Progression Of Allograft Vasculopathy Research Articles

Tripterygium Wilfordii Reduces the Inflammatory Response in Transplant Vasculopathy

Background: Transplant vasculopathy (TV) is the most challenging threat during organ transplantation. The pathological induction of TV results from vascular endothelial cell injury. This study established the in vitro model of TV and investigated the attenuating effect of triptolide (TPL) on TV through multiple in vitro and in vivo assays. Methods: The inflammation model was established by stimulating rat vascular endothelial cells with lipopolysaccharides (LPS). Rat vascular endothelial cells were isolated, cultured, and characterized as CD31-positive. For in vivo assays, Wistar and Sprague–Dawley rats were divided into S-S, W-S and W-S-TPL groups. The transplanted arteries were harvested at 1,4, and 8 weeks post-operation. Results: After LPS treatment, the cell viability was significantly reduced, and the IL-1β and TNF-α levels were significantly elevated, indicating that the LPS-induced in vitro inflammation model was successfully constructed. Nevertheless, the changes in the expression of inflammatory factors and vascular adhesion molecules, as well as the p-p65 levels, which were triggered by LPS, were significantly mitigated upon the stimulation of TPL. Results from rat models showed that intimal thickening was observed in the W-S group and significantly reduced in the TPL-treated group a week after transplantation. Consistent with the in vitro data, VCAM-1, ICAM-1, p-p38, and p-p65 expression was significantly attenuated in the TPL-treated group compared with the W-S group. Conclusion: This work confirmed that TPL may alleviate the progression of allograft vasculopathy and reduce the inflammation process by inhibiting the phosphorylation of p65 and p38, which are the key protein of the NF-κB and MAPK pathway, respectively.

Association of Aspirin Treatment With Cardiac Allograft Vasculopathy Progression and Adverse Outcomes After Heart Transplantation

BackgroundEnhanced platelet reactivity may play a role in cardiac allograft vasculopathy (CAV) progression. The use of antiplatelet agents after heart transplantation (HT) has been inconsistent and although aspirin (ASA) is often a part of the medication regimen after HT, limited evidence is available on its benefit. Methods and ResultsCAV progression was assessed by measuring the difference in plaque volume and plaque index between the last follow-up and the baseline coronary intravascular ultrasound examination. Overall, 529 HT recipients were retrospectively analyzed (337 had ≥2 intravascular ultrasound studies). The progression in plaque volume (P = .007) and plaque index (P = .002) was significantly attenuated among patients treated with early ASA (within the first year after HT). Over a 6.7-year follow-up, all-cause mortality was lower with early ASA compared with late or no ASA use (P < .001). No cardiac deaths were observed in the early ASA group, and the risk of CAV-related graft dysfunction was significantly lower in this group (P = .03). However, the composite of all CAV-related events (cardiac death, CAV-related graft dysfunction, or coronary angioplasty) was not significantly different between the groups (P = .16). ConclusionsEarly ASA use after HT may delay CAV progression and decrease mortality and CAV-related graft dysfunction, but does not seem to affect overall CAV-associated events.

Effects of implanting a long-term left ventricle assist device on post-transplant outcomes.

An increasing number of patients are receiving left ventricle assist devices as a bridge to heart transplantation. The aim of this study was to determine the difference between patients who received transplants from a left ventricle assist device and those who underwent heart transplantation without a prior left ventricle assist device implantation. The study included patients who underwent heart transplantation in our institute between January 2010 and November 2018. The following clinical variables were evaluated: donor characteristics, patient's pre-transplant demographical data, post-transplant data, and patient survival. Cardiac allograft vasculopathy progression was prospectively examined (after 1 month and 12 months after heart transplantation) by coronary optical coherence tomography. We were interested in the difference in 1- and 5-year survival between the left ventricle assist device and non-left ventricle assist device groups. A total of 248 patients were identified; out of them, 48 patients received a left ventricle assist device before heart transplantation, whereas 200 had transplants with no prior left ventricle assist device implantation. There were no significant differences in any donor characteristics. The mean duration of cardiopulmonary bypass time in the non-left ventricle assist device group was 156 versus 175 min in the left ventricle assist device group (p = 0.009), blood loss was 650 versus 1045 mL (p < 0.001), the need to implant an extracorporeal membrane oxygenation was 10% versus 23% (p = 0.02). There was no difference in cardiac allograft vasculopathy progression between the groups 1 year after heart transplantation (p = 0.528). The 1- and 5-year survival, according to Kaplan-Meier, was 80% and 70% in the left ventricle assist device group, compared to 80% and 73%, respectively, in the non-left ventricle assist device group (Log-rank test: p = 0.945). Our results indicate that patients undergoing heart transplantation from left ventricle assist devices suffer significantly more from intraoperative and post-operative complications; however, only insignificant cardiac allograft vasculopathy progression and survival differences between the two groups were observed.

Incidence of Malignancies in Patients Treated With Sirolimus Following Heart Transplantation

BackgroundMalignancy is a major cause of late post-heart transplantation (HT) mortality. Sirolimus (SRL) exerts antiproliferative properties and its long-term use in HT as primary immunosuppression (IS) is associated with decreased mortality risk that is not fully explained by attenuation of cardiac allograft vasculopathy progression. ObjectivesThis study sought to examine whether conversion from calcineurin inhibitor (CNI)-based to SRL-based IS was associated with decreased risk of malignancy post-HT. MethodsOverall, 523 patients underwent HT between 1994 and 2016 at a single institution. The main outcomes included incidence of overall de novo malignancies (excluding non-melanoma skin cancers [NMSCs]), post-transplantation lymphoproliferative disorders (PTLD), and first and subsequent primary occurrences of NMSC post-HT. ResultsThe study identified 307 patients on SRL-based and 216 on CNI-based maintenance IS. Over a median follow-up of 10 years after HT, overall de novo malignancies (non-NMSC) occurred in 31% of CNI patients and in 13% of SRL patients (adjusted hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.18 to 0.62; p < 0.001). The incidence of the first NMSC was similar in the SRL and CNI groups (HR: 0.92; 95% CI: 0.66 to 1.28; p = 0.62). However, conversion to SRL was significantly associated with a decreased risk of subsequent primary occurrences of NMSC compared with that of CNI (adjusted HR: 0.44; 95% CI: 0.28 to 0.69; p < 0.001). The adjusted PTLD risk was significantly decreased in the SRL group (HR: 0.13; 95% CI: 0.03 to 0.59; p = 0.009). Late survival post-HT was markedly decreased in patients who developed non-NMSC, PTLD, or non-PTLD compared with patients who did not develop these malignancies, whereas NMSC had no significant effect on survival. ConclusionsConversion to SRL was associated with a decreased risk of all de novo malignancies, PTLD, and subsequent primary occurrences of NMSC after HT. These findings provided further explanation of the late survival benefit with long-term SRL use.

Germinal Center Alloantibody Responses Mediate Progression of Chronic Allograft Injury.

Different profiles of alloantibody responses are observed in the clinic, with those that persist, often despite targeted treatment, associated with poorer long-term transplant outcomes. Although such responses would suggest an underlying germinal center (GC) response, the relationship to cellular events within the allospecific B cell population is unclear. Here we examine the contribution of germinal center (GC) humoral alloimmunity to chronic antibody mediated rejection (AMR). A murine model of chronic AMR was developed in which T cell deficient (Tcrbd−/−) C57BL/6 recipients were challenged with MHC-mismatched BALB/c heart allografts and T cell help provided by reconstituting with 103 “TCR75” CD4 T cells that recognize self-restricted allopeptide derived from the H-2Kd MHC class I alloantigen. Reconstituted recipients developed Ig-switched anti-Kd alloantibody responses that were slow to develop, but long-lived, with confocal immunofluorescence and flow cytometric characterization of responding H-2Kd-allospecific B cells confirming persistent splenic GC activity. This was associated with T follicular helper (TFH) cell differentiation of the transferred TCR75 CD4 T cells. Heart grafts developed progressive allograft vasculopathy, and were rejected chronically (MST 50 days), with explanted allografts displaying features of humoral vascular rejection. Critically, late alloantibody responses were abolished, and heart grafts survived indefinitely, in recipients reconstituted with Sh2d1a−/− TCR75 CD4 T cells that were genetically incapable of providing TFH cell function. The GC response was associated with affinity maturation of the anti-Kd alloantibody response, and its contribution to progression of allograft vasculopathy related principally to secretion of alloantibody, rather than to enhanced alloreactive T cell priming, because grafts survived long-term when B cells could present alloantigen, but not secrete alloantibody. Similarly, sera sampled at late time points from chronically-rejecting recipients induced more vigorous donor endothelial responses in vitro than sera sampled earlier after transplantation. In summary, our results suggest that chronic AMR and progression of allograft vasculopathy is dependent upon allospecific GC activity, with critical help provided by TFH cells. Clinical strategies that target the TFH cell subset may hold therapeutic potential.This work is composed of two parts, of which this is Part II. Please read also Part I: Alsughayyir et al., 2019.

Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection.In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (TFH) cell differentiation and provision of cognate (peptide-specific) help for maintenance as long-lived GC reactions, which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/recipient mixed haematopoietic chimeras, or from parental strain donors into F1 recipients (neither of which can trigger host adaptive alloimmune responses), nevertheless provoked GC autoimmunity and were rejected chronically, with rejection similarly dependent upon host TFH cell differentiation.Thus, autoantibody responses contribute independently of host adaptive alloimmunity to graft rejection, but require host TFH cell differentiation to maintain long-lived GC responses. The demonstration that one population of helper CD4 T-cells initiates humoral autoimmunity, but that a second population of TFH cells is required for its maintenance as a GC reaction, has important implications for how autoimmune-related phenomena manifest.

Timing of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor initiation and allograft vasculopathy progression and outcomes in heart transplant recipients.

AimsEarly studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new‐generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long‐term CAV progression and clinical outcomes in a large contemporary HT cohort.Methods and resultsWe analysed a cohort of 409 adult HT recipients. CAV progression was assessed by serial coronary intravascular ultrasound volumetric measurements of the differences between baseline and last follow‐up plaque volume (PV) and plaque index (PV/vessel volume ratio). CAV progression and clinical outcomes were compared between the ES (<2 years after HT) and the LS (>2 years after HT) groups. During a median follow‐up of 8.2 years, ES resulted in significantly lower change (Δ) of plaque index (+3.8% ± 1.7% vs. +8.2% ± 3.6%; P = 0.0008) and PV (+0.8 ± 0.3 vs. +1.9 ± 1.2; P = 0.045) compared with LS group. In a Cox proportional hazards regression model and after adjustment for baseline characteristics, ES was associated with a 52% decreased risk of CAV‐associated events (hazard ratio 0.48, 95% confidence interval: 0.27–0.91; P = 0.025) and a 42% decreased risk of the composite endpoint of all‐cause mortality and CAV‐associated events (hazard ratio 0.58, 95% confidence interval: 0.38–0.91; P = 0.019).ConclusionsEarly initiation of statin therapy after HT results in attenuated CAV progression as well as in decreased CAV‐related events and mortality.

Recent Advances in Mammalian Target of Rapamycin Inhibitor Use in Heart and Lung Transplantation.

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly used in cardiothoracic transplantation. Several recent clinical trials have demonstrated their efficacy in combination with reduced cyclosporine dosing in de novo heart transplant recipients, in particular with everolimus. A number of other studies have demonstrated their efficacy for improving renal function and reducing calcineurin inhibitor use, attenuating cardiac allograft vasculopathy progression and reducing cytomegalovirus infections in maintenance heart transplant populations. A growing body of literature, including a small number of clinical trials, now describes the use mTOR inhibitors in lung transplant recipients. The benefits in this population include improved lung and renal function in limited studies. Considerably less evidence is available in pediatric heart transplantation, though similar indications in the maintenance therapy population have been described. The benefits of mTOR inhibitors must be weighed against the increased risk of adverse events and drug intolerance compared with other primary immunosuppressants, and discontinuation rates are particularly high in lung transplant recipients. The risks of surgical wound healing complications in transplant recipients receiving mTOR inhibitors previously or actively supported by mechanical circulatory support devices remains poorly described in the current literature. The current role and recent evidence for mTOR inhibitor use in heart and lung transplantation is examined in this review.

What's Hot, What's New From the 2016 American Transplant Congress.

From June 11-15, 2016 the American Transplant Congress, the joint meeting of the American Society of Transplantation and the American Society of Transplant Surgeons, held its annual meeting in Boston, MA. The meeting, attended by 5200 registrants, included pre-meeting conferences, focused topic sessions, and hundreds of high-quality presentations from the transplant field. This meeting report highlights key findings from specific basic science, translational, and clinical research presentations deemed to have notable impact in thematic areas. In particular, there were a number of transformative studies indicating important advances in the understanding of alloimmunity, chronic rejection, tolerance, and organ-specific outcomes. Many of these results are discussed in the context of the published literature to showcase rapid advances in the transplant field.

Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?

Cardiac allograft vasculopathy (CAV) is a unique multi-factorial pathologic process encountered following heart transplantation. Several risk factors have been identified including a combination of immunologic and non-immunologic processes. Significant research has been conducted to elucidate the driving forces of CAV as well as improved identification, prevention and treatment strategies. Statin therapy following transplant remains the standard of care to help prevent the progression of CAV. The benefits of statin therapy following transplantation correspond to cholesterol control, anti-inflammatory and immunomodulatory mechanisms as well as potentially unknown mechanisms. Despite known drug interactions with calcineurin inhibitors, the use of statins is highly recommended in the current International Society for Heart and Lung Transplantation guidelines. Limited research has been conducted on the impact of higher intensity statin therapy following heart transplant and the relative risks and benefits are unknown. This review focuses on risk factors and pathophysiology of CAV, the role of statin therapy in heart transplantation, and the potential added benefit of more intense statin therapy to limit the progression of this graft-limiting complication.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study.

In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.

Virtual histology findings in rapid cardiac allograft vasculopathy progression and bioresorbable vascular scaffolds

Virtual histology findings in rapid cardiac allograft vasculopathy progression and bioresorbable vascular scaffolds

Allorecognition Pathways in Transplant Rejection and Tolerance

With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

Late Changes in Maximal Intimal Thickness after Heart Transplant: Prognostic Implications and Risk Factors

<h3>Purpose</h3> Intravascular ultrasound (IVUS) provides unique prognostic information on allograft vasculopathy progression by detecting increase in maximal intimal thickness (MIT) during the first post-heart transplant (HT) year. Later changes in coronary morphology, their prognostic relevance, and risk factors are however unexplored. <h3>Methods and Materials</h3> We investigated whether changes in coronary morphology assessed in patients receiving serial IVUS at 1 and 5 years after HT predicted fatal and non-fatal cardiovascular (CV) events. We additionally analyzed the impact of metabolic risk factors on changes in IVUS measurements. <h3>Results</h3> 107 consecutive patients receiving HT between 1999 and 2007 entered the study. During the 11 years of follow-up, incidence of CV death was 8±3% and of CV events was 26±6%. Between year 1 and 5, MIT and intimal volume increased, lumen volume decreased (P<0.001 for all), while vessel volume was unchanged. By Cox's model, only MIT increase was associated with subsequent CV death (RR=4.2 [1.2-12.1] per mm, P=0.03) and CV events (RR=2.6 [1.1-5.6] per mm; P=0.03). By ROC curves, we found that a MIT change cut-off of 0.35mm best identified patients at risk for CV death and events (Figure). Among the metabolic parameters, increasing triglycerides and HDL-cholesterol ≤65mg/dl predicted MIT increase ≥ 0.35mm (P≤0.05). <h3>Conclusions</h3> This study provides the first suggestive evidence that MIT increase represent a relevant prognostic marker also after the first year after HT. In addition, the finding that clinically relevant MIT is predicted by lipid pattern typical of insulin resistance, provide a strong rationale supporting aggressive therapeutic interventions against metabolic abnormalities mid and long-term after HT.

491 Differential Effect of Everolimus and Metabolic Risk Factors on Early vs. Late Progression of Allograft Vasculopathy: Dissecting Two Faces of the Same Disease

Coronary allograft vasculopathy (CAV) is the main cause of graft failure after heart transplantation (HT). Clinical trials showed that everolimus (EVE) prevents early CAV. However, if this property can be replicated in clinical practice and on long-term CAV progression is unexplored.

Sirolimus as Primary Immunosuppression Attenuates Allograft Vasculopathy With Improved Late Survival and Decreased Cardiac Events After Cardiac Transplantation

We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002). Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

81 Early vs. Delayed EVERolimus in De Novo HEART Transplant Recipients

Purpose Multicenter clinical trials showed that everolimus (EVE) associated with low dose cyclosporine (CSA) is superior to azathioprine and equivalent to mycophenolate (MMF) in preventing myocardial acute rejection in de novo heart recipients. In addition, data from randomized and non-randomized studies suggest that EVE may have ancillary properties that may favorably impact long-term survival, by reducing the progression of allograft vasculopathy, the incidence of cytomegalovirus infection, and the onset of post-transplant malignancies. Nonetheless, EVE safety profile still needs to be optimized in particular in the early post-surgery phase, because of a worsening renal function when used with full-dose CSA, and because EVE anti-proliferative properties may delay surgical wound healing and increase the risk for pleural and pericardial effusions. The purpose of this 6-month, controlled, randomized study in de novo heart transplant patients is to compare the occurrence of a composite safety enpoint between a strategy based on delayed introduction of EVE – with MMF as a 4 to 6 weeks bridge in the post-transplant period – and EVE started within post-operative day 5. EVE start dose is adjusted according with some patients' characteristics potentially associated with EVE-related adverse events. This study is sponsored by Novartis Farma Italy and is registered at clinicaltrials.gov ( NCT 01017029 ). Methods and Materials The primary study enpoint is the 6-month composite cumulative incidence of wound healing complications related to initial transplant surgery, pleural/pericardial effusions and occurrence of acute renal insufficiency, defined as GFR ≤ 30/ml/min/1.73m 2 . Results This study has been designed to compare the safety of two EVE strategies of administration that differ from what has been tested in the clinical trials conducted since now. Thus, for patients safety purposes, in the study design we anticipated a pre-specified interim analysis when at least 60 randomized patients completed the first 3-months of follow-up. Conclusions The interim analysis will be completed in January 2011.

Model diagnostics for multi-state models

Multi-state models are a popular method of describing medical processes that can be represented as discrete states or stages. They have particular use when the data are panel-observed, meaning they consist of discrete snapshots of disease status at irregular time points which may be unique to each patient. However, due to the difficulty of inference in more complicated cases, strong assumptions such as the Markov property, patient homogeneity and time homogeneity are applied. It is important that the validity of these assumptions is tested. A review of methods for diagnosing model fit for panel-observed continuous-time Markov and misclassification-type hidden Markov models is given, with illustrative application to a dataset on cardiac allograft vasculopathy progression in post-heart transplant patients.

Long-Term Effect of Folic Acid Therapy in Heart Transplant Recipients: Follow-Up Analysis of a Randomized Study

Folic acid therapy reduces homocysteine plasma levels, which seem to influence occurrence of cardiac allograft vasculopathy, but its effect on medium- or long-term prognosis after heart transplantation is unknown. We analyzed 7-year outcome of 51 recipients randomized to receive 15 mg/day of methyltertrahydrofolate for 1 year after heart transplantation or standard therapy alone (originally, for intravascular ultrasound study of short-term cardiac allograft vasculopathy progression); recipients were observed for a further 5 to 6 years. Overall, 13 deaths occurred (six oncologic, five cardiovascular, two infective). Estimated 7-year survival was better in recipients randomized to folate (88%+/-6% vs. 61%+/-9%, P=0.04). After adjusting for age, pretransplant coronary artery disease, and hyperhomocysteinemia, posttransplant folic acid therapy was associated with lower mortality (relative risk [RR] 0.53, 95% confidence interval [CI] 0.25-0.97; P=0.036), apparently driven by reductions in both cancer-related and cardiovascular causes. Reduced mortality was marked in a high-risk subgroup comprising older recipients and patients transplanted because of coronary artery disease (RR 0.43, 95% CI 0.17-0.85) but not in the lower-risk subgroup (RR 1.11, 95% CI 0.22-5.61). Although further studies are needed, it seems reasonable to suggest folate therapy to heart transplant recipients. It is possible that properties other than homocysteine reduction may provide antitumoral benefits.