© 2000 American Heart Association, Inc.
Vascular Biology |
High Plasma Serotonin Levels in Primary Pulmonary Hypertension
Effect of Long-Term Epoprostenol (Prostacyclin) Therapy
From CR C. Bernard "Pathologie Expérimentale et Communications Cellulaires", IVS and IFR 6, Biochimie et Angio-Hématologie, Hôpital Lariboisière (A.K., J.C., J.-M.L., L.D.), AP-HP, Paris, France; Pneumologie et Réanimation Respiratoire, UPRES "Maladies Vasculaires Pulmonaires," Hôpital Antoine Béclère (M.H., G.S.), AP-HP, Université Paris Sud, Clamart, France; and Centre Chirurgical Marie Lannelongue (P.H.), Université Paris Sud, Le Plessis Robinson, France.
Correspondence to Dr Ludovic Drouet, Service d’Angio-Hématologie, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France. E-mail drouet{at}ccr.jussieu.fr
Abstract—Elevated plasma
serotonin is associated with primary pulmonary
hypertension (PPH). To test whether this elevation could be related to
platelet activation, the 2 pools of blood serotonin
(platelets and plasma) and plasma 5-hydroxyindoleacetic acid
(5-HIAA) as well as markers of platelet activation
(
IIbß3, CD36, P-selectin, and CD63
membrane epitopes) were measured in 16 patients with severe PPH (group
1) before and at days 10 and 40 of treatment with a continuous infusion
of epoprostenol (prostacyclin). The same biological
parameters were also measured in 19 healthy subjects (group
2) and in 10 patients after cardiovascular surgery with
extracorporeal circulation (group 3), a condition known to profoundly
activate the platelets. Twelve PPH patients showed
hemodynamic and clinical improvement, 3 remained
stable, and 1 had the treatment stopped because of clinical
aggravation. At day 0, mean plasma serotonin
(5-hydroxytryptamine [5-HT]) concentration was much
higher in PPH patients than in normal subjects (34.4±21.2 versus
9.1±6.0 nmol/L, respectively; P<0.001) and positively
correlated with total pulmonary resistance. The mean
platelet 5-HT content was not significantly different in PPH
compared with normal individuals. Mean plasma 5-HIAA concentrations
were much higher in PPH than in normal patients (162±57 versus 61±7
nmol/L, respectively; P<0.001). These
parameters did not significantly change during epoprostenol
treatment. There was no correlation between the changes in plasma 5-HT
during treatment and clinical or hemodynamic
improvement. In PPH patients, the mean platelet volume
significantly decreased (ANOVA, P<0.01) during
treatment. Positive correlations were evidenced between the size of
platelets and the number of IIbß3 and
CD36 epitopes. When compared with control platelets, the number of
IIbß3 epitopes detected on PPH
platelets at day 0 tended to be higher, but this difference did not
reach a statistical significance (41 300±7140 for PPH patients versus
36 010±3930 for control subjects, P=0.069). The number
of CD36 epitopes, in the range of controls at day 0 (11 590±5080 for
PPH patients versus 11 900±1790 for control subjects), decreased
during treatment (ANOVA, P=0.038) and became
significantly low at day 40 (8660±3520, P<0.001). The
number of CD63 epitopes was not elevated, and P-selectin was never
detected at any time point on PPH platelets. This
glycoprotein profile indicates that the platelets of
PPH patients were not highly activated but had an accelerated
turnover and returned to normal under epoprostenol treatment without
change of the elevated plasma serotonin, characteristic of
PPH. In conclusion, neither platelet activation nor a significant
alteration of the 5-HT endothelial
metabolism explains the high level of plasma 5-HT in PPH
patients. The 5-HT plasma concentration is not a predictive marker of
the severity of PPH, and its evolution is independent of the clinical
and hemodynamic status. Treatment by a potent
antiaggregating agent, epoprostenol, does not affect the increase of
plasma 5-HT, despite a therapeutic benefit.
Key Words: primary pulmonary hypertension • serotonin • platelet activation • prostacyclin • epoprostenol
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