First year changes of myocardial lymphatic endothelial markers in heart transplant recipients.
OBJECTIVE
The lymphatic system plays an important role in interstitial fluid balance, lipid metabolism, and immune response. The recent introduction of specific lymphatic endothelial cell markers has made the investigation of lymphangiogenesis under various conditions and from small tissue samples feasible. It was the purpose of the study to investigate the changes of myocardial lymphatic endothelial markers during the first 12 months after heart transplantation and to analyze if a correlation between lymphatic markers and rejection can be found.


METHODS
Right ventricular endomyocardial biopsies taken for routine rejection monitoring from 26 heart transplant recipients were investigated. Selected time points were 0.5, 1, 1.5, 6, and 12 months after human heart transplantation (HTX). Immunohistostaining was performed for VEGFR-3, the receptor for lymphangiogenic vascular endothelial growth factors C and D, for LYVE-1, a novel hyaluronan receptor, restricted to lymphatic vessels, and PROX-1, a homeobox gene product, which plays a key role in lymph vessel development and differentiation.


RESULTS
Density of VEGFR-3 positive lymphatics did not change during the first 12 months after transplantation. However, in comparison to the 0.5-month biopsy, density of LYVE-1 and PROX-1 positive lymphatics was significantly decreased at 1 month after transplantation (p<0.03) and at the subsequent time points (p<0.01). Patients with only moderate rejection during the first 12 months (ISHLT<IIIa) had a significantly higher density of VEGFR-3 at 0.5 month in comparison to patients with at least one episode of clinically relevant rejection (ISHLT IIIa or worse, p<0.03).


CONCLUSIONS
Myocardial lymphatics show a significant change of endothelial phenotype after transplantation, as demonstrated by significant quantitative changes of lymphatic endothelial marker density. Patients with at least one rejection of ISHLT IIIa or higher had a significantly lower density of VEGFR-3 at 0.5 month after transplantation. The results of this study warrant further investigation on the impact of transplantation on the lymphatic endothelium. The cause-effect relation between rejection and lymphatic endothelium remains to be investigated.
Geissler
Hans J
HJ
Department of Cardiothoracic Surgery, University of Cologne, Germany. hans.geissler@uk-koeln.de
Dashkevich
Alexey
A
Fischer
Uwe M
UM
Fries
Jochen W U
JW
Kuhn-Régnier
Ferdinand
F
Addicks
Klaus
K
Mehlhorn
Uwe
U
Bloch
Wilhelm
W
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D004699:Endocardium / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology; D016027:Heart Transplantation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D042601:Lymphatic Vessels / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D025521:Tumor Suppressor Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D033921:Vesicular Transport Proteins; D000098551:Prospero-Related Homeobox 1 Protein
D015415:Biomarkers; D006023:Glycoproteins; D018398:Homeodomain Proteins; C119248:LYVE1 protein, human; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D040321:Vascular Endothelial Growth Factor Receptor-3