Venous plasma serotonin is not a proper biomarker for pulmonary arterial hypertension (original) (raw)
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High Plasma Serotonin Levels in Primary Pulmonary Hypertension
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
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 (␣ IIb  3 , 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 (34.4Ϯ21.2 versus 9.1Ϯ6.0 nmol/L, respectively; PϽ0.001) 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 (162Ϯ57 versus 61Ϯ7 nmol/L, respectively; PϽ0.001). 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, PϽ0.01) during treatment. Positive correlations were evidenced between the size of platelets and the number of ␣ IIb  3 and CD36 epitopes. When compared with control platelets, the number of ␣ IIb  3 epitopes detected on PPH platelets at day 0 tended to be higher, but this difference did not reach a statistical significance (41 300Ϯ7140 for PPH patients versus 36 010Ϯ3930 for control subjects, Pϭ0.069). The number of CD36 epitopes, in the range of controls at day 0 (11 590Ϯ5080 for PPH patients versus 11 900Ϯ1790 for control subjects), decreased during treatment (ANOVA, Pϭ0.038) and became significantly low at day 40 (8660Ϯ3520, PϽ0.001). 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.
Serotonin Signaling in Pulmonary Hypertension
Circulation Research, 2006
Mark de Caestecker S erotonin (5-HT, 5-hydroxytryptamine) has long been recognized as one of the most potent naturally occurring pulmonary vasoconstrictors. 1 It was first implicated in the pathogenesis of pulmonary arterial hypertension (PAH) after an outbreak of the disease in Switzerland in the 1960's among patients taking aminorex fumarate, an appetite suppressant that inhibits serotonin uptake by platelets. 2 Since that time further outbreaks of PAH have been identified in Europe and the USA associated with the use of fenfluraminederivate anorexigens, 3-5 eventually leading to their withdrawal from the world market in 1997. Although this was, at least in retrospect, a predictable tragedy, it has ironically opened avenues of research into the biology of serotonin signaling in PAH. As fenfluramine-derivatives are substrates for the serotonin transporter (5-HTT, SERT) proteins, 6 this suggests that abnormal SERT expression or functional activity could play a role in the pathogenesis of PAH. There is now a body of evidence supporting this hypothesis that provides hope for the development of effective therapeutic strategies targeting specific components of this signaling pathway in patients with these diseases. Most of the serotonin produced in the body is secreted by enterochromaffin cells of the intestine into the portal circulation where it is partially metabolized by the liver. However, levels of free circulating serotonin are maintained in the low nanomolar range through energy-dependent SERT-mediated transport into platelets. This led some researchers to hypothesize that fenfluramines might cause PAH by increasing free plasma levels of serotonin. However, this hypothesis is inconsistent with the observation that chronic treatment with fenfluramine-derivatives if anything reduces plasma levels of serotonin. 6 This suggests that other SERT-related effects promote PAH in susceptible patients. This is supported by the observation that patients with idiopathic PAH have increased frequency of the so called L-type polymorphism in the SERT promotor, which is associated with increased SERT expression and activity in platelets and pulmonary artery smooth muscle cells (PASMCs). 7 These studies have recently come under fire as more extensive analyses have failed to confirm an association between the L-genotype and idiopathic or familial PAH. 8,9 Nonetheless, subgroup analysis suggests that the homozygous LL-SERT genotype is associated with early The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Serotonylated fibronectin is elevated in pulmonary hypertension
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2012
Serotonin (5-HT) and fibronectin (FN) have been associated with pulmonary hypertension (PH). We previously reported that FN is posttranslationally modified by tissue transglutaminase (TGase) to form serotonylated FN (s-FN) in pulmonary artery smooth muscle cells and that serotonylation stimulates their proliferation and migration, hallmarks of PH. We hypothesized that s-FN and its binding to TGase are elevated in human and experimental PH. To assess this hypothesis, FN isolation and electrophoretic, immunoblotting, and densitometric techniques were used. Mean ratio of serum s-FN to total FN level (s-FN/FN) was elevated in 19 consecutive pulmonary arterial hypertension (PAH) patients compared with 25 controls (0.3 ± 0.18 vs. 0.05 ± 0.07, P < 0.001). s-FN/FN also was increased in lungs of mice and rats with hypoxia-induced PH and in rats with monocrotaline-induced PH. In mice, the increase was detected at 1 wk of hypoxia, preceding the development of PH. Hypoxic rats had elevated s...
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
2009
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs
The American Journal of Medicine, 1990
We describe a 16-year-old girl with systemiconset juvenile arthritis who presented with pulmonary hypertension, without evidence of pleural or parenchymal involvement of the lung, pulmonary vasculitis, or immune deposition in the pulmonary vasculature. Pleuropulmonary involvement occurs occasionally in juvenile arthritis, but primary pulmonary hypertension has not, to our knowledge, been previously reported. Histocompatibility typing showed positivity for HLA-DR3 and DRw52, both of which are associated with idiopathic pulmonary hypertension in children, and with pulmonary hypertension among patients with systemic sclerosis. Treatment with cyclosporine and corticosteroids resulted in a marked improvement in the clinical findings and pulmonary function in our patient. Systemic-onset juvenile arthritis (JA) is characterized by high spiking fever, rash, lymphadenopathy, hepatosplenomegaly, serositis, and arthritis, and laboratory features of anemia, leukocytosis, thrombocytosis, and elevated serum levels of acute-phase reactants (1). Pulmonary manifestations in children with From the Division of Rheumatology,
Expression of the serotonin 1b receptor in experimental pulmonary hypertension
European Respiratory Journal, 2003
The pathogenesis of pulmonary arterial hypertension (PAH) remains uncertain. Both the serotonin and endothelin (ET) systems are believed to be involved. Recent studies pointed to the importance of the serotonin 2B receptor as a limiting step. The current authors investigated the lung tissue expression of serotonin receptors and of the serotonin transporter (5-HTT) by real-time-quantitative polymerase chain reaction in chronic overcirculation-induced PAH in growing piglets, with and without treatment with the dual ET receptor blocker bosentan. Pulmonary haemodynamic changes were described by pulmonary arterial impedance spectra. Three months after the surgical anastomosis of the left subclavian artery to the pulmonary arterial trunk, there was a shift of the impedance spectra to higher ratios of pressure and flow moduli, with increases in both 0 Hz impedance and characteristic impedance, and these changes were completely prevented by bosentan therapy. There was an increase in the expression of the serotonin 1B receptor. There was no change in the expression of the 5-HTT, and of the serotonin 2B, 1D, and 4 receptors. The overexpression of the serotonin 1B receptor was partially prevented by bosentan therapy. The present authors conclude that this early pulmonary arterial hypertension model is characterised by an endothelin receptor-dependent increased expression of the serotonin 1B receptor.
Platelet Indices in Patients With Pulmonary Arterial Hypertension
Clinical and Applied Thrombosis/Hemostasis, 2011
Background: Pulmonary arterial hypertension (PAH) is a chronic progressive disease characterized by persistent elevation of pulmonary artery pressure. Vasoconstriction, remodeling, and thrombosis cause increased pulmonary vascular resistance and pressure. Previous studies have demonstrated that platelet activation occurs in patients with PAH. Our aim was to assess the mean platelet volume (MPV), an indicator of platelet activation in patients with PAH. Patients and Method: The study group consisted of 22 patients with PAH. An age-, gender-, and body mass index–matched control group was composed of 25 healthy volunteers. All patients underwent physical examination, echocardiography, and diagnostic cardiac catheterization. We measured serum MPV values and platelet counts in patients with PAH and control participant. Results: MPV was significantly higher among the patients with PAH when compared with control group (8.68 ± 0.87 vs 8.02 ± 0.68 fl, respectively; P = .006). Conclusion: We ...
The Journal of laboratory and clinical medicine, 2004
Because atherosclerotic vascular lesions stimulate platelets, the platelets release serotonin (5-hydroxytryptamine, aka 5-HT). We therefore measured 5-HT concentrations not only in platelet-poor plasma but also in whole blood as a means of assessing vascular lesions. The plasma concentration of 5-HT tended to increase with age, whereas that in whole blood decreases. Therefore the ratio of the plasma to the whole-blood concentration of 5-HT (P/WB) increases with age. This may be a result of the activation of platelets in older subjects with atherosclerotic vascular damage. Patients who underwent coronary angiography (CAG) were classified into 4 groups according to diagnosis: effort-induced angina pectoris (eAP), old myocardial infarction (OMI), vasospastic angina pectoris (VSAP), and unstable angina (uAP). The mean plasma 5-HT concentration was significantly (P <.01) greater in patients with eAP, uAP, OMI, and VSAP than in healthy controls, whereas the concentration in whole blood...