Cardiac allograft vasculopathy in Dutch heart transplant recipients

Since the first orthotopic heart transplantation at our centre in June 1984, data of all heart transplant recipients were collected prospectively until December 2012. Patients consented to the use of anonymised data for research purposes. The institutional review board of the Erasmus MC approved the present study.

Only patients ≥18 years who underwent at least one conventional coronary angiography at follow-up were included in the analysis. We recorded recipient-related and donor-related variables based on the clinical relevance and previously published studies on CAV predictors. Recipient pre-transplant clinical variables were age, gender, aetiology of heart failure, creatinine and diabetes. Donor-related data were age, gender and cause of death. Donor-recipient mismatch variables and available immunological information were collected. Data at one year after transplantation included the number of acute rejection episodes, development of cytomegalovirus-related disease, serum creatinine, total cholesterol, triglycerides, diagnosis of hypertension and diabetes. Rejection surveillance was based on endomyocardial biopsies, which were graded according to the Billingham’s criteria until 2004 [11, 12] and subsequently according to the ISHLT revised guidelines [13]. Acute rejections were defined as the treated rejections within the first year after transplantation in each patient. Immunosuppressive medication and the use of statins were recorded at the time of CAV diagnosis or at the time of the most recent angiography for the patients without CAV. Mortality and retransplantation were recorded as outcome events.

Coronary angiography (CAG) was performed per protocol every year until 1990. After 1990, CAG was performed at one year and repeated every year in case of evidence of CAV, otherwise postponed to the fourth year after transplantation [14]. After the fourth year post-transplantation, patients underwent non-invasive myocardial perfusion scintigraphy annually for assessment of ischaemia. CAG was performed in these patients when perfusion scintigraphy was positive, or when ischaemia was suspected based on cardiac markers or clinical, electrocardiographic or echocardiographic criteria. Two cardiologists reviewed all the available coronary angiographies, or, when the CAG images were absent in our archive, the diagnosis of CAV was made from the written report and re-graded according to the 2010 ISHLT criteria [9]. In summary, CAV grade 1 applies to stenosis <70 % of primary or secondary coronary branches, CAV grade 2 applies to stenosis ≥70 % of one primary branch or two secondary branches, CAV grade 3 applies to stenosis ≥70 % of two primary branches or three secondary branches, or if an impaired left ventricular function is associated with any degree of CAV. For each patient we recorded the time from heart transplant until the first CAG showing any degree of CAV.

Although the donors in the Netherlands may be older than in other transplantation settings, CAV prevalence in our cohort was comparable with that presented in the most recent report of the ISHLT [1]. However, the strongest CAV risk factor in our study was older donor age. Donor age has been previously reported to be associated with an increased risk of CAV in the database of the United Network for Organ Sharing (in the United States), as well as in Spanish heart transplant registries [15, 16]. We found that also male donor sex was associated with an increased risk of CAV, irrespective of the gender of the recipient. Other studies have shown that gender mismatch, particularly a male recipient receiving a female donor heart, was associated with decreased survival after transplantation, but the reports are contradictory about its relationship with the risk the CAV [17]. Although we did not collect data on donor risk factors, older and male donors might reasonably have higher rates of hypertension, dyslipidaemia and/or history of smoking, conferring the higher chance of subclinical vascular atherosclerosis that might be correlated to neo-intima fibrosis in CAV. Furthermore, donor-derived immunological factors have been reported to contribute to the development of CAV in addition of recipient immunity [18].

We could not find any recipient-related independent predictors of CAV, although in the univariate analysis the risk of CAV was significantly associated with the treatment with mycophenolate mofetil, while cytomegalovirus disease had a trend towards positive association with CAV. The role of cytomegalovirus disease in the development of CAV has been extensively studied, and a positive association has not always been found, but a recent Spanish report has shown that cytomegalovirus disease and even asymptomatic viraemia are associated with increased risk [3]. The possible explanations for the association between treatment with mycophenolate mofetil and CAV in the univariate analysis, but not in the multivariable analysis, could be an increased susceptibility for cytomegalovirus disease during mycophenolate mofetil treatment, or the need for increased immunosuppression due to rejection episodes. Other studies have shown that high rejection scores or repeated acute cardiac rejections are independent predictors of CAV [7, 19]. We did not find a significant association after Cox regression analysis, although the number of patients without any rejection episodes was higher in the CAV-free cohort as compared with the CAV cohort. No other transplantation treatment was found to be associated with CAV. The use of statins has been associated with increased survival after heart transplantation, and it is recommended in the guidelines for the care of heart transplant recipients [20]. One possible explanation for the lack of a positive effect can be the inclusion of patients transplanted before the statin era in the analysis. The number of patients treated with everolimus, as maintenance therapy before coronary angiography, was too low to assess its association with CAV.

We present the survival curves according to the presence of CAV at four years after transplantation, because all patients then underwent elective coronary angiography, according to the protocol at our centre. After the fourth year, patients underwent myocardial perfusion scintigraphy yearly for evaluation of ischaemia, and coronary angiography was only performed by indication. An important finding of our study was that not only is early CAV diagnosis at four years associated with decreased long-time survival, but also that even mild coronary lesions, scored as CAV grade 1, represent a negative prognostic factor. Although the majority of studies are directed to more advanced degrees of CAV, which are also amenable to interventions, one other recent report showed that persistent mild coronary lesions have a negative prognostic impact [2, 21]. This finding emphasises the role of preventive measures immediately after transplantation, before even mild coronary disease may develop.