Extracorporeal Photopheresis for the Prevention of Early Cardiac Allograft Vasculopathy Detected by Optical Coherence Tomography

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.