Treatment of allograft vasculopathy in heart transplantation

Cardiac allograft vasculopathy remains one of the main causes of morbidity and mortality after heart transplantation, although its impact is becoming somewhat smaller as prophylactic measures are implemented. Advances in the understanding of the molecular and cellular mechanisms involved in the genesis and development of cardiac allograft vasculopathy are opening ways for new diagnostic and therapeutic strategies. Successful prophylaxis of the early stages of the disease has been demonstrated with the use of newer immunosuppressive agents, such as sirolimus and everolimus, that will probably be included in future protocols. For most patients with established cardiac allograft vasculopathy, currently available revascularisation methods and retransplantation are not appropriate options. Antiproliferative agents could provide significant improvement in terms of symptom relief and prognosis, but their definite value must be proven in well-designed trials.     

免疫抑制剂在心脏移植中的应用现状

硫唑嘌呤＋环孢素A＋泼尼松是原位心脏移植术后免疫抑制治疗的经典方案。随着新抗增殖因子及新的免疫诱导因子的出现，新的治疗方法也为治疗提供了新的选择。目前在免疫抑制治疗中被广泛关注的问题包括：急性排斥反应、心脏移植物血管病变的预防以及血管排斥的治疗。如何保护肾功能、延缓心脏移植物血管病变的发展、降低机会性感染等并发症的发生仍然是免疫抑制治疗所面临的挑战。     

Cardiac allograft vasculopathy: the green lane hospital experience 1987-1998

AIMS: To determine the prevalence of cardiac allograft vasculopathy in heart transplant recipients at Green Lane Hospital and to examine potential risk factors for vasculopathy. METHODS: We retrospectively reviewed the coronary angiograms of all cardiac transplant recipients. Angiography was usually performed one, two and five years after operation. The diagnosis of allograft vasculopathy was made if there was any evidence of coronary artery disease. Patients' medical records were reviewed for potential risk factors. RESULTS: Ninety-one patients underwent cardiac transplantation between December 1987 and March 1998. One year survival was 87%. Angiographic evidence of coronary disease was present in 30 patients and in three patients coronary lesions were first identified at post mortem. Vasculopathy was present in 25%, 35% and 61% of patients at one two and five years following transplant. Donor-acquired lesions could not be excluded as few patients had immediate postoperative angiograms for comparison. Five late deaths have been due to vasculopathy. Recipient age, race, donor age and ischaemic time were similar for those with and without vasculopathy. Frequency or severity of acute rejection episodes, cytomegalovirus infection, lipid profiles, diabetes and hypertension were not significantly different in patients with vasculopathy. CONCLUSION: Cardiac allograft vasculopathy is a common finding after heart transplantation. No definite risk factors were identified in this patient group.     

The Role of Allograft Inflammatory Factor-1 in Development of Coronary Artery Vasculopathy

Allograft inflammatory factor-1 (AIF-1) is a 143-amino acid, cytoplasmic, calcium- binding protein that is expressed in a variety of inflammatory situations. Constitutively expressed in leukocytes, AIF-1 is not expressed in unstimulated vascular smooth muscle cells (VSMCs), but is strongly induced in response to injury and inflammatory cytokines. Overexpression of AIF-1 in VSMCs promotes their proliferation by dysregulation of cell cycle protein expression and subsequent shortening of the cell cycle. In cardiac transplant recipients, the expression of AIF-1 mRNA in cardiac allografts correlates with rejection, and the amount of AIF-1 expressed is proportional to the severity of rejection. AIF-1 is expressed in coronary arteries with cardiac allograft vasculopathy, and persistent expression of AIF-1 in the allograft correlates with development of cardiac allograft vasculopathy. The current hypothesis is that the expression of AIF-1 in injured arteries may participate in the progression of cardiac allograft vasculopathy by its ability to promote growth of VSMCs, implicating AIF-1 as a target for treating proliferative arteriopathies. (c) 2002 Prous Science. All rights reserved.     

Immunosuppressive therapy in older cardiac transplant patients

Cardiac transplantation has become an established intervention for end-stage heart disease. Clinical outcomes in older cardiac transplant patients have improved over the last decade and are almost similar to those in younger patients. Nevertheless, morbidity and mortality due to infections, cancer and chronic allograft vasculopathy remain problematic. On the other hand, older transplant patients seem to have lower incidences of acute rejection episodes than younger patients. Conventional immunosuppression with calcineurin-inhibiting drugs, azathioprine and corticosteroids is responsible for a number of adverse effects. Although these adverse effects can also be seen in younger patients, tolerance to these agents seems to decrease with increasing age. In particular, diabetes mellitus, osteoporosis and chronic renal insufficiency are associated with higher morbidity and mortality in older cardiac transplant patients. As the elderly become an ever-increasing segment of the cardiac transplant population, new and innovative immunosuppressive strategies will have to be developed and applied.Currently, the availability of new immunosuppressive drugs means more individualised immunosuppressive protocols can be used. New antibodies for induction therapy, a choice between ciclosporin and tacrolimus, and the advent of mycophenolate mofetil as well as proliferation signal inhibitors (everolimus, sirolimus) have changed immunosuppressive protocols dramatically. Therefore, a generalised protocol for all patients has been replaced by individualised immunosuppression depending on the patient group. Moreover, protocols can be modified during follow-up depending on the individual patient's requirements and problems. Hypertension and hyperlipidaemia could be influenced by the selection of tacrolimus over ciclosporin, and weaning of corticosteroids might have a positive impact on osteoporosis or diabetes. There is also no clear evidence that tacrolimus is associated with a higher risk for new onset of diabetes. Chronic renal insufficiency can be managed with calcineurin inhibitor-free immunosuppression consisting of mycophenolate mofetil and proliferation signal inhibitors. Both everolimus and sirolimus also seem to have a protective effect against the onset of graft vasculopathy and some sorts of cancer after cardiac transplantation. As a general rule, however, older cardiac transplant patients should be treated with lower doses and fewer immunosuppressive drugs to avoid over-immunosuppression.     

Everolimus: an immunosuppressive agent in transplantation

Everolimus is a novel immunosuppressive agent related to sirolimus. It is a proliferation signal inhibitor with an improved pharmacokinetic profile and bioavailability compared with sirolimus. Everolimus has been shown to be as effective as mycophenolate mofetil in reducing acute rejection in renal transplantation. In cardiac transplant recipients, it is superior to azathioprine in reducing acute rejection and cardiac allograft vasculopathy. Its use is also associated with a decrease in cytomegalovirus infection. However, coadministration with calcineurin inhibitors requires careful dose adjustment to prevent renal toxicity. Antiproliferative effects of everolimus may abrogate the increased risk of malignancy seen in solid organ transplantation.     

Everolimus: an immunosuppressive agent in transplantation

Everolimus is a novel immunosuppressive agent related to sirolimus. It is a proliferation signal inhibitor with an improved pharmacokinetic profile and bioavailability compared with sirolimus. Everolimus has been shown to be as effective as mycophenolate mofetil in reducing acute rejection in renal transplantation. In cardiac transplant recipients, it is superior to azathioprine in reducing acute rejection and cardiac allograft vasculopathy. Its use is also associated with a decrease in cytomegalovirus infection. However, coadministration with calcineurin inhibitors requires careful dose adjustment to prevent renal toxicity. Antiproliferative effects of everolimus may abrogate the increased risk of malignancy seen in solid organ transplantation.     

Effects of immunoglobulin to prevent coronary allograft vasculopathy in heart transplantation

INTRODUCTION: Although 100,000 cardiac transplants have been performed, coronary allograft vasculopathy (CAV), which is a phenomenon of chronic rejection, is still a serious problem. AREAS COVERED: Several adhesion molecules, cytokines, and chemokines play a critical role in the process. Recent investigations have proved some promising methodologies for preventing or treating rejection. Although immunoglobulins are known to be an effective treatment in many diseases, their effect on cardiac transplantation or CAV is to be elucidated. EXPERT OPINION: In this review article, we described some promising methodologies that use immunoglobulins to prevent CAV. Immunoglobulins may be used to prevent CAV.     

Is everolimus useful in preventing allograft rejection and vasculopathy after heart transplant?

The main cause of illness and death after the first year of heart transplantation is vasculopathy of the cardiac allograft, probably initiated by early immunological and non-immunological endothelial damage. The incidence of multiple episodes of grade 3A rejection 6 months after primary heart transplantation was lower with everolimus (1.5 mg, 8.1% and 3 mg, 6.6%) than in the azathioprine group (14%). Allograft vasculopathy was less frequent with everolimus than azathioprine. A follow-up study is necessary to determine whether these effects translate into the important end points of reduced incidences of death, graft loss or a second transplantation.     

Everolimus: a proliferation signal inhibitor targeting primary causes of allograft dysfunction

Allograft dysfunction remains a major problem for long-term graft survival after kidney and heart transplantation. Current immunosuppressive regimens do not completely address the causes of allograft dysfunction which include acute rejection episodes, complications of immunodeficiency (for example, cytomegalovirus infection), nephrotoxicity from calcineurin inhibitors (cyclosporine and tacrolimus) and vascular remodeling and vasculopathy. Everolimus is a potent immunosuppressor that inhibits growth factor-stimulated proliferation of hematopoietic and nonhematopoietic cells, including vascular smooth muscle. Everolimus is indicated for the prophylaxis of acute rejection in kidney and heart transplant patients in a combined regimen with cyclosporine microemulsion and corticosteroids. Everolimus is formulated as both a tablet and a tablet for oral solution. It is rapidly absorbed and displays dose-proportional, stable pharmacokinetics. Everolimus has equivalent efficacy to mycophenolate mofetil in reducing the incidence of acute rejection after renal transplantation and superior efficacy to azathioprine after heart transplantation. Combination of everolimus with cyclosporine allows dose-reduction of cyclosporine while maintaining efficacy due to the synergistic immunosuppressive effects of the combination. Everolimus reduces intimal thickening of blood vessels to the graft and the incidence of allograft vasculopathy in heart transplantation. In both kidney and heart transplantation, the incidence of cytomegalovirus infection was lower in everolimus-treated patients compared with patients receiving the control treatment. Everolimus-related adverse events include elevated cholesterol and triglycerides, which respond to treatment, and decreased platelet count, which is transient. Nephrotoxicity may result from the combination of everolimus with full-dose cyclosporine but is mitigated by reducing the dose of cyclosporine. Everolimus is initiated at 0.75 mg b.i.d. with dose adjustments guided by therapeutic drug monitoring of predose blood levels. In clinical development trials, everolimus has demonstrated the ability to reduce the incidence of acute rejection episodes, cytomegalovirus infection and cardiac vasculopathy, thus addressing the primary causes of allograft dysfunction.     

Everolimus: a review of its use in renal and cardiac transplantation

Everolimus (Certican) is an orally administered mammalian target of rapamycin inhibitor (proliferation signal inhibitor) derived from sirolimus (rapamycin), which is used as part of immunosuppressant therapy in kidney and heart transplantation. When evaluated as part of triple therapy with ciclosporin and corticosteroids, everolimus showed equivalent efficacy to mycophenolate mofetil after renal transplantation, and superiority to azathioprine in cardiac transplant recipients, in terms of reducing efficacy failure after transplantation. Everolimus potentiates ciclosporin-associated nephrotoxicity, and it is recommended that concentration-controlled everolimus is used with reduced-dosage ciclosporin in order to limit renal toxicity while retaining immunosuppressive efficacy. Ongoing trials with everolimus, such as the evaluation of ciclosporin-withdrawal strategies, should help clarify its optimal usage. The use of everolimus may be associated with reduced rates of cytomegalovirus (CMV) infection and of cardiac allograft vasculopathy. Available data suggest that everolimus may be cost-neutral for healthcare providers.     

Effects of immunoglobulin to prevent coronary allograft vasculopathy in heart transplantation

Introduction: Although 100,000 cardiac transplants have been performed, coronary allograft vasculopathy (CAV), which is a phenomenon of chronic rejection, is still a serious problem.

Areas covered: Several adhesion molecules, cytokines, and chemokines play a critical role in the process. Recent investigations have proved some promising methodologies for preventing or treating rejection. Although immunoglobulins are known to be an effective treatment in many diseases, their effect on cardiac transplantation or CAV is to be elucidated.

Expert opinion: In this review article, we described some promising methodologies that use immunoglobulins to prevent CAV. Immunoglobulins may be used to prevent CAV.     

Recent developments on coronary microvasculopathy after heart transplantation: a new target in the therapy of cardiac allograft vasculopathy

Heart transplantation (HTx) is the treatment of choice for patients with refractory end-stage heart diseases. Although the procedure is considered effective in extending and improving quality of life, the onset of cardiac allograft vasculopathy (CAV) continues to limit the long-term success of HTx. Emerging data indicate that the endothelium plays a significant role in the onset, progression and complication of this multifactorial disease, with both immunologic and nonimmunologic risk factors contributing to its development. Improving our understanding of the integral role of the coronary microcirculation in CAV is of crucial clinical interest since it could provide further insights into the related pathophysiological mechanisms and possible new strategies for CAV prevention and therapy. Assessment of coronary microvasculopathy has been shown to be of predictive value after HTx. Predominant allograft microvascular dysfunction is detectable in 15-20% of patients after HTx. Very recently, stenotic microvasculopathy (detected in biopsy samples) has been characterized as a prognostic factor for long-term survival after HTx. The ability to detect and distinguish changes in epicardial and microvascular function may aid in identifying modifiable factors that lead to CAV. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), may have a beneficial effect on coronary microcirculation after HTx, although there is still a need to confirm the impact of vasodilators in improving the prognosis of HTx patients. We review the role of coronary microvasculopathy in HTx, its prevention and new potential pharmacological interventions.     

Allograft-induced proliferation of vascular smooth muscle cells: potential targets for treating transplant vasculopathy

Despite advances in immunosuppressive drugs, coronary artery transplant vasculopathy (CATV) is the major cause of graft failure that limits long-term survival of cardiac transplantation. The pathogenesis of CATV involves a chronic immune response of the recipient to the donor vasculature in which activated recipient immune cells damage the endothelium and produce cytokines, resulting in vascular smooth muscle cell (VSMC) activation. Activated VSMC migrate from the media into the lumen, proliferate, and elaborate cytokines and matrix proteins, resulting in loss of lumen diameter and vascular contractility. Because of its extensive nature, interventions which are successful in patients with conventional coronary artery disease are often not applicable to the majority of patients with CATV. Although intended for immune suppression, many immunosuppressive agents owe at least part of their efficacy to their anti proliferative effects on VSMC, including rapamycin, mycophenolic acid, cyclosporin, calcium channel blockers, and HMG CoA reductase inhibitors. Because activation of VSMC is responsible for most of the obliterative arterial intimal thickening present in solid organ allografts, the induction of expression of a selected set of genes may reflect the status of acceptance of the vasculature by the recipient, and the activation, migration, and proliferation of VSMC represent potential points for therapeutic intervention. The risk of infection and malignancy associated with immunosuppressive therapy further promote the need to identify a molecular target which directly modulates the VSMC response to injury. This review will summarize the anti proliferative effects that immunosuppressive drugs have on VSMC proliferation. We will also describe efforts to define the genes which regulate the vascular response to allograft injury, and describe how some of these proteins may represent targets to reduce VSMC proliferation and attenuate CATV.     

Immunosuppressive strategies and management

<正>Advances in immunosuppressive therapy have significantly improved short-term allograft and patient survival.However,chronic allograft failure,antibody mediated rejection,recurrent diseases and immunosuppressive drug associated adverse effects remain serious barriers to long-term survival and quality of life.New immunosuppressive agents and protocols are being evaluated to combat these problems.Importantly, clinicians must work to manage post-transplant complications and avoid complex medication regimens,which will potentiate drug interactions and non-compliance.     

The use of mycophenolate mofetil in transplant recipients

With the development of new immunosuppressive agents, the focus of anti-rejection therapy has shifted from prevention of acute allograft rejection to an emphasis on sufficient immunosuppression with minimal toxicity. Mycophenolate mofetil (MMF) is a recently developed immunosuppressive drug, which acts to inhibit T and B cell proliferation by blocking the production of guanosine nucleotides required for DNA synthesis. It also prevents the glycosylation of adhesion molecules that are involved in attachment of lymphocytes to endothelium and potentially in leukocyte infiltration of an allograft during an immune response. High-quality randomized clinical trials have demonstrated that MMF, when used with cyclosporine (CsA) and steroids, reduces the frequency and severity of acute rejection episodes in kidney and heart transplants, improves patient and graft survival in heart allograft recipients and increases renal allograft survival at 3 years. It has also been effective in reversing acute and resistant rejection episodes in heart, kidney and liver recipients. The ability of MMF to facilitate sparing of other immunosuppressive agents, particularly in CsA-related nephrotoxicity, is also promising. By permitting reduction in CsA doses, MMF may stabilize or improve renal graft function in patients with CsA-related nephrotoxicity or chronic allograft nephropathy. Early results of phase I and II trials evaluating MMF therapy in liver and combined pancreas/kidney transplant recipients are encouraging. The main adverse effects associated with oral or intravenous MMF are gastrointestinal and hematologic in nature. Although the direct costs of using MMF vs. azathioprine (AZA) are higher, the decreased incidence and treatment of acute rejection in patients treated with MMF supports its use as a cost-effective option during the first year following transplantation.Thus, MMF has become an important therapeutic tool in the transplant clinician's armamentarium. Ongoing issues to be resolved in clinical trials include the role of MMF in the absence of other potent agents, e.g., as monotherapy or with a steroid but without calcineurin inhibitor; whether MMF will have an impact on chronic allograft dysfunction; and the cost-effectiveness of treatment following the first year of transplantation.     

糖尿病心肌病发病机制的研究进展

糖尿病威胁人类的健康日益突出.高血糖引起的心血管并发症涉及到心肌病变和血管病变.而糖尿病引起的糖尿病心肌病发病机制是由多因素所致,糖尿病通过各种心肌细胞器结构的改变(线粒体、内质网等)、信号途径、酶学及基因学的变化和炎症因子等病理机制,导致心脏纤维化、心肌肥厚、心脏扩大、心力衰竭和心律失常.本综述详细阐述糖尿病心肌病发病机制的研究进展.     

Everolimus: efficacy and safety in cardiac transplantation

Importance of the field: Prognosis after cardiac transplantation continues to improve with long-term outcomes limited by malignancy and coronary allograft vasculopathy (CAV). Everolimus may potentially reduce these late term complications, while maintaining the low cellular rejection rates seen with standard therapy.

Areas covered in this review: Multiple studies have demonstrated the efficacy of everolimus in reducing acute rejection in heart transplant patients, progression and development of CAV, and the prevention and treatment of common malignancies, including skin cancer and Kaposi sarcoma. This review re-examines these studies with a focus on patient tolerability and safety.

What the reader will gain: Tolerability and safety of everolimus remain a concern with pneumonitis, effusions, mouth ulcers, edema and impaired wound healing associated with morbidity and mortality. Studies have repeatedly demonstrated renal function deterioration with concomitant everolimus and a standard dose calcineurin inhibitor (CNI). This impact can be partly reduced with CNI dose reduction without an increase in the rate of rejection.

Take home message: If future studies confirm reduced CAV and malignancy rates, everolimus will become an important agent in de novo and maintenance immunotherapy in cardiac transplantation. Patient centered immunotherapy is preferred to protocol-based immunotherapy as it allows tailoring of immune therapy to each individual patient's rejection risk and side profile.     

Strategies for Minimizing Hyperlipidemia After Cardiac Transplantation

Allograft coronary artery disease represents a major limitation to long-term survival after cardiac transplantation. Hyperlipidemias have been linked to the development of native coronary atherosclerosis, and hyperlipidemic states have correlated with the severity of allograft coronary artery disease. Heart transplant recipients typically manifest increases in plasma levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and triglycerides within the first 3–12 months following transplantation. Factors known to promote post-transplant hyperlipidemia include the use of corticosteroids, cyclosporine (interference with clearance and increased oxidizability of LDL), sirolimus (hypertriglyceridemia), and patient-specific causes of hyperlipidemia which contributed to their underlying heart disease. Hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors are the foundation of antilipid therapy following cardiac transplantation. Pravastatin is effective in lowering plasma cholesterol levels and is associated with a decreased incidence and progression of allograft coronary artery disease. All HMG-CoA reductase inhibitors except pravastatin are metabolized by the hepatic cytochrome P450 system which metabolizes cyclosporine, increasing the risk of myostitis when they are used in large dosages with cyclosporine. Simvastatin, atorvastatin and fluvastatin have been studied in heart transplant recipients. Gemfibrozil has proved effective in transplant recipients when there is isolated marked elevation of plasma triglyceride levels. When hyperlipidemia persists despite therapy, some benefit may result with conversion from cyclosporine to tacrolimus. Although a definitive link between hyperlipidemia and allograft coronary disease has yet to be proven, available evidence points to abnormal lipid metabolism as part of the complex etiologic machinery driving the process of ‘chronic rejection’. Consensus exists within the transplant community that a HMG-CoA reductase inhibitor such as pravastatin, should be part of the routine post-transplant drug regimen, and persistent hyperlipidemia should be aggressively treated.