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The Impact of Ventricular Assist Device Prior to Transplantation on Morphological Parameters in Cardiac Allografts /// Въздействие на вентрикуларните помощни устройства преди трансплантация върху морфологичните параметри при сърдечните алографи
Wassilew, Katharina / Василев, Катарина
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Due to the shortage of donor organs, mechanical circulatory support systems (MCS) are now widely used as a treatment option to bridge the failing heart to transplantation. There are limited data, suggesting that prolonged use of ventricular assist device (VAD) therapy may result in cardiac allograft dysfunction, as MCS patients show a higher frequency of antibody-mediated rejection (AMR) episodes. We aimed to analyze the effects of MCS on cardiac AMR with regards to capillary C3d and C4d depositions. Regarding the functional parameters, both acute cellular rejection (ACR) and an increase of interstitial fibrosis (IF) often correlate with impaired ventricular function. The innate immune system, in particular macrophages, plays an important role in the resorptive process of ACR and is, on the other hand, known to promote IF. In this study we aimed to analyze the effect of ACR and specifically of the level of macrophages on the degree of IF in right ventricular endomyocardial biopsies (EMBs) of cardiac allografts. Methods: We evaluated all consecutive EMBs of cardiac allografts from 254 patients taken between 01/2011 and 12/2012.With regard to pre-transplant MCS treatment, patients were divided into two groups (MCS group n=82 patients, non-MCS group n=138 patients). The MCS patients were subdivided into groups regarding the device used (HeartMate II, HeartWare, Novacor, Incor, Excor). Patients were excluded from the analysis if they had an MCS system that was used in fewer than five of the study population patients. Tissue sections of formalin-fixed paraffin-embedded EMBs were evaluated histologically using conventional histology (hematoxylin-eosin stained slides) and immunohistochemical stains for a lymphocyte marker (CD3) and a pan- macrophage marker (CD68) for ACR, which has been classified according to the ISHLT. Statistical analysis was done using Fisher’s exact tests, bootstrapped Cochran-Mantel-Haenzsel test, GLM methods and tree analysis. In addition, immunohistochemical stains (complements C3d and C4d) were used to evaluate the EMBs regarding AMR. The amount of macrophages was assessed by eyeballing irrespective of the presence of ACR. The EMBs were also evaluated for level of IF on a collagen stain (Sirius red) and further quantified using NIKON software (NIS elements AR 4.10.02). Fisher’s exact test was performed to analyze the relationship between C4d and C3d in both patient groups. The Cochran-Mantel-Haenzsel test was applied to assess significance of the differences in interactions between groups. To evaluate the impact of bridge- to- transplant mechanical circulatory support on development on transplant vasculopathy in cardiac allografts, the intramyocardial terminal arterial network was assessed using conventional histology and immunohistochemistry (CD31, alpha actin). Results: In the study population as a whole there is a positive correlation between C3d and C4d (p=0.007), with 64% concordant cases (107 negative and 33 positive out of 220 in total). Analyzing the two groups separately a significant C3d/C4d correlation was found only for the MCS group (p=0.002, odds ratio=4.185, non-MCS group p=0.418, odds ratio=1.392). While there was a significant difference in C4d deposition between the overall MCS group (n=82) and the non-MCS-group (p=0.021, odds ratio=0.524), the Excor patients (39/82) did not show an increase in C4d depositions (p=0.838, odds ratio 1.11). Patients with the remaining MCS types (43/82) showed signs of antibody-mediated rejection in the form of C4d depositions in significantly more cases than the non-MCS group (p=0.003, odds ratio=2.97). The density of macrophages correlated with ACR (p=0.000) and with both pure IF (p= 0.017) and overall IF (p= 0.001). Interestingly, ACR appeared to have no direct impact on pure or overall IF (p=0.749, p=0.760) In addition, there was an adverse correlation between MCS-treatment and transplant vasculopathy of the myocardial terminal vascular network with a significant difference in presence of transplant vasculopathy in 62% of MCS-group compared 75% of patients without MCS support (p = 0.03, odds- ratio= 0.45). The Excor patients (39/82) did not show a decrease in transplant vasculopathy (p=0.31, odds ratio 0.66) on the contrary to the remaining MCS types (p=0.03, odds ratio=0.45). Conclusions: Only in patients with pre-transplant MCS does C3d correlate with capillary C4d depositions. This circumstance may beneficially complement existing diagnostic criteria for AMR. As well, the results suggest that not the MCS treatment as such, but the type of device used, may influence the outcome of cardiac allografts with regard to AMR, which may be due to allosensitation to the different device materials. Our results suggest that both the density of tissue macrophages and the macrophages of the inflammatory infiltrate in the resorptive process of ACR are important predictive factors for the remodeling in cardiac allografts. In addition, the Excor MCS system appears to have a protective effect on the development of transplant vasculopathy in cardiac allografts.