Plasma serotonin levels are normal in pulmonary arterial hypertension

doi:10.1016/j.pupt.2007.01.003

Pulmonary Pharmacology & Therapeutics

Volume 21, Issue 1, February 2008, Pages 112-114

https://doi.org/10.1016/j.pupt.2007.01.003 Get rights and content

Abstract

Serotonin (5-HT) has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We hypothesized that plasma 5-HT would be elevated in PAH related to associated conditions. We performed a prospective cohort study of 21 patients with PAH undergoing initial right heart catheterization and 6 healthy controls. Platelet-free plasma 5-HT levels were similar in patients with idiopathic PAH, PAH related to associated conditions, and healthy controls. Higher 5-HT levels correlated with increased six-minute walk distance (r=0.55, p=0.04). These data suggest that plasma 5-HT levels are normal in PAH. Plasma 5-HT may therefore not be a useful biomarker in this condition.

Introduction

Serotonin (5-HT) is a potent pulmonary vasoconstrictor and platelet aggregator that has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). Most human circulating 5-HT is stored in platelets, while only platelet-free plasma 5-HT has potent vascular activity. Two previous studies (N=16 each) have shown increased plasma 5-HT levels in patients with idiopathic PAH (IPAH) [1], [2]. In addition, a 5-HT promoter polymorphism has been associated with the risk of PAH in one population, although this association was not seen in other populations [3], [4], [5]. We therefore hypothesized that plasma 5-HT levels would be significantly elevated in PAH related to associated conditions (APAH).

Section snippets

Methods

We performed a prospective cohort study of patients with PAH undergoing initial right heart catheterization at our center beginning in November 2001. We excluded patients already receiving targeted PAH treatment. We also included age- and gender-matched healthy controls. The Columbia University Institutional Review Board approved the study.

A bionutritionist counseled subjects to avoid 5-HT-rich foods, alcohol and coffee for 48 h before phlebotomy; subjects recorded foods eaten during this

Results

We enrolled 28 PAH patients and 8 controls; 21 patients and 6 controls were compliant with dietary restrictions and comprised the final study sample (Table 1). Two PAH patients had collagen vascular disease, 3 had HIV, 5 had congenital cardiac shunts (2 repaired), 6 had portopulmonary hypertension, and 5 had IPAH.

Patients with APAH did not have elevated plasma 5-HT levels compared to controls (Fig. 1; p=0.51). Patients with IPAH also had 5-HT levels similar to those of controls. In fact, only 1

Discussion

We found that patients with APAH and IPAH had plasma 5-HT levels that were similar to those of healthy controls. These results differ from those of previous studies in which PAH was associated with dramatically higher 5-HT levels (>30 nmol/L) [1], [2]. There are a number of possible explanations for these discrepant findings.

First, we specifically focused on patients with APAH, whereas prior studies predominantly included patients with IPAH. Of note, however, 5-HT levels were also normal in

Acknowledgments

The authors wish to thank May Huang, M.S. and the staff of the Irving Center for Clinical Research at Columbia University for their assistance with this study.

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Cited by (24)

Inhibition of serotonin synthesis: A novel therapeutic paradigm
2020, Pharmacology and Therapeutics
Citation Excerpt :
Several lines of evidence support an important pathogenetic role of serotonin in PAH. Some (but not all) studies showed that this disease with high mortality and few therapeutic options is accompanied by increased blood serotonin levels (Herve et al., 1995; Lederer et al., 2008). Fenfluramine, a substance which releases serotonin from neurons and thereby efficiently suppresses appetite also releases it from platelets and thereby induces PAH as unwanted side effect.
The rate-limiting enzyme in serotonin synthesis is tryptophan hydroxylase (TPH). There are two independent serotonin systems in the body characterized by two isoforms of TPH, TPH1 and TPH2. While TPH2 synthesizes serotonin in the brain, TPH1 is expressed in the gut and in other peripheral tissues and supplies platelets in the circulation with serotonin. This duality of the serotonin system is enforced by the blood-brain barrier which is impermeable for serotonin. In the brain serotonin acts as neurotransmitter and is a main target for the treatment of psychiatric disorders. In the periphery it is released by platelets at the site of activation and elicits numerous physiological effects. TPH1 deficient mice were shown to be protected from diverse diseases including hemostatic, inflammatory, fibrotic, gastrointestinal, and metabolic disorders and therefore serotonin synthesis inhibition emerged as a reasonable therapeutic paradigm. Recently the first TPH inhibitor, telotristat ethyl, came on the market for the treatment of carcinoid syndrome. This review summarizes the state of development and the therapeutic opportunities of such compounds.
Comparison of pre-analytical conditions for quantification of serotonin in platelet-poor plasma
2019, Practical Laboratory Medicine
Citation Excerpt :
In the present study we compared different pre-analytical methods described in publications that presents low serotonin concentrations in PPP from healthy individuals; Yubero-Lahoz et al. [8] reporting a mean serotonin PPP concentration of 0.62 ± 0.12 ng/mL (N = 15), Lederer et al. [10], who prepared PPP as advised by IBL [7], reported a mean plasma serotonin concentration of 0.11 ng/mL (N = 6) and Frost et al. [9] reported mean serotonin PPP concentration of 3.51 ± 0.49 ng/mL (N = 18). We do however suspect that there may be a calculation error in the paper by Lederer et al. [10], since Lederer et al. give the value as 1.3 nmol/L when discussing the 97th percentile value given in the IBL kit literature, when it is actually stated as 7.5 ng/mL by IBL (equal to 42.5 nmol/L, using the correct conversion factor of 5.67 to go from ng/mL to nmol/L). Thus, it appears that when converting from ng/mL to nmol/L, Lederer et al. divided their ng/mL results by 5.67 instead of multiplying by 5.67, and thus, the reported value of Lederer of 0.63 nmol/L (~0.11 ng/mL) was probably actually 20 nmol/L (~3.5 ng/mL).
Reported concentrations of serotonin in platelet-poor plasma (PPP) in healthy subjects vary widely due to different pre-analytical procedures.
To examine how different pre-analytical conditions affect the measured concentration of serotonin in PPP.
Six pre-analytical protocols were compared for preparation of PPP from EDTA whole blood for quantification of serotonin from nine healthy individuals. Three combinations of centrifugation with a mild centrifugation of gel-free EDTA tubes followed by a stronger centrifugation were compared to single-stage centrifugation of EDTA tubes with separator gel and heat shock treatment of blood prior to centrifugation. All samples were analysed using the same enzyme linked immunosorbent assay (ELISA) method.
Findings show that two consecutive centrifugations; first a mild centrifugation at 100 or 200×g followed by centrifugation at 4500 or 14500×g resulted in the lowest serotonin concentration in PPP.
Two successive centrifugations to produce PPP for serotonin analysis; first a mild centrifugation to avoid mechanical stress on the platelets, and next a stronger centrifugation to remove platelets, is superior to the use of gel tubes and heat shock treatment.
Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension
2016, Journal of the American College of Cardiology
Citation Excerpt :
Serotonin (5-hydroxytryptamine) and the serotonin metabolite 5-hydroxyindoleacetic acid are tryptophan metabolites formed in pulmonary artery endothelial cells by TH (Figure 4A). These metabolites may contribute to pulmonary vasoconstriction and proliferation of pulmonary artery smooth muscle cells, but their storage in platelets and low abundance in plasma make them challenging and often unreliable to measure as PH biomarkers (2,34). Plasma levels of TCA cycle intermediates, like IDO-TMs, were closely associated with hemodynamic indexes of RV-PV function in our study.
Pulmonary hypertension and associated right ventricular (RV) dysfunction are important determinants of morbidity and mortality, which are optimally characterized by invasive hemodynamic measurements.
This study sought to determine whether metabolite profiling could identify plasma signatures of right ventricular-pulmonary vascular (RV-PV) dysfunction.
We measured plasma concentrations of 105 metabolites using targeted mass spectrometry in 71 individuals (discovery cohort) who underwent comprehensive physiological assessment with right-sided heart catheterization and radionuclide ventriculography at rest and during exercise. Our findings were validated in a second cohort undergoing invasive hemodynamic evaluations (n = 71), as well as in an independent cohort with or without known pulmonary arterial (PA) hypertension (n = 30).
In the discovery cohort, 21 metabolites were associated with 2 or more hemodynamic indicators of RV-PV function (i.e., resting right atrial pressure, mean PA pressure, pulmonary vascular resistance [PVR], and PVR and PA pressure-flow response [ΔPQ] during exercise). We identified novel associations of RV-PV dysfunction with circulating indoleamine 2,3-dioxygenase (IDO)–dependent tryptophan metabolites (TMs), tricarboxylic acid intermediates, and purine metabolites and confirmed previously described associations with arginine–nitric oxide metabolic pathway constituents. IDO-TM levels were inversely related to RV ejection fraction and were particularly well correlated with exercise PVR and ΔPQ. Multisite sampling demonstrated transpulmonary release of IDO-TMs. IDO-TMs also identified RV-PV dysfunction in a validation cohort with known risk factors for pulmonary hypertension and in patients with established PA hypertension.
Metabolic profiling identified reproducible signatures of RV-PV dysfunction, highlighting both new biomarkers and pathways for further functional characterization.
Key role of the RhoA/Rho kinase system in pulmonary hypertension
2011, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
The mechanism by which this occurs has not been well characterised, but GEF activation facilitates the exchange of GDP-bound RhoA for GTP-bound RhoA, rendering RhoA active. GTP-bound RhoA then translocates from the cytosol to the membrane to interact with downstream targets [15], thus eliciting cellular responses. There is also evidence that Ca2+, acting though calmodulin, can activate RhoA [16].
Pulmonary hypertension (PH) is a general term comprising a spectrum of pulmonary hypertensive disorders which have in common an elevation of mean pulmonary arterial pressure (mPAP). The prototypical form of the disease, termed pulmonary arterial hypertension (PAH), is a rare but lethal syndrome with a complex aetiology characterised by increased pulmonary vascular resistance (PVR) and progressive elevation of mPAP; patients generally die from heart failure. Current therapies are inadequate and median survival is less than three years. PH due to chronic hypoxia (CH) is a condition separate from PAH and is strongly associated with chronic obstructive pulmonary disease (COPD). An early event in the pathogenesis of this form of PH is hypoxic pulmonary vasoconstriction (HPV), an acute homeostatic process that maintains the ventilation–perfusion ratio during alveolar hypoxia. The mechanisms underlying HPV remain controversial, but RhoA/Rho kinase (ROK)-mediated Ca²⁺-sensitisation is considered important. Increasing evidence also implicates RhoA/ROK in PASMC proliferation, inflammatory cell recruitment and the regulation of cell motility, all of which are involved in the pulmonary vascular remodelling occurring in all forms of PH. ROK is therefore a potential therapeutic target in treating PH of various aetiologies. Here, we examine current concepts regarding the aetiology of PAH and also PH due to CH, focusing on the contribution that RhoA/ROK-mediated processes may make to their development and on ROK inhibitors as potential therapies.
Pulmonary apelin levels and effects in rats with hypoxic pulmonary hypertension
2009, Respiratory Medicine
Citation Excerpt :
However, measurements of endothelin-1 are complicated by intrapersonal variability,3 a short half life in plasma and pulmonary clearance.4 A few studies on plasma concentrations of serotonin have reported conflicting results of elevated5 and normal6 concentrations in patients with severe pulmonary hypertension. NO is difficult to measure in the blood, and the second messenger cGMP is also regulated by the natriuretic peptides.4
The peptide apelin is localised in the vascular endothelium and highly expressed in pulmonary tissue. The aim of this study was to investigate whether apelin could be a potential lung-derived plasma marker for pulmonary hypertension, and study the effect of apelin in pulmonary arteries.
Apelin protein levels were measured in the lung, right ventricle, and plasma from normoxic and chronic hypoxic rats with pulmonary hypertension. Isolated intrapulmonary arteries were mounted in microvascular myographs and the effect of apelin investigated. Finally, the distribution of apelin receptors in pulmonary tissue was visualised by immunohistochemistry.
Total pulmonary apelin content was not changed by hypoxia. Right ventricular apelin concentrations and content were lower than in the lung, but increased substantially in hypoxia in correlation with right ventricular pressure. Plasma apelin did not reflect pulmonary or right ventricular apelin levels. In pulmonary arteries from normoxic rats, apelin inhibited vasoconstriction to endothelin-1 and angiotensin-II. However, in arteries from hypoxic rats, apelin failed to inhibit contraction to angiotensin-II and endothelin-1. No difference in immunoreaction for apelin receptors was found in lung sections and arteries from normoxic versus chronic hypoxic rats.
Apelin changes in the right ventricle seem more specific for pulmonary hypertension than do changes in pulmonary tissue, which does not speak in favour of apelin as a lung-derived marker for this disease. During normoxic conditions, apelin has a modulating effect on vasoconstriction which is lost in chronic hypoxia. This may reflect alterations in the signal transduction downstream of the apelin receptor.
Serotonin transporter polymorphisms in patients with portopulmonary hypertension
2009, Chest
The long allele of a functional promoter polymorphism in the serotonin transporter (SERT) is associated with an increased risk of some forms of pulmonary arterial hypertension. We hypothesized that the long allele or other polymorphisms in SERT would be associated with an increased risk of portopulmonary hypertension (PPHTN) in patients with advanced liver disease.
We performed a multicenter case-control study. Subjects undergoing liver transplant evaluation at seven centers were prospectively screened for the presence of PPHTN using transthoracic echocardiography. PPHTN was confirmed by right heart catheterization using standard criteria.
The study sample included 30 case patients with PPHTN and 109 control subjects with advanced liver disease. There was no significant association between the long allele and case status in an adjusted additive model (odds ratio, 0.63; 95% confidence interval, 0.33 to 1.21; p = 0.17). If anything, LL genotype tended to be associated with a lower risk of PPHTN. There were no associations between other SERT polymorphisms and PPHTN.
SERT polymorphisms are not associated with the risk of PPHTN in patients with advanced liver disease. Other clinical or genetic risk factors may play a role in this complication of portal hypertension.

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^☆: Funded by NIH HL67771, HL072739, HL082895, and RR00645.

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Plasma serotonin levels are normal in pulmonary arterial hypertension☆

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgments

Am J Med

Ann Allergy Asthma Immunol

J Chromatogr B Biomed Sci Appl

Am J Cardiol

Pulm Pharmacol Ther

High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy

Arterioscler Thromb Vasc Biol