Primary Pulmonary Hypertension Patients Research Articles

Pediatric lung transplant: do primary pulmonary hypertension patients have worse outcome?

High mortality risk has been reported for primary pulmonary hypertension (PPH) pts undergoing lung transplantation (LTx). Do PPH children have worse outcomes after LTx than cystic fibrosis (CF) children? All pediatric PPH pts undergoing LTx at our institution were compared to CF pts undergoing LTx in the same period. Data collected: demographics, echocardiograms, ischemic times, cardiopulmonary bypass times (CPB), perioperative and 1-year survival. From 1994-2002, 10 PPH children (3M:7F; mean age at Tx 13.7 ± 3.4 years) underwent LTx. Seven were on IV prostacyclin and 3 took oral beraprost prior to Tx. There were 5 living donor double lobar lung (LDL) Txs and 5 cadaveric double LTxs. Prior to Tx, all PPH pts had severe right ventricular and right atrial dilatation with pancaking of the left ventricle. Mean tricuspid regurgitation gradient prior to Tx was 102.5 ± 18.4 mmHg (range 74-140 mm Hg). Six pts were NYHA Class III and 4 were NYHA Class IV. Mean PPH ischemic times were 148.1 ± 83.4 min (range 52.5- 294 min). Mean CPB times were 139.9 ± 40.6 min (range 85-214 min). 9 PPH pts survived the perioperative period (90%); 1 pt expired from non-specific graft failure. Of the 9 surviving pts, 1 pt is <6 months post-Tx and 8 pts have survived >1 year (100%). During the same period, 41 CF pts (22M:19F; mean age at Tx 14.9 ± 3.5 years) were transplanted. There were 34 LDL and 7 cadaveric LTxs. Mean CF ischemic times were 99.7 ± 52.6 min (range 44.5-249 min). Mean CPB times were 124.2 ± 36.2 min (range 75-260 min). Of 41 CF pts, 38 survived the perioperative period (93%). One-year CF Tx survival was 92%. There was no difference between groups in age (p = 0.33), gender distribution (p = 0.29), CPB time (p = 0.25), perioperative mortality (p = 1.0), or 1-year survival (p = 1.0). There was a significant difference in ischemic times (p = 0.02) and type of Tx surgery (p = 0.04). We conclude that pediatric PPH pts have similar perioperative and 1-year survival compared to CF pts undergoing LTx. Our findings support lung transplantation as a viable therapeutic option for pediatric PPH pts who fail to respond to medical therapy.

Epoprostenol therapy decreases elevated circulating levels of monocyte chemoattractant protein-1 in patients with primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a rare disease characterized by progressively increased resistance of the pulmonary arteries associated with vascular remodeling. Infiltration of inflammatory cells in affected vessels is a common pathological finding. Monocyte chemoattractant protein-1 (MCP-1) is recognized as a potent chemotactic and activating factor for monocytes and leukocytes, but its significance in PPH is unclear. Serum MCP-1 concentrations were measured in 16 PPH patients and the results were compared with those in 16 normal controls. MCP-1 concentrations in PPH patients (265.6+/-29.5 pg/ml) were significantly elevated compared with those in normal controls (119.6+/-6.9 pg/ml, p<0.0001). In 9 patients (3 men, 6 women; mean age, 29+/-3 years), repeated MCP-1 and hemodynamic measurements were performed prior to and during intravenous epoprostenol therapy. During a mean follow-up period of 7+/-1 months, MCP-1 concentrations were significantly reduced (288.8+/-122.8 to 185.9+/-117.5 pg/ml, p<0.01). Circulating MCP-1 concentrations are increased in PPH patients, but can alleviated by chronic intravenous epoprostenol therapy. The increase in MCP-1 might be one of the important factors responsible for the disease development in patients with PPH.

BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, in which heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR2) gene (BMPR2) have been identified. We conducted a molecular study of BMPR2 mutations in 4 Japanese families with familial PPH and 30 Japanese patients with sporadic PPH, and found 13 different mutations, of which 10 were novel, including missense (n=2), nonsense (n=4), frameshift (n=3), and splice-donor site (n=1) mutations. In total, BMPR2 mutations were found in all 4 familial PPH cases and 12 (40%) of the sporadic PPH cases. Further, a majority of the mutations found were predicted to cause premature termination, as previously reported. In the 9 mutations found in the sporadic cases, 2 were shown to be de novo, 2 were shared in multiple cases, 1 was shared with an FPPH case, and 1 was the same as previously reported in Caucasian FPPH. These results indicate that a substantial portion of Japanese PPH patients carry BMPR2 mutations with considerable heterogeneity.

Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension.

Appetite-suppressant drug fenfluramine is implicated in primary pulmonary hypertension (PPH) but the molecular pathways that mediate this effect are unknown. A mouse model incriminates the serotonin 5-HT(2B) receptor but contrasts with other models where this receptor has been shown to mediate pulmonary arterial relaxation via nitric oxide production. We analyzed the human 5-HT(2B) gene in 10 patients with appetite-suppressant drug-associated PPH. A mutation causing premature truncation of the protein product was found in one patient. The mutation was not found in 80 control subjects and no 5-HT(2B) mutation was found in 18 PPH patients not associated with appetite-suppressants. Functional analysis of the transfected receptor expressed either transiently in COS cells or stably in CHO cells demonstrated that the mutated receptor fails to activate the second messenger inositol-phosphates cascade and subsequent intracellular calcium release, in spite of normal expression at the cell membrane. The mutated receptor had no constitutive activity, and produced no dominant negative effect on the wild-type receptor. Loss of serotonin 5-HT(2B) receptor function may predispose to fenfluramine-associated PPH in man.

A novel mechanism for pulmonary arterial hypertension?

The pathophysiology of primary pulmonary hypertension (PPH) involves alterations in vascular reactivity, vascular structure, and interactions of the vessel wall with circulating blood elements.1 An imbalance of vasodilator and vasoconstrictor influences is likely to be an early derangement. Progressive intimal and medial thickening, due to proliferation and migration of vascular smooth muscle cells and fibroblasts, reduces the cross-sectional area of the pulmonary microvasculature, causing fixed alterations in pulmonary resistance. Contributing to the progressive increase in pulmonary resistance is thrombosis of the small pulmonary vessels, which explains the benefit of anticoagulation in these patients. In advanced disease, “plexiform arteriopathy” of the small pulmonary vessels is observed. These lesions proliferate into the lumen, creating high-resistance, convoluted endoluminal channels. There is some controversy regarding the nature of the cells constituting these lesions, one group suggesting they are of endothelial origin, whereas more recent evidence indicates that they are myofibroblasts.2,3 See p 1493 The normal pulmonary endothelium maintains a low vascular resistance, suppresses vascular smooth muscle growth, inhibits platelet adherence and aggregation, and stems inflammation. In patients with PPH, the endothelium has lost these vasoprotective functions.1 The endothelium of the PPH patient is characterized by the increased elaboration of vasoconstrictors, mitogens, and prothrombotic and proinflammatory mediators (such as thromboxane, endothelin, plasminogen activator inhibitor, and 5-lipooxygenase). These endothelial alterations promote the pathophysiology of PPH. Furthermore, there is less influence of the countervailing factors prostacyclin and NO. Endothelium-derived NO plays a critical role in pulmonary …

Inflammation in pulmonary arterial hypertension.

Inflammatory mechanisms appear to play a significant role in some types of pulmonary hypertension (PH), including monocrotaline-induced PH in rats and pulmonary arterial hypertension of various origins in humans, such as connective tissue diseases (scleroderma, systemic lupus erythematosus, mixed connective disease), human immunodeficiency virus infection, or plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal (M) protein and skin changes (POEMS) syndrome. Interestingly, some patients with severe pulmonary arterial hypertension associated with systemic lupus erythematosus have experienced significant improvements with immunosuppressive therapy, emphasising the relevance of inflammation in a subset of patients presenting with PH. Patients with primary PH (PPH) also have some immunological disturbances, suggesting a possible role for inflammation in the pathophysiology of this disease. A subset of PPH patients have been shown to have circulating autoantibodies, including antinuclear antibodies, as well as elevated circulating levels of the pro-infammatory cytokines, interleukins -1 and -6. Lung histology has also revealed inflammatory infiltrates in the range of plexiform lesions in patients displaying severe PPH, as well as an increased expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and fractalkine. Further analysis of the role of inflammatory mechanisms is necessary to understand whether this component of the disease is relevant to its pathophysiology.

Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31

ObjectivesThe aim of our study was to identify genetic causes of primary pulmonary hypertension (PPH), to estimate the proportion of families with mutations in the BMPR2 (bone morphogenetic protein receptor type 2) gene, and to examine whether genetic heterogeneity might play a role. BackgroundThe BMPR2 mutations have been identified in a substantial portion of patients with familial or sporadic PPH. However, the genetic cause of PPH remains unclear in at least 45% of families. MethodsWe investigated 130 members of 10 families with at least 1 PPH patient, recruited without selection for familial disease. Manifest PPH was documented in 21 individuals. An increase in pulmonary artery systolic pressure (PASP) above 40 mm Hg during supine bicycle exercise was found in 46 healthy individuals. Their PASP increased from 21.0 ± 4.6 mm Hg at rest to 54.0 ± 9.8 mm Hg during exercise. In 51 relatives, PASP values were normal at rest and during exercise, and 12 members were classified as status unknown. ResultsTwo families showed a mutation in the BMPR2 gene. Three families with no BMBR2 mutation showed evidence for linkage to a more proximal location on chromosome 2q31 (odds ratio [OR] for linkage 1.1·106:1). This locus, designated PPH2, maps in-between the markers D2S335 and D2S2314. We obtained significant support for heterogeneity in PPH with an OR of 2.8·1011. ConclusionsWe conclude that PPH may be a genetically heterogeneous disorder with at least two—and possibly more—causative genes.

Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells.

Pulmonary vascular medial hypertrophy in primary pulmonary hypertension (PPH) is mainly caused by increased proliferation and decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). Mutations of the bone morphogenetic protein (BMP) receptor type II (BMP-RII) gene have been implicated in patients with familial and sporadic PPH. The objective of this study was to elucidate the apoptotic effects of BMPs on normal human PASMCs and to examine whether BMP-induced effects are altered in PASMCs from PPH patients. Using RT-PCR, we detected six isoforms of BMPs (BMP-1 through -6) and three subunits of BMP receptors (BMP-RIa, -RIb, and -RII) in PASMCs. Treatment of normal PASMCs with BMP-2 or -7 (100-200 nM, 24-48 h) markedly increased the percentage of cells undergoing apoptosis. The BMP-2-mediated apoptosis in normal PASMCs was associated with a transient activation or phosphorylation of Smad1 and a marked downregulation of the antiapoptotic protein Bcl-2. In PASMCs from PPH patients, the BMP-2- or BMP-7-induced apoptosis was significantly inhibited compared with PASMCs from patients with secondary pulmonary hypertension. These results suggest that the antiproliferative effect of BMPs is partially due to induction of PASMC apoptosis, which serves as a critical mechanism to maintain normal cell number in the pulmonary vasculature. Inhibition of BMP-induced PASMC apoptosis in PPH patients may play an important role in the development of pulmonary vascular medial hypertrophy in these patients.

Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: increased frequency and association with preserved haemodynamics.

HYPOTHESIS/INTRODUCTION: A polymorphic marker within the angiotensin- converting enzyme (ACE) gene has been associated with circulating and tissue ACE activity and with a variety of forms of cardiovascular disease. Since angiotensin II (Ang II) causes pulmonary vasoconstriction and vascular and myocardial remodelling, we postulated a role for the renin-angiotensin system and the ACE DD genotype in the pathophysiology of primary pulmonary hypertension (PPH) and in the right ventricular response to pressure overload in these patients. The incidence of the ACE DD genotype was evaluated in 60 patients with severe PPH compared with two normal control populations, a group of healthy population-based controls (n=158) and subjects found suitable for cardiac organ donation (n=79). Genomic DNA extracted from peripheral leukocytes was amplified using the polymerase chain reaction to detect polymorphic markers. Haemodynamics were determined by right heart catheterisation in a subset of the PPH patients. The frequency of the ACE DD genotype was 45% in the patients with PPH, compared with 24% in the organ donors, and 28% in population-based healthy controls (p=0.01 for chi-square test). Of the 32 PPH patients with baseline haemodynamics, 12 exhibited the ACE DD genotype and 20 were non-DD. While the mean pulmonary artery pressure and the duration of symptoms attributable to pulmonary hypertension was not different between the DD and non-DD groups, cardiac output was significantly lower (3.29+0.27 vs. 5.07+0.37 L/minute, p=0.002) and the mean right atrial pressure tended to be higher (8.85+1.29 vs. 4.92+1.27 mmHg, p=0.08) in the non-DD group. The reduction in cardiac output seen in the non-DD group was not due to a difference in heart rate, but to a significant reduction in stroke volume, consistent with a decreased contractile state. In addition, non-DD patients exhibited a significantly worse functional capacity (NYHA Class 3.14+0.12 vs. 2.40+0.28, p=0.02). 1) The ACE DD genotype is significantly increased in patients with severe PPH compared with normal controls, suggesting that certain individuals may be genetically predisposed to developing pulmonary hypertension. 2) The ACE DD genotype is associated with preserved right ventricular function in PPH patients, supporting a compensatory myocardial or inotropic role for Ang II in the pressure overloaded right ventricle.

Pulmonary function in primary pulmonary hypertension

ObjectivesThe study was done to ascertain the degree to which abnormalities in resting lung function correlate with the disease severity of patients with primary pulmonary hypertension (PPH). BackgroundPatients with PPH are often difficult to diagnose until several years after the onset of symptoms. Despite the seriousness of the disorder, the diagnosis of PPH is often delayed because it is unsuspected and requires invasive measurements. Although PPH often causes abnormalities in resting lung function, these abnormalities have not been shown to be statistically significant when correlated with other measures of PPH severity. MethodsResting lung mechanics and diffusing capacity for carbon monoxide DLcowere assessed in 79 patients whose findings conformed to the classical diagnostic criteria of PPH and who had no evidence of secondary causes of pulmonary hypertension. These findings were correlated with severity of disease as assessed by cardiac catheterization, New York Heart Association (NYHA) class, and cardiopulmonary exercise testing. ResultsWhen PPH patients were first evaluated at our referral clinic, the DLcoand lung volumes were decreased in approximately three-quarters and one-half, respectively. The decreases in DLco, and to a lesser extent lung volumes, correlated significantly with decreases in peak oxygen uptake (reflecting maximum cardiac output), peak oxygen pulse (reflecting maximum stroke volume), and anaerobic threshold (reflecting sustainable exercise capacity) and higher NYHA class. ConclusionsPatients with PPH commonly have abnormalities in lung mechanics and DLcolevels that correlate significantly with disease severity. These measurements can be useful in evaluating patients with unexplained dyspnea and fatigue.

Endothelin-1 and functional tissue factor: a possible relationship with severity in primary pulmonary hypertension.

Although dysfunctional endothelium, vasoconstriction, and in situ thrombosis are characteristics of primary pulmonary hypertension, the role that plasma vasomotor and coagulation factors play in this phenomenon are not completely understood. The aim of this work was to ascertain the diagnostic value of endothelin-1, thrombomodulin, tissue factor, and tissue factor pathway inhibitor, as well as their correlation with endothelial dysfunction in primary pulmonary hypertension patients. We analyzed the plasmatic concentration and chromogenic of the above-mentioned molecules using immunoenzymatic techniques. Patients were divided into responders and nonresponders on the basis of their hemodynamic response to a vasodilator trial. We found a continuous increase in endothelin-1 levels and a continuous decrease in functional tissue factor in the control group, responders, and nonresponders, respectively. Moreover, the patients showed a moderate decrease in thrombomodulin levels compared with the control group, without statistical significance. These results support a previous description of a decrease in thrombomodulin levels in primary pulmonary hypertension patients and suggests that an alteration of endothelin-1 and functional tissue factor could be related to a worsening of endothelial function and, indirectly, with the clinical severity of primary pulmonary hypertension.

Therapy with prostanoids and transplantation in patients with primary pulmonary hypertension

Without treatment, patients with primary pulmonary hypertension (PPH) survive less than 3 years after diagnosis. We assessed the outcome of PPH patients with transplantation (Tx) and pre-transplant use of prostanoids.

Therapy for primary pulmonary hypertension.

Therapy for primary pulmonary hypertension.

Genetics and Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is a serious pulmonary vascular disease occurring mostly in adult women. Although its occurrence in families was reported within a few years after the original clinical report, PPH was formerly believed rarely to have a genetic basis. Recent progress has not only clarified a basic molecular mechanism for PPH in families, but has also identified mutations of the same gene in many sporadic PPH patients, suggesting that its basis is commonly genetic. Extensive investigations in many centers are now in progress to provide a complete dissection of all the pathogenetic mechanisms of PPH.

Primary pulmonary hypertension: Current therapy

Because the causes of primary pulmonary hypertension (PPH) remains unknown, the therapeutic approach of the disease can be only empirical, based on the pathology and pathobiology of pulmonary circulation. Despite the inability to cure the disease, therapeutic advances over the past 20 years have contributed to an improvement of quality of life and prolonged survival in PPH patients. Current therapeutic approach of PPH mostly includes limitation of physical activity, long-term anticoagulation, and vasodilator therapy. Among all tested oral vasodilators, calcium-channel blockers are the most efficient long-term therapies by improving symptoms and hemodynamics in a subset of PPH patients (10% to 15%) who acutely respond to such drugs. Acute pulmonary vasodilator response to inhalation of nitric oxide can predict acute and chronic responses to oral calcium-channel blockers. A better understanding of the pathogenesis of PPH has changed the focus of medical treatments from purely chronic vasodilator therapy to the evaluation of agents, such as prostaglandins, that may reverse the proliferation of pulmonary vascular cells and result in regression of the pulmonary vascular hypertrophy and remodeling. Long-term treatment with intravenous epoprostenol (prostaglandin I 2 or prostacyclin) improves exercise capacity, hemodynamics and survival in most patients with PPH in functional class NYHA III or IV, and may be currently considered as the “gold standard” therapy for severe patients. However, response to long-term epoprostenol therapy may be incomplete, adverse effects are common, and survival remains unsatisfactory (55% at 5 years). In such patients with severe pulmonary hypertension refractory to medical therapy, atrioseptostomy and lung transplantation can be indicated. Copyright 2002, Elsevier Science (USA). All rights reserved. Progress in Cardiovascular Diseases, Vol. 45, No. 2, (September/October) 2002: pp 115-128

Circulating Monocytes from Patients with Primary Pulmonary Hypertension Are Hyporesponsive

Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology characterized by arterial thickening and remodeling. The transcription factor NF-κB is responsible for the activation of several cytokines and growth factor genes reported to be associated with PPH. Our previous study showed NF-κB activation in alveolar macrophages from PPH patients, suggesting the presence of a localized pulmonary inflammatory response. In PPH, circulating monocyte activity has not been previously examined. The present study was undertaken to determine whether circulating monocytes also showed evidence of activation, which could suggest a systemic response to PPH injury. Results indicated that NF-κB activation in monocytes from PPH patients did not differ from that of healthy controls. However, mRNA expression was decreased compared to controls for NF-κB-regulated genes, granulocyte macrophage colony-stimulating factor, interleukin-6, macrophage inflammatory protein-1α (MIP-1α), and vascular endothelial growth factor. MIP-1α protein secretion from PPH monocytes was also lower than that of controls cultured with and without endotoxin. Expression of the surface activation markers HLA-DR and CD-14 were significantly reduced on monocytes from PPH patients compared to healthy controls. Toll-like receptor-4 (TLR-4) expression was significantly increased on monocytes from PPH patients while TLR-2 remained unchanged. Thus, our data are the first to show that monocytes in PPH have decreased activation and are hyporesponsive to lipopolysaccharide (LPS) stimulation. The monocyte LPS hyporesponsiveness may in part be the result of decreased CD-14 expression, since LPS responsiveness is dependent on the physical association of LPS/CD-14 complexes with TLR-4, and without this association signal transduction does not occur. These data indicate that although PPH is a localized pulmonary disorder, there are alterations in the systemic compartment. What remains unknown is how the reduced activation of monocytes in PPH is related to the pulmonary vascular lesion.

Elevation of ELISA D-Dimer Levels in Patients with Primary Pulmonary Hypertension

Background: Vasoconstriction, vascular wall remodeling and thrombosis are considered as possible etiologies of primary pulmonary hypertension (PPH). D-dimer, a degradation product of fibrin, has been increasingly used as a marker and prognostic factor in various diseases. Objective: To assess elevated ELISA D-dimer levels as a marker of endogenous fibrinolysis in patients with PPH. Patients and Methods: Comparison of ELISA D-dimer levels of 12 PPH patients (11 female, 1 male) aged 27–73 years (median 51 years) with those of sex- and age-matched healthy controls. Results: Eleven patients had New York Heart Association (NYHA) class III or IV symptoms, and one patient had NYHA class II symptoms. All patients with PPH were treated with anticoagulants and vasodilators: 5 patients were treated with continuous intravenous prostacyclin, 4 patients with continuous UT-15 and 2 patients with intermittent intravenous iloprost. Mean ELISA D-dimer levels ± SD were significantly higher in the PPH group than in the matched control group (473 ± 109 vs. 182 ± 103 ng/ml; mean difference: 291 ± 79, 95% CI: 240–341, p < 0.0001). Conclusion: These results suggest the possible involvement of endogenous fibrinolysis in the pathophysiology of PPH.

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH). Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31. The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.

Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension.

Because of high pulmonary vascular resistance in patients with primary pulmonary hypertension (PPH), right atrial pressure may exceed left atrial pressure during exercise, resulting in a right-to-left shunt via a patent foramen ovale (PFO). This shunting would disturb arterial PCO2 and H+ homeostasis if the pulmonary blood were not simultaneously hyperventilated to compensate for the high CO2 and H+ in the shunted blood. This article first hypothesizes and then describes unique changes in gas exchange when right-to-left exercise-induced shunting (EIS) occurs. Retrospectively, the cardiopulmonary exercise tests of 71 PPH patients were studied. Criteria postulated to document hyperventilation of the pulmonary blood flow due to a right-to-left EIS were (1) an abrupt and sustained increase in end-tidal O2 with a simultaneous sustained decrease in end-tidal CO2; (2) an abrupt and sustained increase in the respiratory exchange ratio; and (3) usually, an associated decline in pulse oximetry saturation. Each patient was evaluated for a PFO with resting echocardiography. The investigators interpreting the gas exchange evidence of EIS were blinded to the echocardiographic readings. Forty-five percent of the patients had demonstrable EIS by gas exchange criteria. Almost all were also positive for a PFO by echocardiography. Using the resting echocardiograph as the reference, the sensitivity, specificity, positive and negative predictive values, and accuracy were all between 90% to 96%. Exercise-induced right-to-left shunting can be detected by noninvasive, cardiopulmonary exercise testing in patients with PPH.

Increased Levels of Prostaglandin D2 Suggest Macrophage Activation in Patients With Primary Pulmonary Hypertension

TXA(2) (thromboxane A(2)) is a lipid mediator believed to be produced primarily by platelets in normal subjects, although macrophages are capable of synthesis. There is increased production of TXA(2) in patients with primary pulmonary hypertension (PPH), which may reflect augmented production by macrophages. The objective of this study was to determine if macrophages are activated in PPH and whether they contribute to the increased production of TXA(2). Case control. University hospital. We measured the urinary metabolites of three mediators that predominantly derive from different cell types in vivo: (1) TX-M (platelets and macrophages), a TXA(2) metabolite; (2) prostaglandin D(2) (PGD(2)) metabolite (PGD-M); and (3) N-methylhistamine (mast cells), a histamine metabolite, in 12 patients with PPH and 11 normal subjects. The mean (+/- SEM) excretion of both TX-M and PGD-M at baseline was increased in PPH patients, compared to normal subjects (460 +/- 50 pg/mg creatinine vs 236 +/- 16 pg/mg creatinine [p = 0.0006], and 1,390 +/- 221 pg/mg creatinine vs 637 +/- 65 pg/mg creatinine [p = 0.005], respectively). N-methylhistamine excretion was not increased compared to normal subjects. There was a poor correlation between excretion of TX-M and PGD-M (r = 0.36) and between excretion of PGD-M and methylhistamine (r = 0.09) in individual patients. In patients with PPH, increased levels of PGD-M, without increased synthesis of N-methylhistamine, suggest that macrophages are activated. The lack of correlation between urinary metabolite levels of TXA(2) and PGD(2) implies that macrophages do not contribute substantially to elevated TXA(2) production in patients with PPH. They may, however, have a role in the pathogenesis and/or maintenance of PPH, which warrants further investigation.