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Editorial Comment: Heart Transplantation, Cardiac Allograft Vasculopathy and Proliferation Signal Inhibitors

One year patient and graft survival after heart transplantation are excellent but cardiac allograft vasculopathy (CAV) remains a major cause of long-term patient morbidity and mortality. Fifty percent of heart transplant recipients experience CAV within five years of transplantation (1); CAV and late graft failure from CAV account for 30% of deaths post-heart transplantation (2). The Editors of Transplantation are pleased to present this journal supplement devoted to cardiac allograft vasculopathy and the potential usefulness of proliferation signal inhibitor (PSI) immunosuppressive drugs in preventing or moderating CAV. Guest Editor Anne Keogh, of the Heart and Lung Transplant Unit of St. Vincent’s Hospital, Sydney, Australia, provides a detailed summary of the gross pathology of CAV (progressive thickening of the intima of the entire length of the affected epicardial and intramyocardial arteries) versus the usual coronary artery disease (CAD; focal and eccentric plaques largely in proximal coronary vessels). The immunologic (human leukocyte antigen mismatch, chronic inflammation, acute rejection) and non-immunologic (cytomegalovirus infection, ischemia-reperfusion injury, donor brain death) factors which enhance CAV development along with traditional CAD risk factors are detailed. CAV has limited amenability to usual treatments of stenting and bypass grafting compared with CAD. Preventing and slowing progression of CAV in de novo heart transplant recipients are therapeutic priorities, i.e. by reduction of immunologic and non-immunologic factors as well as standard cardiac risk factors. In addition, the use of proliferation signal inhibitors (PSIs) sirolimus (Rapamune, Wyeth Pharmaceuticals) and everolimus (Certican, Novartis Pharma AG), has been associated with a reduction in intimal thickening and reduced CAV incidence in both ex vivo models and de novo heart transplant recipients (3– 4). Conversion to sirolimus in maintenance heart transplant recipients with existing CAV resulted in slowing of progression of CAV and fewer clinical events related to CAV (5). Keogh maintains that PSIs could be used in de novo and maintenance heart transplant recipients to reduce the impact of CAV on long-term outcomes of heart transplantation. Maria Frigerio and colleagues of Milan, Italy, present a detailed discussion of the diagnosis and prognosis after CAV development and its overall impact on patient outcome. CAV is usually under diagnosed by coronary angiography. Intravascular ultrasound (IVUS) is the gold standard for CAV diagnosis; normal maximal intimal thickness (MIT) for allograft coronary vessels is 0.1 to 0.3 mm. An MIT of 0.5 mm at any time after transplantation is associated with a worse prognosis. Serial IVUS examinations are used to evaluate therapies to prevent the onset and progression of CAV. Non-invasive tests (stress echocardiography, scintillography) evaluate the effect of CAV on cardiac function and perfusion and serve as prognostic/screening tests to identify patients needing invasive testing. Biological markers for the risk of development of CAV (C-reactive protein, cardiac angiotensin II receptor gene transcripts, and asymmetric demethylarginine [ADMA]) have recently been shown to correlate with increased probability to develop CAV. The International Society for Heart and Lung Transplantation Registry data estimate the incidence of CAV to be 7–9% at one year, 30% at five years, and close to 45% at eight years; the risk of death at five years is increased by 40% in those with a diagnosis of CAV at one year (2). Frigerio and co-authors make a strong case to prevent CAV by implementing all strategies that will minimize both immunologic and non-immunologic causes of CAV (above) as well as traditional cardiac risk factors. They advocate utilization of PSIs in de novo heart transplant recipients. As the number of maintenance heart transplant patients increases, the CAV related morbidity and mortality will grow. They note that the possibility of controlling progression and increasing patient survival and quality of life by conversion to PSIs is promising and should be verified with further clinical studies. Howard Eisen from Drexel University College of Medicine in Philadelphia and Xiaolan Yang of Novartis Pharma AG in Basel present an interesting analysis of how use of PSIs in cardiac transplantation could impact the burden of major adverse cardiac events (MACE) following heart transplantation. PSIs reduced the incidence of CAV in de novo heart transplant recipients and resulted in a lower incidence of MACE at four years post-transplant (5). They analyzed the economic health care burden of MACE through analysis of hospitalization costs from the 2003 US Healthcare Cost and Utilization Project. Everolimus treatment was associated with a reduction in the mean cost of MACE per patient. They also analyzed previously published data on the incidence of MACE in maintenance heart transplant patients converted to sirolimus. They determined that the average cost of MACE per patient was almost 10,000 US dollars versus about 38,000 US dollars in patients remaining on their original immunosuppressive program, a reduction of about 75%. They conclude that the antiproliferative benefits of PSI therapy in reducing the incidence and progression of CAV are associated with reduced healthcare costs that result from MACE in both de novo and maintenance heart transplant recipients. Frigerio and colleagues present a concluding case report manuscript describing a patient in whom a PSI (everolimus) was introduced eight years post-transplant. The patient had CAV detected four years post-transplant and suffered a myocardial infarct 7.5 years post-transplant which was successfully treated by percutaneous transluminal angioplasty and stenting of an occluded left anterior descending artery. A month later everolimus was substituted for azathioprine. One year later follow-up coronary angiography was unchanged with a patent stent and stable diffuse CAV. The authors identify various problems occurring with late PSI conversion. The authors suggest a number of long-term heart transplant reCopyright © 2006 by Lippincott Williams & Wilkins ISSN 0041-1337/06/8208S-1 DOI: 10.1097/01.tp.0000245501.53813.49