Endothelin in coronary endothelial dysfunction early after human heart transplantation.
BACKGROUND
Cytokines and growth factors released as part of the immune response to alloantigenic stimuli are capable of regulating endothelin-1 expression in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vasculopathy.


METHODS
We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myocardial endothelin-mRNA expression in 33 cardiac transplant recipients in the early, stable phase 5+/-3 months after orthotopic heart transplantation. Coronary microvascular function was determined as endothelium-dependent with acetylcholine and endothelium-independent with adenosine using intracoronary Doppler-FloWire. The percentage of the epicardial diameter changes was measured using quantitative coronary angiography. Intravascular ultrasound was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR.


RESULTS
The aortic endothelin levels were significantly increased in transplant recipients compared to nontransplanted patients (11.8+/-2.2 vs 7.2+/-0.9 fmol/mL; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvascular (r = 0.37; P < 0.05) and epicardial (r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA signal intensity was associated with significantly reduced coronary flow response to acetylcholine compared to patients with low myocardial gene expression (coronary flow reserve 2.4+/-0.9 vs 3.4+/-0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression.


CONCLUSIONS
Coronary endothelial vasomotor dysfunction after cardiac transplantation is associated with an increased myocardial endothelin mRNA expression and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the acceleration of the atherosclerotic process in transplant patients.
Weis
M
M
Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, University of Munich, Germany. Micha.Weis@t-online.de
Wildhirt
S M
SM
Schulze
C
C
Rieder
G
G
Wilbert-Lampen
U
U
Wolf
W P
WP
Arendt
R M
RM
Enders
G
G
Meiser
B M
BM
von Scheidt
W
W
D000328:Adult; D015415:Biomarkers; D001706:Biopsy; D001783:Blood Flow Velocity; D006328:Cardiac Catheterization; D017023:Coronary Angiography; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D018618:Echocardiography, Doppler, Color; D016232:Endothelins / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D015870:Gene Expression; D016027:Heart Transplantation; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011863:Radioimmunoassay; D018084:Ultrasonography, Interventional; D014664:Vasodilation
D015415:Biomarkers; D016232:Endothelins; D012333:RNA, Messenger