Endothelin-1 Across the Lung Circulation in Patients With
Pulmonary Arterial Hypertension and Influence
of Epoprostenol Infusion
Nedim Selimovic, MD, PhD,
a
Bert Andersson, MD, PhD,
a
Claes-Håkan Bergh, MD, PhD,
a
Egidija Sakiniene, MD, PhD,
b
Hans Carlsten, MD, PhD,
b
and Bengt Rundqvist, MD, PhD
a
Background: The endothelin-1 (ET-1) system plays a pathophysiologic role in patients with pulmonary arterial
hypertension (PAH). Results from previous studies assessing the transpulmonary gradient of ET-1
have been inconsistent. The influence of an intravenous epoprostenol infusion on the transpulmo-
nary ET-1 gradient is unknown.
Methods: In a prospective investigation, serum concentrations of ET-1 were measured in 39 consecutive
patients (31 women; mean age, 20 –77 years) with pulmonary hypertension (33 with PAH) and
compared with 20 controls. The effect of intravenous epoprostenol administration on the
transpulmonary gradient of ET-1 was analyzed in 13 patients with pulmonary hypertension. Blood
samples were taken simultaneously from the pulmonary artery and radial artery.
Results: The serum levels of ET-1 were significantly higher in the arterial (3.9 1.28 vs 2.53 0.24 pg/ml,
p 0.001) and mixed venous blood samples (3.9 1.21 vs 2.52 0.29 pg/ml, p 0.001) in
patients with pulmonary hypertension than in controls. The arterial/venous ratio of ET-1 in patients
(1.0 0.1) and in the control group (1.0 0.05) was similar (p = 0.79). During intravenous
epoprostenol infusion, there were no changes in the mean transpulmonary ET-1 gradient (0.98
0.07 vs 0.96 0.09, p = 0.52), despite significant hemodynamic changes.
Conclusion: The ET-1 radial artery/pulmonary artery ratio of unity indicates a balanced release and clearance of
ET-1 across the lung circulation in controls and in patients with different forms of pulmonary
hypertension. ET-1 levels across the pulmonary circulation did not change during epoprostenol
infusion. J Heart Lung Transplant 2009;28:808 –14. Copyright © 2009 by the International Society
for Heart and Lung Transplantation.
Pulmonary arterial hypertension (PAH) is a progressive
vascular disease characterized by the vascular remodel-
ing of small pulmonary arterioles leading to increased
pulmonary vascular resistance and fatal right heart
failure.
1
Although vasoconstriction may be important in
the pathophysiology of PAH, microvascular narrowing
and obliteration by cell proliferation are prominent in
PAH vasculopathy.
2
Experimental investigations and clinical studies indi-
cate that the endothelin (ET) system plays an important
pathophysiologic role in pulmonary hypertension.
3–10
Increased levels of ET-1 have been shown in plasma
11
and lung tissue
12
from patients with PAH. The increased
ET levels in patients with PAH have also been shown to
correlate with pulmonary hemodynamics
13–15
and with
an adverse outcome.
16
In patients with PAH associated
with connective tissue disease, the role of the ET
system is less clear. A previous study of patients with
scleroderma showed that serum levels of ET-1 were
increased in patients with and without pulmonary
hypertension.
17
The pulmonary clearance of ET-1 is mediated by ET
B
receptors in a unidirectional process, with no evidence
of return into the circulation.
18,19
The human lung is a
major site for the clearance and production of ET-1. The
human lung removes about 50% of circulating ET-1 but
releases a quantitatively similar amount into the circu-
lation, thereby explaining the absence of an arterio-
venous ET-1 gradient across the pulmonary circulation
in healthy individuals.
14,18
In patients with idiopathic
PAH (IPAH), previous studies assessing the transpulmo-
nary gradient of ET-1 have produced inconsistent re-
sults.
11,15,18
The transpulmonary gradient of ET-1 in
patients with PAH associated with connective tissue
disease has not been studied to the same degree.
From the
a
Department of Cardiology,
b
Department of Rheumatology,
Sahlgrenska University Hospital, Gothenburg, Sweden.
Submitted February 13, 2009; revised March 20, 2009; accepted
April 8, 2009.
Reprint requests: Nedim Selimovic, MD, PhD, Sahlgrenska University
Hospital, Department of Cardiology, Gothenburg, SE 413 45 Gothen-
burg, Sweden. Telephone: +46-313-427-570. E-mail: nedim.selimovic@
vgregion.se
Copyright © 2009 by the International Society for Heart and Lung
Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/
j.healun.2009.04.017
808