Morphological and quantitative changes of the initial myocardial lymphatics in terminal heart failure.
BACKGROUND
Terminal heart failure is associated with chronic myocardial edema, which in part is compensated by increased myocardial lymph flow. However, little is known about the impact of terminal heart failure on lymphangiogenesis. The purpose of the study was to investigate the morphological and quantitative changes of the initial myocardial lymphatics in terminal heart failure.


METHODS
Paraffin-embedded left ventricular endomyocardial biopsies, taken during heart transplantation from 7 heart transplant recipients (failing heart) and 8 heart transplant donors (control), were investigated by immunohistostaining and triple immunofluorescence for lymphatic endothelial markers LYVE-1, PROX-1, and VEGFR-3. The vessel density was calculated and the ratio of open versus collapsed vessels was estimated by analyzing randomly selected marked vessels.


RESULTS
The absolute densities of lymph vessels in failing and control myocardium were not significantly different for all investigated markers. The ratio of open LYVE-1 positive lymph vessels in failing heart was significantly higher than in control (64+/-12.5 vs. 44.3+/-9.3, p<0.008). There was no difference for the ratio of open VEGFR-3 vessels between groups (69.0+/-17.5 vs. 70.7+/-17.2). Triple fluorescent immunohistostaining revealed in failing hearts LYVE-1 and PROX-1 positive open vessels, which were VEGFR-3 negative. VEGFR-3 positive, but LYVE-1 and PROX-1 negative vessels could also be seen.


CONCLUSIONS
Myocardial initial lymphatics in patients with terminal heart failure undergo significant morphological changes in comparison to normal hearts. The ratio of open LYVE-1 vessels was higher in failing hearts by no difference in absolute densities for all markers. These findings suggest that appositional growth of initial lymphatics, rather than "de novo" genesis from pluripotent stem cells or sprouting from preexisting venous vessels, may be the predominant mechanism of lymphangiogenesis in terminal heart failure.
Dashkevich
Alexey
A
Department of Cardiovascular Surgery, University Medical Center Freiburg, Freiburg, Germany. alexey.dashkevich@uniklinik-freiburg.de
Bloch
Wilhelm
W
Antonyan
Albert
A
Fries
Jochen U W
JU
Geissler
Hans Joachim
HJ
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology*; D016027:Heart Transplantation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008208:Lymphatic System / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D014019:Tissue Donors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
D015415:Biomarkers; 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