Extracorporeal Photopheresis and Early Cardiac Graft Vasculopathy

Heart transplantation is a golden standard for the treatment of terminal heart failure. The major cause of death in late posttransplant period is cardiac allograft vasculopathy (CAV). This posttransplant complication develops slowly over several years, and when diagnosed either by conventional coronary angiography or due to graft failure, it is often too advanced and difficult to treat since it is diffuse coronary artery disease.

Therefore, early prevention of CAV is a subject of major interest in the transplant cardiology. Since CAV is associated with immune factors, immunomodulatory therapeutic options, like extracorporeal photopheresis are lately being investigated.

Unlike conventional coronary angiography, optical coherence tomography (OCT) is able to detect the development of CAV in the earliest phase, i.e. even in the first post-transplant year.

In our study, we plan to investigate the prophylactic effect of extracorporeal photopheresis in the early development of cardiac graft vasculopathy detected by OCT.

Introduction

Heart transplant is golden standard in the treatment of terminal heart failure. Although patients' survival improved due to new advanced surgical techniques and the use of modern immunosuppressants, the posttransplant period of these patients is still fraught with complications and associated with reduced life expectancy compared to healthy individuals. Morbidity and mortality in the early post-transplant period are mainly associated with infections, acute graft rejection, multiorgan failure, and unspecified graft failure. In the late posttransplant period, the main cause of death is cardiac allograft vasculopathy (CAV). It should be emphasized that 30% of patients after 5 years and 50% after 10 years have angiographic changes in coronary arteries. Unlike atherosclerosis in the native heart that is typically focal, noncircumferential and usually localized in proximal segments of coronary arteries, CAV is a diffuse disease with concentric intimal hyperplasia and thickening of microvasculature media. It is a multifactorial disease caused by the immune, but also other non-immune factors: cellular and humoral (antibody-mediated) graft rejection, donor-specific anti-HLA antibodies, CMV infection, and hypercholesterolemia. The pathophysiology of immune-mediated development of CAV is based on T-cell and vascular endothelial interaction. According to the previously known association between graft rejection and development of coronary vasculopathy, routine clinical follow-up of transplanted patients includes regular myocardial biopsies with pathohistological analysis for cellular and humoral rejection.

Although CAV sometimes develops rapidly, it is usually slowly progressive disease associated with the development of chronic humoral graft rejection. Since symptoms and signs of CAV are usually absent or atypical (due to afferent and efferent graft denervation), early diagnosis is extremely important. For that reason, according to current recommendations of International Society for Heart and Lung Transplantation (ISHLT), regular periodic coronary angiographies are being performed. Nowadays, modern transplant centers, besides classical coronary angiography, perform intravascular ultrasound (IVUS) for coronary artery imaging. It provides a measurement of intimal thickness and today it is the gold standard in early detection of vasculopathy. However, due to the better spatial resolution of coronary artery layers, especially the intimal layer, in comparison to IVUS, optical coherence tomography (OCT) is started to use more often in the detection of CAV.

Despite many efforts, there are still no effective measures for CAV prevention. Out of all examined options, statin therapy and use of mTOR inhibitors as a part of the immunosuppressive regimen is providing best, but still not effective enough. Since the development of CAV is associated with various immune factors, immunomodulatory therapeutic options are being investigated. One of those options is extracorporeal photopheresis. It is an immunoregulatory method that divides patients' peripheral blood into two fractions: leukocyte-rich and leukocyte-poor fraction. The first fraction is immediately returned in circulation, and another one is exposed to UVA irradiation to achieve the immunomodulatory effect, i.e. increase in regulatory T-cell activity. This reduces rejection and graft vasculopathy as a result of an excessive immune response to the transplanted organ. The positive effect of this therapeutic method on CAV development was confirmed in one small study where pathomorphological changes of coronary arteries were detected using IVUS. Moreover, maintenance immunosuppressive therapy in study patients included a combination of cyclosporin and azathioprine, inferior to contemporary immunosuppressive combinations.

Hypothesis Extracorporeal photopheresis, along with other standard methods of treatment after heart transplantation significantly reduces the development of cardiac allograft vasculopathy as detected with optical coherence tomography.

Materials and methods:

This is a controlled prospective study of de novo heart transplant patients followed at the the Department for intensive care unit, arrhytmias and transplantation cardiology at University Hospital Center Zagreb. We plan to enroll 25 consecutive patients after heart transplant after signing an informed consent form. All patients will be treated with standard immunosuppressive protocol and have a standard follow-up with regular biopsies. The number of patients (12-13) determined by chance will receive additional treatment with extracorporeal photopheresis (ECP) according to a predetermined protocol. During the first post-transplant year, these patients will undergo 10 ECP treatments, each pair of treatment given on two consecutive days. Complete blood count, electrolytes and coagulation parameters are performed prior to the procedure. Since psoralen application can cause photosensitivity, patients are advised to avoid sun exposure for 24 hours. The procedure will be performed in the Department for transfusion and transplantation biology at University Hospital Center Zagreb.

All patients included in the study will undergo two coronary angiographies with OCT imaging - the initial within the first three months after heart transplantation, and the second 12 months after heart transplantation. Ilumien Optis System platform with Dragonfly Optis Imaging catheter will be used to acquire high-resolution images. OCT images acquired at basal and control will be used for statistical analysis of ECP effect on the development of cardiac allograft vasculopathy. OCT acquisition will be performed in all three major coronary arteries. The analysis will be performed in a blinded fashion. For quantification of intimal tissue hyperplasia, we will measure maximal and median intimal thickness, maximal and mean intima area, as well as volumetric indices including intimal volume, plaque volume, and plaque index. These parameters will be normalized to measured segment length. Qualitative intimal tissue analysis will be performed as well. All plaques in the acquired segments will be characterized and sized according to luminal presentation and mapped for serial assessment.

During the study, we will collect patients' medical history data, anthropometric measurements, and laboratory tests results. According to the standard protocol of myocardial biopsies and pathological analysis, results regarding graft rejection will be used in the comparative analysis of photopheresis efficacy.

Eligibility Criteria:
Inclusion Criteria:

* age \>18 and \<65
* primary orthotopic heart transplant
* early photopheresis
* adequate intravenous approach
* signed informed consent

Exclusion Criteria:

* aphakia
* psoralen hypersensitivity
* active retinal disease - photosensitive diseases
* splenectomy
* L \<2000; Hb \<70 g/L
* coagulopathy