Pathology Of Pulmonary Arterial Hypertension Research Articles

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

The phosphodiesterase-5 inhibitor vardenafil reduces oxidative stress while reversing pulmonary arterial hypertension

Oxidative stress is implicated in the pathology of pulmonary arterial hypertension (PAH). Previously, we demonstrated that vardenafil, a phosphodiesterase-5 inhibitor, has potential as therapy for PAH, although the mechanism remained uncharacterized. Here, we aimed to determine baseline levels of oxidative stress in PAH and investigate whether vardenafil affects oxidative stress levels while improving PAH. Sprague-Dawley rats with monocrotaline-induced PAH were administered oral vardenafil 1 mg kg⁻¹ day⁻¹ for 21 days (n = 12). Treatment-naive patients (n = 15) with PAH were treated with vardenafil 5 mg twice daily for 3 months. Haemodynamic data and plasma levels of nitrate/nitrite and products of oxidative damage were determined in rats and patients. Histopathology, immunohistochemistry, and assessments of oxidative/anti-oxidative enzyme expression were performed in rat lung tissue. Compared with baseline (patients) or untreated controls (rats), vardenafil significantly reduced pulmonary vascular resistance and increased cardiac output (CO). In rats, vardenafil suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodelling, and right ventricular hypertrophy. Vardenafil significantly reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2α and 3-nitrotyrosine, and significantly increased nitric oxide (NO) levels in rats and patients. Furthermore, vardenafil significantly increased endothelial NO synthase expression and superoxide dismutase activity, and down-regulated nicotinamide adenine dinucleotide phosphate oxidase expression in rat lung tissue. Vardenafil reduces oxidative stress in rats and humans while improving PAH, warranting investigation of oxidative stress pathways as targets for PAH therapy.

Microparticles from PAH animals increase adhesion molecule expression in the pulmonary microcirculation

Microparticles (MPs) are submicron vesicles released by cells into the circulation. Once generated, MPs can activate cells downstream. MP counts are increased in many diseases, including pulmonary arterial hypertension (PAH). We investigated whether MPs from animals with PAH stimulate the expression of adhesion molecules in pulmonary endothelium. The Sugen/Hypoxia/Normoxia rat model was used in this study. This model develops vascular lesions which are characteristic of the human PAH pathology. MPs were isolated from the blood of control, Sugen only, and PAH animals. Pulmonary artery endothelial cells (PAECs) and pulmonary microvascular endothelial cells (MVECs) were treated with serum free media with or without MPs for 24 hours. Cells were then lysed. ICAM‐1 and E‐selectin expression was measured by western blotting. No changes were observed in ICAM‐1 expression in PAECs exposed to serum free media, control MPs, Sugen MPs, or PAH MPs. However, preliminary data suggests that both ICAM‐1 and E‐selectin expression are increased in MVECs exposed to MPs from PAH animals. E‐selectin appears to be increased in PAECs in response to control and PAH MPs. Our data suggests that PAECs and MVECs respond differently to MPs from PAH animals. These findings highlight the heterogeneity of endothelial cells in the pulmonary circulation and could indicate that MPs impact the homeostasis of the pulmonary microcirculation in PAH.This research is funded by AHA 11 (SDG7390037) Grant and NHLBI T32 (HL076125) Training Grant.

Role of Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a relentless course toward heart failure and ultimately death [1-3]. Although existing therapies improve patients’ quality of life and symptoms, none of the currently approved therapies can reverse the disease or significantly reduce mortality. The treatment is also extremely expensive and often associated with side effects. As such, furthering our understanding of the mechanisms and pathology of PAH is important to support more effective therapeutic target identification.

Evolving Management of Pediatric Pulmonary Arterial Hypertension: Impact of Phosphodiesterase Inhibitors

The treatment of pulmonary arterial hypertension (PAH) has undergone significant change in recent years, improving both quality of life and survival for patients. One of the principal new agents is sildenafil, a phosphodiesterase-V inhibitor with great PAH efficacy. Its success has led to consideration of other phosphodiesterase inhibitors not yet licensed for pediatric PAH including tadalafil and vardenafil, among others. This article summarizes the evidence base for phosphodiesterase inhibitors used to ameliorate pediatric PAH pathology and associated symptoms. It also analyzes their suitability for contemporary practice with the aim of clarifying and helping to direct regimens that produce improved patient outcomes.

Pulmonary arterial hypertension: bridging the present to the future

The past decade has witnessed extensive progress in basic and clinical research in the field of pulmonary hypertension (PH), a group of chronic conditions characterised by high pressure in the pulmonary circulation. National and international PH registries have achieved much to advance our understanding of the epidemiology, demographics, aetiology, clinical course, haemodynamics, disease management and treatment outcomes of PH [1–7]. Therapies available to target the pathology of pulmonary arterial hypertension (PAH) have expanded considerably and more options are expected in the near future [8, 9]. Although this progress has steadily improved the outlook for PAH patients, there remains a need for further developments to ensure that advances continue to be made. The articles and case reports in this issue of the European Respiratory Review discuss key and current issues in the management of patients with PH. The authors, all experts in the field of PH, delivered the presentations upon which the articles are based at the 11th International Pulmonary Hypertension Forum in Dublin, Ireland on May 12–13, 2012. This annual platform for the exchange of knowledge and experience among clinicians and researchers was attended by over 1,000 healthcare professionals from all over the world, highlighting the continuing interest in this devastating group of diseases. The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines provide a clear classification of the major clinical subcategories of PH [10, 11], based on shared pathophysiological mechanisms, similar clinical presentations and therapeutic approaches [12]. It is Group 1 PH, namely PAH, that has been subject to the most rapid advancement in terms of knowledge and treatment options in the past decade. Because this group of patients is treatable, accurate and prompt diagnosis are particularly critical; PAH patients receiving treatment in World …

Imatinib Attenuates Hypoxia-induced Pulmonary Arterial Hypertension Pathology via Reduction in 5-Hydroxytryptamine through Inhibition of Tryptophan Hydroxylase 1 Expression

Whether idiopathic, familial, or secondary to another disease, pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, neointimal hyperplasia, medial hypertrophy, and adventitial fibrosis. Imatinib, a potent receptor tyrosine kinase inhibitor, reverses pulmonary remodeling in animal models of PAH and improves hemodynamics and exercise capacity in selected patients with PAH. Here we use both imatinib and knockout animals to determine the relationship between platelet-derived growth factor receptor (PDGFR) and serotonin signaling and investigate the PAH pathologies each mediates. We investigated the effects of imatinib (100 mg/kg) on hemodynamics, vascular remodeling, and downstream molecular signatures in the chronic hypoxia/SU5416 murine model of PAH. Treatment with imatinib reduced all measures of PAH pathology observed in hypoxia/SU5416 mice. In addition, 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) expression were reduced compared with the normoxia/SU5416 control group. Imatinib attenuated hypoxia-induced increases in Tph1 expression in pulmonary endothelial cells in vitro via inhibition of the PDGFR-β pathway. To better understand the consequences of this novel mode of action for imatinib, we examined the development of PAH after hypoxic/SU5416 exposure in Tph1-deficient mice (Tph1(-/-)). The extensive changes in pulmonary vascular remodeling and hemodynamics in response to hypoxia/SU5416 were attenuated in Tph1(-/-) mice and further decreased after imatinib treatment. However, imatinib did not significantly further impact collagen deposition and collagen 3a1 expression in hypoxic Tph1(-/-) mice. Post hoc subgroup analysis suggests that patients with PAH with greater hemodynamic impairment showed significantly reduced 5-HT plasma levels after imatinib treatment compared with placebo. We report a novel mode of action for imatinib, demonstrating TPH1 down-regulation via inhibition of PDGFR-β signaling. Our data reveal interplay between PDGF and 5-HT pathways within PAH, demonstrating TPH1-dependent imatinib efficacy in collagen-mediated mechanisms of fibrosis.

The Estrogen Puzzle in Pulmonary Arterial Hypertension

> New Scientist: What do you think most about during the day? > > Stephen Hawking: Women. They are a complete mystery. > > —Stephen Hawking at 70 – exclusive interview at the New Scientist, Jan 4, 2012 The biology of pulmonary arterial hypertension (PAH) is full of mysteries, and one of its longer-standing ones has also intrigued and inspired both scientists and artists throughout history: the female sex. Although affecting patients of all ages and both sexes, PAH preferentially affects young women, suggesting that the female sex is a risk factor for PAH. Even in heritable PAH associated with autosomal dominant mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2), women after puberty are ≈2.5 times more likely to develop PAH than males.1 In idiopathic PAH the female/male ratio ranges from 1.7:1 or 1.9:1 to 4.1:1 in 3 published PAH registries (the National Institutes of Health registry in the 80s,2 the French registry,3 and the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL),4 respectively). On the other hand, the disease can be more severe in men. Female animals with PAH tend to have lower pulmonary artery pressures and better outcomes compared with males,5 and similarly, male PAH patients have higher mortality than females.6 The basis for this apparent paradox remains unknown. Article see p 1087 Estrogens exert their effects through both genomic effects, by activating their cytosolic or membrane-bound receptors, and nongenomic effects, by activating membrane G protein–coupled estrogen receptors. For example, via the nongenomic effects, estrogens promote the release of both prostacyclin and nitric oxide while, via the genomic effects, they decrease the expression of endothelin 1 under hypoxia, all promoting vasoconstriction in the pulmonary circulation.5 Yet, the pathology of PAH is driven not by vasoconstriction, but rather by a proproliferative and antiapoptotic diathesis throughout the pulmonary arterial wall. The main circulating estrogen in …

Severe Pulmonary Arterial Hypertension Induced by SU5416 and Ovalbumin Immunization

The combination of chronic hypoxia and treatment of rats with the vascular endothelial growth factor (VEGF) receptor blocker, SU5416, induces pulmonary angio-obliteration, resulting in severe pulmonary arterial hypertension (PAH). Inflammation is thought to contribute to the pathology of PAH. Allergic inflammation caused by ovalbumin (OVA) immunization causes muscularization of pulmonary arteries, but not severe PAH. Whether disturbance of the immune system and allergic inflammation in the setting of lung endothelial cell apoptosis causes PAH is unknown. We investigated the effects of OVA-allergic inflammation on the development of PAH initiated by VEGF blockade-induced lung endothelial cell apoptosis. OVA-immunized rats were treated with SU5416 to induce pulmonary vascular endothelial cell apoptosis. The combination of OVA and SU5416 treatment resulted in severe angio-obilterative PAH, accompanied by increased IL-6 expression in the lungs. c-Kit(+) and Sca-1(+) cells were found in and around the lung vascular lesions. Pan-caspase inhibiton, dexamethasone treatment, and depletion of B-lymphocytes using an anti-CD20 antibody suppressed this remodeling. OVA immunization also increased lung tissue hypoxia-induced factor-1α and VEGF expression. Our results also suggest that the increased expression of hypoxia-induced factor-1α and IL-6 induced by the allergic lung inflammation may be a component of the pathogenesis of PAH.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

A novel murine model of severe pulmonary arterial hypertension.

The complex pathologies associated with severe pulmonary arterial hypertension (PAH) in humans have been a challenge to reproduce in mice due to the subtle phenotype displayed to PAH stimuli. Here we aim to develop a novel murine model of PAH that recapitulates more of the pathologic processes, such as complex vascular remodeling and cardiac indices, that are not characteristic of alternative mouse models. Inhibition of vascular endothelial growth factor receptor (VEGFR) with SU5416 combined with 3 weeks of chronic hypoxia was investigated. Hemodynamics, cardiac function, histological assessment of pulmonary vasculature, and molecular pathway analysis gauged the extent of PAH pathology development. The combination of VEGFR inhibition with chronic hypoxia profoundly exacerbated all measures of PAH-like pathology when compared with hypoxia alone (> 45 mm Hg right ventricular pressure, > 0.35 right ventricular hypertrophy). The changes in pulmonary vascular remodeling in response to hypoxia were further enhanced on SU5416 treatment. Furthermore, hypoxia/SU5416 treatment steadily decreased cardiac output, indicating incipient heart failure. Molecular analysis showed a dysregulated transforming growth factor-β/bone morphogenetic protein/Smad axis in SU5416- and/or hypoxia-treated mice as well as augmented induction of IL-6 and Hif-1α levels. These changes were observed in accordance with up-regulation of Tph1 and Pdgfr gene transcripts as well as a rise in platelet-rich serotonin. Biomarker analysis in response to VEGFR inhibition and/or hypoxia revealed distinct signatures that correlate with cytokine profiles of patients with idiopathic PAH. These data describe a novel murine model of PAH, which displays many of the hallmarks of the human disease, thus opening new avenues of investigation to better understand PAH pathophysiology.

Suppression of tissue inhibitors of metalloproteinases may reverse severe pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary vascular resistance and vascular remodeling leading to right heart failure and early death. The pathology of PAH is associated with endothelium dysfunction and vascular remodeling in pulmonary arteries. In diseased pulmonary arteries, the balance between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) is broken down. In this process, TIMP are up-regulated, which inhibits MMP, promotes extracellular matrix (ECM) deposition and finally leads to vascular remodeling. So, what would happen to PAH if the expression of TIMP was down-regulated in diseased pulmonary vessels? We hypothesize that the attenuation of TIMP at the advanced stage of PAH might reverse severe PAH, via ameliorating vascular remodeling and endothelium repair.

Phosphodiesterase type 5 inhibitors in the treatment of pulmonary arterial hypertension

The pathology of pulmonary arterial hypertension (PAH) is characterized by vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. Experimental studies have shown the beneficial effect of phosphodiesterase type 5 (PDE-5) inhibitors on pulmonary vascular remodeling and vasodilatation. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil which significantly improve clinical status, exercise capacity and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in management of PAH. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia.

Pharmacotherapeutic Management of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a disabling chronic disorder of the pulmonary vasculature, which is characterized by increased pulmonary artery pressure as a result of increased pulmonary vascular resistance. The pathology of PAH is characterized by pulmonary vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. These changes are a result of an imbalance between vasodilators (prostacyclin, nitric oxide, vasoactive intestinal peptide) and vasoconstrictors (thromboxane A2, endothelin, serotonin), growth inhibitors and mitogenic factors, and antithrombotic and prothrombotic factors. Recent advances in treatment are directed at restoring the balance between these systems. Endothelin receptor antagonists (bosentan, ambrisentan, sitaxsentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), and prostacylin (epoprostenol, iloprost, treprostinil, beraprost) represent the different classes of medications that are currently used in monotherapy and in combination to treat PAH. The purpose of this drug highlight is to provide the reader with an update of the pharmacotherapeutic treatment of PAH.

Role of Combination Therapy in the Treatment of Pulmonary Arterial Hypertension

As a result of the multimechanistic pathology of pulmonary arterial hypertension (PAH), combination therapy is emerging as a potential treatment option. Recent guidelines from the American College of Chest Physicians and expert consensus from the American College of Cardiology Foundation and American Heart Association do not definitively support or disapprove of combination pharmacotherapy for the treatment of PAH. Published trials have investigated different combinations including endothelin receptor antagonists with prostanoids, prostanoids with phosphodiesterase inhibitors, and phosphodiesterase inhibitors with endothelin receptor antagonists. Pertinent trials on combination pharmacotherapy for PAH were identified through a MEDLINE search of literature from 1967-2009 in addition to a manual search of references from the articles retrieved. Search results identified 12 trials that evaluated combination therapy for PAH; some included an add-on agent for patients who failed treatment with monotherapy and others were placebo controlled. Even with the published data, the overall consensus is unclear. Well-designed, larger trials with validated end points are needed to further identify when to initiate combination therapy for the treatment of PAH. Meanwhile, perhaps the most appropriate situation for using combination pharmacotherapy may be in the setting of a lack of clinical improvement or deterioration.

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1- and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1- and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11betaHSD2 (11beta-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

Computed axial tomography evidence of left atrial enlargement: a predictor of elevated pulmonary capillary wedge pressure in pulmonary hypertension

One of the commonest causes of pulmonary hypertension (PH) is left heart dysfunction associated with elevated pulmonary capillary wedge pressure (PCWP). In contrast, the pathology of pulmonary arterial hypertension (PAH) originates in the pulmonary vascular bed. Accurate diagnosis of PAH requires right heart catheterization (RHC) with normal PCWP. This study examines the role of computed tomography of the chest (CT chest) in evaluating left atrial (LA) size as an indicator of elevated PCWP in patients undergoing PH evaluation. CT chest and RHC data were reviewed in 37 subjects at the Baylor PH Center. Both subjective estimates and objective measurements of left atrial size from the CT chest were recorded separately by 3 investigators. Patients were categorized as Group I (small-normal LA) and Group II (large LA) and RHC results compared.The objective and subjective measurements were compared by receiver operator characteristic (ROC). The mean PCWP was 12 +/- 6 mmHg in Group I and 21 +/- 7 mmHg in Group II (P = 0.001). The estimated LA area was 19.4 +/- 4.9 cm(2) in Group I and 39.9 +/- 7.6 cm(2) in Group II (mean +/- SD; P < 0.001). The estimated LA area, corrected for the chest wall length, was 0.78 +/- 0.19 cm(2) and 1.65 +/- 0.26 cm(2) in Groups I and II, respectively (P < 0.001). Significant correlations were found between uncorrected PCWP and LA area (R = 0.45, P = 0.005), corrected PCWP and LA area (R = 0.47, P = 0.003), and the subjective observer impression of LA enlargement and measured PCWP (R = 0.51, P = 0.001). In this pilot study, enlarged LA area on the CT chest was associated with an elevated PCWP on RHC. For patients undergoing PH evaluation, increased LA area on CT chest could suggest left heart dysfunction in patients as a possible cause of PH.

Thrombin induces fibronectin-specific migration of pulmonary microvascular endothelial cells: requirement of calcium/calmodulin-dependent protein kinase II

Pulmonary arterial hypertension (PAH) is a progressive disease of excess vasoconstriction and vascular cell proliferation that results in increased pulmonary vascular resistance and right heart failure. We have previously shown (66) that tissue factor expression is increased in the abnormal vessels of patients and rats with PAH. We hypothesized that tissue factor and its downstream mediator, thrombin, would promote migration of endothelial cells (EC) and the vascular pathology of PAH. Immunostaining revealed EC and a fibronectin-enriched matrix within the "plexiform-like" lesions in a rat model of severe PAH. In a modified Boyden assay, protease-activated receptor 1 (PAR1; thrombin receptor) stimulation by agonist peptide or thrombin induced pulmonary microvascular EC (PMVEC) migration when the cells were interacting with fibronectin, but not with other extracellular matrix proteins. Thrombin/fibronectin-induced migration was confirmed in wound healing and angiogenesis assays and was abrogated by the PAR1 antagonist SCH79797 and soluble RGD peptide. This fibronectin dependence was unique to PAR1 activation; other EC agonists evaluated did not induce migration on any matrix, and 10% FBS stimulated similar levels of migration on all matrix proteins tested. Thrombin/fibronectin stimulated autophosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII) in PMVEC, and inhibitors of CaMKII blocked thrombin-induced migration on fibronectin, but had no effect on migration induced by 10% FBS. In contrast, EC isolated from the proximal pulmonary artery migrated in response to most agonists independent of the matrix substrate. Our findings illustrate EC heterogeneity in a single tissue and indicate a novel role for CaMKII in mediating EC migration. Because PMVEC have been shown to have impressive proliferative potential, thrombin/fibronectin-stimulated migration of these cells to a site of injured endothelium is a potential mechanism by which thrombin contributes to the development of vascular lesions in PAH.

Pathology of Pulmonary Arterial Hypertension

The pathological features of pulmonary arterial hypertension are highlighted in this review, which can serve as a guide to diagnosis and identification of potential cellular targets for novel lines of therapy. It also emphasizes the variability of pathological processes found in pulmonary hypertensive lungs collected by the Pulmonary Breakthrough Initiative of the Cardiovascular Medical Research Fund. This initiative is aimed at banking properly phenotyped lung tissue and implementing relevant human lung-based investigations of pulmonary arterial hypertension. This effort has led to an insight of site-specific heterogeneity of relevant pulmonary vascular pathologies and how associated histopathological processes, including interstitial fibrotic and inflammatory findings, may need to be considered in the development of future therapies. We also highlight the pulmonary vascular pathology in schistosomiasis-associated pulmonary arterial hypertension, possibly the most frequent cause of pulmonary hypertension worldwide.

Pulmonary Arterial Hypertension and HIV Infection

Pulmonary arterial hypertension (PAH) is a rare but life-threatening complication of human immunodeficiency virus (HIV) infection. PAH can complicate the course of HIV infection regardless of the route of HIV transmission, the stage of HIV infection, and the degree of immunosuppression. The clinical presentation and underlying pathology of PAH associated with HIV infection (PAH-HIV) are similar to those encountered in other forms of PAH, although there are data suggesting a greater inflammatory component in the HIV-related form. Given the good long-term prognosis of HIV patients with highly active antiretroviral treatments and the severity of PAH in HIV-infected patients, screening for pulmonary hypertension according to a precise algorithm is warranted in HIV-infected patients presenting with dyspnea not explained by another cause. In all cases, right heart catheterization must be performed to establish the diagnosis of PAH. Beneficial effects of antiretroviral treatments on PAH-HIV still remain to be proven. Patients with PAH-HIV appear to respond well to treatment with the prostacyclin epoprostenol, although continuous intravenous infusion is associated with a range of potential complications. Treatment with the oral dual endothelin receptor antagonist bosentan has been shown to benefit patients with PAH-HIV without adversely affecting the control of HIV infection, and resulted in functional and hemodynamic normalization in approximately 20% of patients. Other PAH therapies, including prostacyclin analogs, type 5 phosphodiesterase inhibitors, and single endothelin receptor antagonists, have yet to be evaluated in PAH-HIV.