.[Medline] [Order article via Infotrieve]
  65. Davis SF, Yeung AC, Meredith I, Charbonneau F, Ganz P, Selwyn AP, Anderson TJ. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant. Circulation. 1996;93:457-462.[Abstract/Free Full Text]
  66. Yeung AC, Anderson T, Meredith I, Uehata A, Ryan TJ, Selwyn AP, Mudge GH, Ganz P. Endothelial dysfunction in the development and detection of transplant coronary artery disease. J Heart Lung Transplant. 1992;11:S69-S73.[Medline] [Order article via Infotrieve]
  67. Treasure CB, Vita JA, Ganz P, Ryan TJ Jr, Schoen FJ, Vekshtein VI, Yeung AC, Mudge GH, Alexander RW, Selwyn AP, Fish RD. Loss of coronary microvascular response to acetylcholine in cardiac transplant patients. Circulation. 1992;86:1156-1164.[Abstract/Free Full Text]
  68. Nitenberg A, Aptecar E, Benvenuti C, Benhaiem N, Tavolaro O, Loisance D, Cachera JP. Effects of time and previous acute rejection episodes on coronary vascular reserve in human heart transplant recipients. J Am Coll Cardiol. 1992;20:1333-1338.[Abstract]
  69. Mullins PA, Chauhan A, Sharples L, Cary NR, Large SR, Wallwork J, Schofield PM. Impairment of coronary flow reserve in orthotopic cardiac transplant recipients with minor coronary occlusive disease. Br Heart J. 1992;68:266-271.
  70. Weis M, Hartmann A, Olbrich HG, Schacherer C, Wiemer J, Hör G, Zeiher AM. Prognostic significance of coronary flow reserve on left ventricular ejection fraction in heart transplant patients. Circulation. 1995;92(suppl I):I-245. Abstract.
  71. Vekshtein VI, Alexander RW, Yeung AC, Plappert T, St. John Sutton MG, Ganz P. Coronary atherosclerosis is associated with left ventricular dysfunction and dilation in aortic stenosis. Circulation. 1990;82:2068-2074.[Abstract/Free Full Text]
  72. Clausell N, Butany J, Molossi S, Lonn E, Gladstone P, Rabinovitch M, Daly PA. Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries. J Am Coll Cardiol. 1995;26:110-119.[Abstract]
  73. von Scheidt W, Koglin J, Weis M, Gross T, Meiser BM, Überfuhr P. Epicardial and microvascular manifestations of transplant vasculopathy: two distinct entities. J Heart Lung Transplant. 1997;16:85. Abstract.
  74. Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB, Wiederhold V, Stinson EB. A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. N Engl J Med. 1993;328:164-170.[Abstract/Free Full Text]
  75. Ritz MA, Lüscher TF, Bühler FR. Different potency of endothelium derived relaxing factors against thromboxane and endothelin-1 in coronary arteries: comparison with nitrovasodilator and calcium antagonists. Coron Artery Dis. 1992;2:1001-1008.
  76. Takami H, Backer CL, Crawford SE, Pahl E, Mavroudis C. Diltiazem preserves direct vasodilator response but fails to suppress intimal proliferation in rat allograft coronary disease. J Heart Lung Transplant. 1996;15:67-77.[Medline] [Order article via Infotrieve]
  77. Mehra MR, Ventura HO, Smart FW, Collins TJ, Ramee SR, Stapleton DD. An intravascular ultrasound study of the influence of angiotensin-converting enzyme inhibitors and calcium entry blockers on the development of cardiac allograft vasculopathy. Am J Cardiol. 1995;75:853-854.[Medline] [Order article via Infotrieve]
  78. Kobayashi J, Crawford SE, Backer CL, Zales VR, Takami H, Hsueh C, Huang L, Mavroudis C. Captopril reduces graft coronary artery disease in a rat heterotopic transplant model. Circulation. 1993;88:286-290.
  79. Yang Z, Arnet U, von Segesser L, Siebenmann R, Turina M, Lüscher TF. Different effects of angiotensin-converting enzyme inhibition in human arteries and veins. J Cardiovasc Pharmacol. 1993;22:517-522.
  80. Lewis EJ, Hunsicker LG, Bain RP, Roihde RD, and the Collaborative Study Group. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462.[Abstract/Free Full Text]
  81. von der Leyen H, Gibbons GH, Morishita R, Lewis NP, Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci U S A. 1995;92:1137-1141.[Abstract/Free Full Text]
  82. Drexler H, Fischell TA, Pinto FJ, Chenzbraun A, Botas J, Cooke JP, Alderman EL. Effect of L-arginine on coronary endothelial function in cardiac transplant patients. Circulation. 1994;89:1615-1623.[Abstract/Free Full Text]
  83. Lou H, Kodama T, Wang YN, Katz NM, Foegh ML. L-Arginine modulates vascular cell proliferative response to IGF-I and IL-6 in cardiac transplant recipients. J Heart Lung Transplant. 1996;15(part 2):S39. Abstract.
  84. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Troisan K, Hamilton MA, Moriguchi JD, Kawata N, Hage A, Drinkwater DC, Stevenson LW. Effects of pravastatin on outcome after cardiac transplantation. N Engl J Med. 1995;333:621-627.[Abstract/Free Full Text]
  85. Doyle JW, Kandutsch AA. Requirement for mevalonate in cycling cells: quantitative and temporal aspects. J Cell Physiol. 1988;137:133-140.[Medline] [Order article via Infotrieve]
  86. Cutts JL, Scallen TJ, Watson J, Bankhurst AD. Role of mevalonic acid in the regulation of natural killer cell cytotoxicity. J Cell Physiol. 1989;139:550-557.[Medline] [Order article via Infotrieve]
  87. Cutts JL, Bankhurst AD. Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin-2. J Cell Physiol. 1990;145:244-252.[Medline] [Order article via Infotrieve]
  88. Fyfe AI, Harper CM. HMG-CoA reductase inhibitors activated monocyte/macrophage surface expression of class I and II HLA molecules. Circulation. 1995;92(suppl I):I-498. Abstract.
  89. Notarbartolo A, Davi G, Averna M, Barbagallo CM, Ganci A, Giammarresi C, La Placa P, Patrono C. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15:247-251.[Abstract/Free Full Text]
  90. Lou H, Kodama T, Maurice PF, Kolatkar NS, Wang Y, Katz NM, Foegh ML. Angiopeptin suppresses T-lymphocyte, macrophage infiltration and MHC class II antigen in the coronary artery following cardiac transplantation. Circulation. 1995;92(suppl I):I-704. Abstract.
  91. Foegh ML. Angiopeptin: a treatment for accelerated myointimal hyperplasia. J Heart Lung Transplant. 1992;11:S28-S31.[Medline] [Order article via Infotrieve]
  92. Meiser BM, von Scheidt W, Mair H, Kur F, Detter C, Überfuhr P, Kreuzer E, Foegh M, Reichart B. Short-term angiopeptin treatment significantly reduces intimal proliferation after heart transplantation. J Heart Lung Transplant. 1995;14(part 2):S56. Abstract.
  93. Russell ME, Hancock WH, Wallace AF, Glysing-Jensen T, Willett TA, Sayegh MH. Chronic cardiac rejection in the Lew to F344 rat model. J Clin Invest. 1996;97:833-838.[Medline] [Order article via Infotrieve]
  94. Mehra MR, Ventura HO, Chambers R, Smart FW, Stapleton DD. The prognostic impact of immunosuppression and cellular rejection on cardiac allog