Hypoxia and myocardial remodeling in human cardiac allografts: a time-course study.
BACKGROUND
Cardiac allografts are known to develop myocardial fibrosis, which may be a cause of progressive cardiac dysfunction. Apart from the renin-angiotensin and transforming growth factor-beta system, hypoxia has been proposed as an important player in the pathogenesis of fibrosis, but its significance remains unclear. This study examines the degree of myocardial fibrosis, cellular remodeling and hypoxic signaling over a time-course of 10 years after human cardiac allograft transplantation.


METHODS
Serial right ventricular biopsies of 57 patients were collected in 6-month intervals after cardiac transplant surgery for a total of 10 years to allow a retrospective longitudinal analysis. Over this period, tissue remodeling, including interstitial fibrosis and cellular changes, were determined morphometrically. Immunohistochemistry (IHC) was used to analyze expression of the following hypoxia-related proteins: hypoxia-induced factor 1-alpha (HIF1alpha); the oxygen sensor prolyl hydroxylase 3 (PHD3); and vascular endothelial growth factor (VEGF).


RESULTS
Fibrosis increased significantly from 12.6 +/- 6.5% at the point of transplantation throughout follow-up to 28.8 +/- 7.7% at 10 years. The DNA content and number of nuclei changed over the period of follow-up, displaying signs of cellular hypertrophy and a loss of myocytes. Whereas HIF1alpha expression revealed a U-shaped pattern with both early and late elevation during fibrogenesis, PHD3 and VEGF expression patterns showed a gradual increase with PHD3 decreasing again in later fibrogenesis.


CONCLUSIONS
In cardiac allografts, extensive and progressive tissue remodeling is present. Hypoxia may play a role in this process by up-regulating HIF1alpha and leading to differential regulation of pro-angiogenic signals.
Gramley
Felix
F
Department of Cardiology and Vascular Medicine, University of Mainz, Langenbeckstrasse 1, Mainz, Germany. gramley@hotmail.com
Lorenzen
Johann
J
Pezzella
Francesco
F
Kettering
Klaus
K
Himmrich
Ewald
E
Plumhans
Cedric
C
Koellensperger
Eva
E
Munzel
Thomas
T
D004719:Endomyocardial Fibrosis / Q000453:epidemiology / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases / Q000453:epidemiology*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000453:epidemiology; D000860:Hypoxia / Q000453:epidemiology / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D014184:Transplantation, Homologous; D020257:Ventricular Remodeling / Q000502:physiology*