Treprostinil in advanced experimental pulmonary hypertension: beneficial outcome without reversed pulmonary vascular remodeling.
BACKGROUND
Beneficial effects of treprostinil, a stable prostacyclin analogue, were demonstrated in patients with pulmonary arterial hypertension (PAH). Although regression of pulmonary vascular remodeling has been suggested as therapeutic mechanism, its mode of action remains unknown.


METHODS
Flow-associated PAH was created in rats by injection of monocrotaline (60 mg/kg) combined with an abdominal aortocaval shunt. Subsequently, rats were treated with subcutaneous treprostinil (50 ng/kg/min, treated; n = 8) or saline (untreated; n = 9). A control group underwent sham-surgery (n = 8). Animals were sacrificed at symptoms of cardiac failure, together with their matched controls.


RESULTS
Dyspnea and weight loss determined the moment of sacrifice in 8/9 untreated animals (89%) versus in one of eight treated animals (13%; log-rank test survival curves; P = 0.02). Mean pulmonary arterial pressure increased in the model (42 +/- 2 mm Hg in untreated vs. 18 +/- 1 in controls; P < 0.01) and decreased by 8 mm Hg after therapy (34 +/- 3 mm Hg, P = 0.04 vs. untreated). No effects of treatment on right ventricular hypertrophy could be demonstrated. Quantitative morphometry of pre- and intra-acinar pulmonary arteries revealed no effects of treatment on vessel histopathology.


CONCLUSIONS
Treprostinil treatment improved clinical course and ameliorated symptoms of heart failure in a model of advanced PAH. However, beneficial effects were not associated with reversed structural remodelling of the pulmonary vasculature.
van Albada
Mirjam E
ME
Department of Pediatrics, Division of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. m.e.van.albada@med.umcg.nl
van Veghel
Richard
R
Cromme-Dijkhuis
Adri H
AH
Schoemaker
Regien G
RG
Berger
Rolf M F
RM
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D011464:Epoprostenol; C427248:treprostinil