Transplant Vasculopathy Research Articles

Chemokines and Transplant Vasculopathy

Transplant vasculopathy (TV) remains the leading cause of late death among heart transplant recipients. Transplant vasculopathy is characterized by progressive neointimal proliferation, leading to ischemic failure of the allograft. Multiple experimental and clinical studies have shown that injury to the graft at various stages of transplantation can be a risk factor for development of transplant vasculopathy. The hallmark of cardiac allograft injury is the infiltration of leukocytes. Recruitment of leukocytes requires intercellular communication between infiltrating cells, endothelium, parenchymal cells, and components of extracellular matrix. These events are mediated via the generation of adhesion molecules, cytokines, and chemokines. The chemokines, by virtue of their specific cell receptor expression, can selectively mediate the local recruitment/activation of distinct leukocytes/cells, allowing for migration across the endothelium and beyond the vascular compartment. This report provides a comprehensive review of the chemokines that participate in the development of transplant vasculopathy.

ATF-4 and Vascular Injury

See related article, pages 378–387 Smooth muscle proliferation and neointimal formation are characteristic features of vascular lesions that develop after vascular injury and contribute to the development of occlusive vascular lesions after percutaneous coronary interventions and in transplant vasculopathy. The traditional model for the development of these vascular lesions has postulated that a complex interplay among locally released growth factors and cytokines, circulating platelets and inflammatory cells, local smooth muscle and endothelial cells, and perhaps circulating precursor cells involving multiple cellular processes such as adhesion, proliferation, migration, and apoptosis is orchestrated at many levels, resulting in vascular stenosis. The temporal and spatial complexity of the overall process and the diverse contributions of various components have provided many opportunities for study, but identifying and linking the various critical steps in the development of occlusive vascular lesions has remained challenging. Although numerous studies examining roles of vascular signaling pathways and vascular transcription factors have been published, a clear picture of how signaling and transcription are intertwined remains elusive. In this issue of Circulation Research , Malabanan et al present a comprehensive series of experiments linking the transcription factor activating transcription factor (ATF)-4 to intimal thickening after injury and identify both upstream and downstream associated growth factor pathways, thereby providing additional insight into the orchestrated activation of transcriptional and signaling pathways in vascular disease.1 The authors initially identified ATF-4 as a potential regulator of neointimal formation through a microarray screen for genes induced in smooth muscle cells (SMCs) by fibroblast growth factor (FGF)-2. FGF-2 has been identified previously as a major smooth muscle mitogen and has been implicated in the pathogenesis of atherosclerosis and restenosis after angioplasty.2–4 FGF-2 is normally stored and rapidly secreted after injury3 and functions in both an autocrine and paracrine fashion. To confirm the microarray …

Detection of significant coronary artery stenosis with 64-slice computed tomography in heart transplant recipients: a comparative study with conventional coronary angiography

The present study evaluates clinical feasibility of cardiac multidetector computed tomography angiography (MDCTA) to detect significant stenosis of coronary vessels due to transplant vasculopathy (TVP) after heart transplantation (HTx). Twenty-eight consecutive male HTx-recipients scheduled for their annual routine conventional coronary angiography (CCA) additionally underwent 64-slice MDCTA. Two patients were excluded from further MDCTA analysis. Out of 371 remaining coronary vessel segments evaluable by CCA, MDCTA was able to depict 302 (81.4%) in diagnostic image quality. On a segment based analysis, sensitivity, specificity, diagnostic accuracy (DA), negative predictive value (NPV), and positive predictive value (PPV) for detection of significant stenosis were calculated with 87.5%, 97.3%, 97.0%, 99.7%, and 46.7%, respectively. On a patient-based evaluation, sensitivity, specificity, DA, NPV, PPV were 100%, 81%, 84.6%, 100% and 55.6%, respectively. Evaluation of stenosis degree by MDCTA showed systematic overestimation of 4.4%. A moderate to good agreement comparing both modalities was found (Pearson's correlation coefficient: 0.64). High NPV suggesting 64-slice MDCTA being a reliable diagnostic tool for ruling out significant stenosis due to TVP in HTx patients. But its clinical value in these particular patients needs further investigation.

Fluvastatin in the Prevention of Renal Transplant Vasculopathy: Results of a Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial. The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (deltaVvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of deltaVvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria. A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The deltaVvintima/artery was not different between treatment and placebo groups (6.9+/-8.2% vs. 6.9+/-7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (kappa 0.86 vs. 0.33). In summary, there were no differences in deltaVvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.

Quilty in biopsy is associated with poor prognosis after heart transplantation

We tested if Quilty (endocardial infiltration of lymphocytes) in routinely processed endomyocardial biopsy is associated with poor outcome after heart transplantation (HTx). Biopsies ( n = 9829) harvested within the first post-transplant year from 938 patients (778 men, mean age 49 years) were evaluated for Quilty and acute cellular rejection (according to the International Society for Heart and Lung Transplantation, ISHLT, classification). Transplant vasculopathy was evaluated by coronary angiography, and severe stenosis was found in 19% of patients. Survival was tested by Kaplan–Meier and Cox regression analyses for all-cause mortality and major cardiac events (lethal acute cellular rejection, graft loss or myocardial infarction). We found 1840 (19%) Quilty-positive biopsies in 487 Quilty-positive patients (52%). Quilty was more prevalent in women ( p = 0.038) and younger men ( p = 0.001), and was correlated with ISHLT grade 1R (OR 1.45, 95% CI 1.36–1.55; p < 0.001) and ISHLT grade 2R (OR 2.48, 95% CI 2.21–3.41; p < 0.001). Quilty in any biopsy was associated with a higher all-cause mortality (log rank p = 0.045) due to a higher risk for major cardiac event ( p = 0.0001). Multivariate regression analysis showed Quilty (RR 1.69, 95%CI 1.05–2.73) and transplant vasculopathy (RR 2.78, 95%CI 1.68–4.61) as risk factors for major cardiac events and treated hyperlipidemia as lowering the risk for major cardiac events (RR 0.47, 95%CI 0.28–0.77). Quilty is associated with graft loss and poor outcome post HTx. Index biopsy during the first post-transplant year is a useful tool to identify patients at risk and is recommended during routine post-transplant management.

Inhibition of Smooth Muscle Cell Migration and Proliferation by Statins

Vascular smooth muscle cell (SMC) migration and proliferation contribute to the pathobiology of atherosclerosis and of instent restenosis, transplant vasculopathy and vein by-pass graft failure. Since mevalonate (MVA) and other intermediates of cholesterol biosynthesis (isoprenoids) are necessary for cell migration and proliferation, inhibition of 3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase, the rate limiting step of the MVA pathway, has the potential to result in antiatherosclerotic effects. Indeed statins, competitive inhibitors of the HMG-CoA reductase, have shown the capability to interfere with migration and proliferation of SMC in diverse experimental models. Here we summarize in vitro, in vivo, and ex vivo evidence of the inhibitory effects of statins on SMC proliferation and migration and discuss the molecular mechanisms involved in their pharmacodynamic action. Altogether, this evidence suggests direct vascular antiatherosclerotic properties of statins. However, it is important to mention that statins failed to prevent intimal thickening when studied in clinical setting characterized by accelerated vascular SMC proliferation and migration (e.g. restenosis after PTCA and instent restenosis), thus leaving open the question of the clinical relevance of these direct vascular effects of statins.

Supraventricular Tachycardia After Orthotopic Cardiac Transplantation

The purpose of this study was to define the incidence, mechanisms, and management, including catheter ablation, of supraventricular tachycardia (SVT) in a large series of patients after orthotopic heart transplantation (OHT). Supraventricular arrhythmias are frequently encountered after OHT, but their characteristics in this population have not been well established. We analyzed the incidence, clinical course, and management of SVTs in a cohort of 729 adult patients who underwent OHT. Furthermore, the mechanisms of arrhythmias among the patients referred for electrophysiological study (EPS) and ablation were also characterized. The most common arrhythmia was atrial flutter, which occurred in 9% of this cohort. Persistent or paroxysmal atrial fibrillation occurred in 7%, the majority (57%) in the perioperative period. Persistent or paroxysmal atrial fibrillation was observed in OHT patients, beyond the post-operative period, only in the presence of rejection or transplant vasculopathy. Other persistent or paroxysmal SVTs were seen in 47 stable OHT patients (7%). Of these, 24 patients (4%) underwent EPS. Accessory and dual atrioventricular nodal pathways in the donor heart caused SVT in 3 patients. Macro-reentrant atrial tachycardia was seen in 7 patients, and isthmus-dependent atrial flutter occurred in 14 patients. The majority of SVTs in stable OHT patients can be attributed to macro-reentrant tachycardias (flutter and scar reentry). Catheter ablation is effective in management of these SVTs. Atrial fibrillation was never encountered in stable patients in our series, and its occurrence should prompt an evaluation for acute rejection and/or vasculopathy.

Chronic allograft nephropathy--clinical guidance for early detection and early intervention strategies

Improvements in reducing acute rejection rates following kidney transplantation in the last decade have not been mirrored by improvements in long-term graft survival rates [1,2]. One of the major causes of late graft loss in renal transplant recipients is chronic allograft nephropathy (CAN) [3–5] (Figure 1). CAN is highly prevalent in renal transplant recipients, with moderate to severe CAN present in 24.7% of recipients at 1 year post-transplant and in 89.8% of recipients by 10 years post-transplant [6]. CAN is defined by the histopathological features of interstitial fibrosis and tubular atrophy, but can also be associated with subclinical rejection, transplant glomerulopathy [6–8] or transplant vasculopathy caused by smooth muscle cell proliferation [4,9]. Therefore, the term CAN is being employed quite widely to describe a clinical syndrome instead of defining the presence of interstitial fibrosis or tubular atrophy. In order to avoid misinterpretations of this term, at the most recent ‘Banff’ meeting, it was proposed that pathologists no longer use this term, and simply refer to interstitial fibrosis and tubular atrophy (IF/TA) [10]. The term ‘chronic rejection’ has also been suggested as a possible replacement for CAN. However, this implies the pathology has an immune aetiology. As a pathological change often precedes any deterioration in function, the alternative term ‘chronic allograft dysfunction’ also has limitations. The revised Banff classification now recognizes chronic antibody-mediated rejection, in addition to IF/TA, broadening the underlying pathological lesions and pathophysiology of patients with

Drug-eluting stents for the treatment of coronary lesions in cardiac transplant vasculopathy: acute and mid-term clinical and angiographic outcomes

Cardiac allograft vasculopathy (CAV) is the major cause of graft failure and death in cardiac transplant recipients after transplantation. We aimed to evaluate the clinical and angiographic outcomes of patients with evidence of CAV who were treated percutaneously with drug-eluting stents (DES-PCI). Between December 2002 and September 2005, we reviewed the baseline procedural characteristics and the clinical outcome of consecutive cardiac transplanted recipients with evidence of CAV treated with DES-PCI, eligible for at least 9 months of follow-up. Fifteen consecutive patients received a total of 18 coronary DESs. Total treated lesions were 20; 12 (60%) involved the left anterior descending artery. CAV was focal in nine patients, diffuse in five patients, and mixed in only one patient. Mean time interval from transplantation to DES implantation was 126 +/- 44 months. Angiographic and procedural success was 100%. There were no adverse in-hospital events. During follow-up (17.9 +/- 8.4 months), two patients died of noncardiac cause. Six patients required a new percutaneous intervention for a repeat revascularization rate of 40%: one patient underwent target lesion revascularization because of in-DES restenosis, one patient had target vessel revascularization because of a new coronary lesion proximal to the stent. Finally, four more patients underwent repeat DES-PCI in a coronary vessel other than the treated one. Although DES implantation seems to be associated with a high procedural success rate and a low restenosis rate, the repeat revascularization rate due to CAV progression remains in nearly half of our study patients.

Dual immunosuppression enhances vasomotor injury: Interactive effect between endothelin-1 and nitric oxide bioavailability

Cyclosporine A and corticosteroids are associated with many side effects, such as endothelial dysfunction and transplant vasculopathy. We examined the effects of cyclosporine A and hydrocortisone exposure on endothelial function of the rat thoracic aorta. Lewis rats were injected with cyclosporine A, hydrocortisone, cyclosporine A + hydrocortisone, or intraperitoneal saline daily for 2 weeks. Endothelial-dependent and independent vascular relaxation were assessed in isolated segments of thoracic aorta, as well as endothelin-1-induced vasoreactivity. Protein expression of endothelial nitric oxide synthase, endothelin(A), and endothelin(B) receptors were also determined in the thoracic aorta. Exposure to cyclosporine A and cyclosporine A + hydrocortisone resulted in a reduction in endothelial-dependent vasorelaxation compared with control and hydrocortisone (P = .001). Cyclosporine A and hydrocortisone-treated rats demonstrated increased vasoreactivity to endothelin-1 compared with control, whereas cyclosporine A + hydrocortisone treatment resulted in a synergistic increase (P = .04). All treatment groups displayed a significant reduction in endothelial nitric oxide synthase expression compared with control (P = .001). Endothelin(A) receptor expression was increased in all treatment groups with a synergistic effect seen after cyclosporine A + hydrocortisone treatment. No differences were seen in endothelin(B) receptor expression. Cyclosporine A and hydrocortisone induce vasomotor dysfunction with a synergistic impairment observed after concomitant exposure. Our findings suggest that the resultant vasomotor dysfunction is the result of alterations in both nitric oxide and endothelin-1 regulation.

In Vivo Platelet–Endothelial Cell Interactions in Response to Major Histocompatibility Complex Alloantibody

Platelets recruit leukocytes and mediate interactions between leukocytes and endothelial cells. Most studies examining this important platelet immune function have focused on the development of atherosclerosis, but similar mechanisms may contribute to acute and chronic vascular lesions in transplants. Platelets have been described as markers of transplant rejection, but little investigation has critically examined a role for platelets in transplant vasculopathy and, in particular, alloantibody-mediated transplant rejection. We now demonstrate using a skin transplant model that alloantibody indirectly induces platelet activation and rolling in vivo. Repeated IgG2a alloantibody injections result in sustained platelet-endothelial interactions and vascular pathology, including von Willebrand factor release, small platelet thrombi, and complement deposition. Maintenance of continued platelet-endothelial interactions are dependent on complement activation. Furthermore, we demonstrate that platelets recruit leukocytes to sites of alloantibody deposition and sustain leukocyte-endothelial cell interactions in vivo. Taken together, our model demonstrates an important role for platelets in alloantibody induced transplant rejection.

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

Anti-HLA Abs have been shown to contribute to the process of transplant vasculopathy by binding to HLA class I molecules expressed by the endothelial and smooth muscle cells of the graft and transducing intracellular signals that elicit cell proliferation. The aim of this study was to determine the role of mammalian target of rapamycin (mTOR) in HLA class I-induced endothelial cell proliferation and to explore in depth the relationship between mTOR complexes and their downstream targets following ligation of HLA class I molecules by anti-HLA Abs. We used small interfering RNA technology to abrogate mTOR, rapamycin-insensitive companion of mTOR (rictor), or regulatory associated protein of mTOR (raptor) to study the function of these gene products to activate proteins involved in MHC class I-induced cell proliferation and survival. Knockdown of mTOR inhibited class I-mediated phosphorylation of proteins downstream of mTOR complex 1 and mTOR complex 2. Furthermore, knockdown of mTOR, rictor, or raptor blocked HLA class I-induced endothelial cell proliferation. Long-term pretreatment with the mTOR inhibitor rapamycin significantly blocked both mTOR-raptor and mTOR-rictor complex formation. Interestingly, rapamycin also blocked class I-induced Akt phosphorylation at Ser(473) and Bcl-2 expression. These results support the role of anti-HLA Abs in the process of transplant vasculopathy and suggest that exposure of the graft endothelium to anti-HLA Abs may promote proliferation through the mTOR pathway.

A New T-Cell Receptor Transgenic Model of the CD4+ Direct Pathway: Level of Priming Determines Acute Versus Chronic Rejection

T-cell receptor transgenic (TCR-tg) mouse models with direct CD4 alloreactivity will help elucidate mechanisms of transplant rejection and tolerance in vivo. Although such models exist, they are limited by unusual strain combinations or are based on model antigens. A TCR-tg mouse with direct CD4 specificity in the widely used BALB/c donor --> C57BL/6 host strain combination was created. This TCR-tg mouse, named 4C, was selected for reactivity against BALB/c dendritic cells in order to model early priming events after transplantation. The response of 4C T cells to skin and heart transplants were characterized. The alloantigen is restricted by I-A and appears to be widely distributed in mouse tissues. 4C T cells are able to acutely reject skin but not heart allografts. Paradoxically, heart grafts elicited a stronger proliferation and effector function of TCR-tg T cells than skin grafts. 4C T cells caused cardiac allograft vasculopathy in the absence of other T cells and alloantibodies, suggesting a role for the direct pathway in chronic rejection. Augmentation of priming with an infusion of donor-derived dendritic cells resulted in acute heart allograft rejection by 4C T cells, demonstrating that the level of priming can play a role in determining acute versus chronic rejection by the CD4 direct pathway. Rejection of a graft by the direct CD4 pathway is determined by graft susceptibility to rejection, as well as the degree of T-cell priming caused by the graft. Grafts that are not acutely rejected can develop transplant vasculopathy mediated by the direct CD4 T cells.

509: Ebstein-Barr and ParvoB19 Viruses Are Risk Factors for Late Onset Microvasculopathy after Heart Transplantation

Viral infections have been identified as risk factors for the development of epicardial transplant vasculopathy after heart transplantation (HTx). However their role in the development of microvasculopathy remains unknown.

519: Correlates of Mortality and Major Events in Heart Transplant Recipients Treated by Coronary Stents for Transplant Vasculopathy

519: Correlates of Mortality and Major Events in Heart Transplant Recipients Treated by Coronary Stents for Transplant Vasculopathy

A Decade of Percutaneous Coronary Interventions in Cardiac Transplant Recipients: A Monocentric Study in 160 Patients

Transplant vasculopathy is a long-term complication of cardiac transplantation. Percutaneous transluminal coronary angioplasty (PCI) is a method of choice for local revascularization that is also increasingly used in heart transplant patients. Between October 1989 and November 2006, 160 adult cardiac transplant recipients (19 women) with mean age at heart transplantation of 47 +/- 12 years underwent PCI in 502 coronary segments during 319 catheterizations (balloon only, 209; bare metal stents, 227, drug-eluting stents, 66). Concomitant medical therapy, procedural data, primary success, recurrence of stenosis, and cardiac events (cardiac death or repeat transplantation) were analyzed retrospectively. Multivariate Cox proportional hazards analysis was performed. Stents reduced early and mid-term recurrence of stenosis but had no impact on graft survival. Drug-eluting stents did not improve the restenosis rate. Immunosuppression with mycophenolate mofetil and concomitant treatment with statins and clopidogrel were significantly associated with reduced recurrence of stenosis and prolonged graft survival. Low steroid dosage was associated with a positive impact on graft survival. Stenting in heart transplant patients has no impact on graft survival despite high primary success and deferred recurrence of stenosis. Early reduction of steroids, immunosuppression by mycophenolate mofetil, and concomitant treatment with statins are likely to reduce recurrent stenosis and to improve graft survival in heart transplant patients needing PCI. Long-term treatment with clopidogrel deserves further assessment.

The effect of FK778 on the development and progression of chronic transplant vasculopathy

The effect of FK778 on the development and progression of chronic transplant vasculopathy

Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator‐Activated Receptor‐γ: Therapeutic Implications for Cardiovascular Diseases

Proliferation of vascular smooth muscle cells (SMCs) is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD), used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPAR is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPAR in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPAR in SMCs and outline the therapeutic implications of PPAR activation for the treatment and prevention of atherosclerosis and its complications.

Involvement of glutathione/glutathione S‐transferase antioxidant system in butyrate‐inhibited vascular smooth muscle cell proliferation

Vascular smooth muscle cell (VSMC) proliferation is an important etiological factor in vascular proliferative diseases such as primary atherosclerosis, hypertension, arterial and in-stent restenosis, and transplant vasculopathy. Our studies established that butyrate, a bacterial fermentation product of dietary fiber and a chromatin modulator, is a potent inhibitor of VSMC proliferation. The cardiovascular health benefits of a high-fiber diet, the principle source of butyrate in the body, have been known for a long time, however, very little is known about the antiatherogenic potential of butyrate. Because oxidative stress plays an important role in the pathogenesis of atherosclerosis, we examined involvement of the glutathione/glutathione S-transferase (GST) antioxidant system in butyrate's inhibition of VSMC proliferation. Treatment of proliferating VSMCs with butyrate leads to the induction of several GSTs. Interestingly, our study also demonstrated the nuclear localization of GST-P1 (GST-7-7), which is considered to be a cytosolic protein; this was demonstrated using immunostaining and was corroborated by western blotting. Also, the butyrate-induced antiproliferative action, and the induction of GST-P1 and its nuclear localization are downregulated when butyrate is withdrawn. Furthermore, assessment of intracellular glutathione levels reveals their augmentation by butyrate. Conversely, butyrate treatment reduces the levels of reactive oxygen species in VSMCs. Collectively, the butyrate-treatment-related increase in glutathione content, the reduction in reactive oxygen species, the upregulation of GST and the nuclear localization of GST-P1 in growth-arrested VSMCs imply that butyrate's antiproliferative action involves modulation of the cellular redox state. Thus, induction of the glutathione/GST antioxidant system appears to have other regulatory role(s) besides detoxification and regulation of the cellular redox state, for example, cell-cycle control and cell proliferation, which are both critical to atherogenesis.

Abstract 2093: Myocardial Upregulation of mRNA Angiotensin II Receptor Subtype 1 (AGTR1) at One Year of Heart Transplantation is Associated with Worse Long-term Clinical Outcome Including Skin Cancer.

Background: We have previously shown that myocardial upregulation of mRNA gene expression of angiotensin II receptor subtype 1 (AGTR1) is associated with transplant vasculopathy evidenced by coronary intravascular ultrasound at one year following heart transplantation. Objectives: This study was undertaken to evaluate the long-term clinical outcome of heart transplant patients in relation to upregulation of mRNA AGTR1. Methods: A total of 45 heart transplant patients, mean age 55±12 years (78% male) had heart biopsy analysis for mRNA AGTR1 (Taqman PCR) at one year of transplantation. Dual Immunofluorescence staining for AGTR1 and vWF was also performed. Patients were divided into 2 groups according to the mRNA AGTR1 expression: Group I (n= 24), AGTR1 ≤2.0 and Group II (n=21), AGTR1 &gt; 2.0. Patients underwent annual coronary angiography and were followed up for a mean period of 7.6±2.1 years. Transplant coronary vasculopathy was defined as angiographic evidence of coronary obstruction greater than 30% in the absence of donor coronary artery disease. Results: The 2 groups had similar baseline characteristics. During follow up, Group II patients tended to have increased risk of diabetes mellitus (57.1% versus 29.2%, P= 0.058) and renal insufficiency (61.9% versus 33.3%, P= 0.055) defined by serum creatinine greater than 1.5 mg/dl. Group II patients had a worse survival (10 year K-M survival: 61% versus 86%, log-rank P= 0.061) and increased vasculopathy (10 year K-M freedom from vasculopathy: 19% versus 66%, log-rank P= 0.036). Since the renin-angiotensin system has been implicated in the development of various cancers, we also evaluated the clinical outcome of malignancy in relation to mRNA AGTR1. Interestingly, the 10 year K-M freedom from any malignancy tended to be worse in Group II patients (46% versus 77%, log-rank P= 0.063) and statistically significantly different in skin cancer (57% versus 86%, log-rank P= 0.034). Conclusions: Myocardial upregulation of mRNA AGTR1 at one year of heart transplantation is associated with worse clinical outcome including skin cancer. These findings may call for the need of prospective randomized trials to evaluate if the natural course of these patients could be altered with the use of angiotensin receptor blockers.