Forms Of Pulmonary Arterial Hypertension Research Articles

Hypertension pulmonaire et maladies hépatiques

Portopulmonary hypertension (PoPH) is defined by the combination of portal hypertension and precapillary pulmonary hypertension (mPAP ≥ 25 mmHg, PCWP < 15 mmHg and PVR > 3 Wood units). PoPH is characterised by pathobiological mechanisms that are similar to other forms of pulmonary arterial hypertension. Prevalence of PoPH is estimated at 0.5-5% among patients with portal hypertension with or without cirrhosis. Treatment strategies most commonly employed for PoPH patients are based on recommendations for idiopathic PAH management. Indeed, the choice of specific PAH treatment must take account the severity of the underlying liver disease. Prognosis of PoPH patients is dependent on both the severity of PAH and of the underlying liver disease. PoPH may be a contraindication for orthotopic liver transplantation (OLT) if mean pulmonary arterial pressure is > 35 mmHg associated with severe right ventricular dysfunction or high level of pulmonary vascular resistance (> 3-4 Wood units). Bridge therapy with specific PAH therapies should be considered in those patients in an attempt to improve pulmonary hemodynamic and thereby allow OLT with acceptable risk. Recent data suggest that stabilize, improve or cure PoPH seems to be possible by combining specific PAH therapies and liver transplantation in selected patients. Clinical and experimental evidences suggest that IFN therapy may be a possible risk factor for PAH.

A Surgical Lung Biopsy Case of Pulmonary Veno-occlusive Disease Associated with Limited Cutaneous Systemic Sclerosis

Pulmonary veno-occlusive disease (PVOD), a rare form of pulmonary arterial hypertension (PAH) characterized by a progressive obstruction of small pulmonary veins, is both difficult to diagnose and treat effectively. We reported a case of limited cutaneous systemic sclerosis complicated with PAH in which early definitive diagnosis of PVOD was made by surgical lung biopsy. A 53-year-old Japanese woman, with no history of smoking, was admitted to our hospital because of dry cough and progressive dyspnea. She had Raynaud’s phenomenon, gastroesophageal reflux and skin sclerosis and she was positive for anticentromere antibody. Chest high-resolution computed tomography (HRCT) revealed diffuse centrilobular ground-glass opacities and septal lines in addition to mediastinal lymph node enlargement; radiographic triad of HRCT signs of PVOD. PAH was found by right heart catheterization. Although limited cutaneous systemic sclerosis-associated PAH was diagnosed, histological findings obtained by surgical lung biopsy showed not only wall thickening of muscular arteries and arterioles but diffuse occlusion of pulmonary venules, that is, PVOD. In addition, pleuritis and limited, mild cellular interstitial pneumonia was also observed. First-line corticosteroid therapy and careful combination therapy with sildenafil and ambrisentan initially stabilized her symptoms and pulmonary hemodynamics, but she died due to cardiac arrest approximately 2.5 years after initiating PAH therapy. The need to establish a correct and early diagnosis of PVOD is important because of the impaired prognosis of these patients and their risk of developing severe pulmonary edema with specific PAH therapy. HRCT is a useful noninvasive diagnostic modality in the evaluation of suspected PVOD.

Portopulmonary Hypertension in Patients Undergoing Liver Transplantation: A Case Report

Portopulmonary hypertension (PPH) is a form of pulmonary arterial hypertension, characterized by elevation of pulmonary arterial pressure due to increased resistance to pulmonary blood flow. It is a consequence of portal hypertension, associated or not with liver disease. A retrospective study of patients undergoing liver transplantation was carried out in the Liver Transplantation Unit of the Clinics Hospital of the State University of Campinas (UNICAMP) from 1991 to 2012, covering 389 transplants. Although 50 (12.9%) patients presented with mean pulmonary arterial pressure (MPAP) > 25 mmHg, only one case (0.25%) met the diagnostic criteria for PPH: a 43-year-old female patient with advanced liver disease, caused by primary biliary cirrhosis with portal hypertension, diagnosed as mild portopulmonary hypertension and diagnosed in the operating room. PPH is a serious complication of portal hypertension. It is related to the great difficulty in diagnosis and the high mortality rate due to right heart failure. PPH is an entity with a low frequency of occurrence in individuals undergoing liver transplantation, although there is a wide variation in the prevalence rate presented in the literature and the definitive diagnosis should be confirmed with right heart catheterization.

The Exceptional and Far-Flung Manifestations of Heart Failure in Eisenmenger Syndrome

Dramatic advances in the diagnosis and treatment of congenital heart disease (CHD), the most common inborn defect, has resulted in a growing population of adults with CHD. Eisenmenger syndrome (ES) represents the extreme form of pulmonary arterial hypertension associated with CHD, characterized by markedly increased pulmonary vascular resistance with consequently reversed or bidirectional shunting. While ES is a direct consequence of a heart defect, it is a fundamentally multisystem syndrome with wide-ranging clinical manifestations. The introduction of targeted pulmonary hypertension therapies aimed has subtly shifted clinical focus from preventing iatrogenic and other adverse events toward cautious therapeutic activism.

The management of adult female patients with Eisenmenger syndrome and advanced pulmonary arterial hypertension treatment: single center experience and follow-up for 5 years

Eisenmenger syndrome (ES) occurs as the most advanced form of pulmonary arterial hypertension (PAH) in patients with congenital heart disease. In this study, we aimed to evaluate the management of ES patients, follow-up and specific PAH treatment applying and clinical outcomes during 5 years. During the period of the month between May 2008 and 2013 ES female patients were included in the study and followed an average for 5 years. Clinical findings, brain natriuretic peptide levels, transthoracic and right heart catheterization findings, 6-min walking test distance were recorded. PAH specific treatment as bosentan, iloprost and sildenafil was given to patients according to guidelines. The patients were evaluated with 3 months intervals as requirement for hospitalization, combination treatment, and mortality. A total of 12 patients were included in the study. All of the patients were women, the mean age was 36.5. As prognostic echocardiographic data, the patients had high pulmonary artery pressure (109.81 ± 24.94 mmHg) related with increased right ventricular wall thickness, elevated right atrial pressure, severe pulmonary regurgitation in 40%, shortened pulmonary acceleration time, diminished myocardial tissue Doppler velocities of the left and right ventricles, increased right atrium area/left atrial area ratio (1.35 ± 0.40), lower right ventricular fractional area change. During the follow-up period of 5 years, a total of 16 events occurred. Combination treatment was required in 8 patients. Eisenmenger syndrome is a multi-system affecting disease and due to high morbidity and mortality risk patients with ES should be followed by specialized centers. PAH specific treatment improves the disease course and survival of patients.

Letter to the Editor Natural killer cell-mediated immune deficiency or compromise in patients with portopulmonary hypertension

Portopulmonary hypertension (POPH) is a form of pulmonary arterial hypertension (PAH) in the setting of portal hypertension, and is associated with a poor prognosis [1]. The underling etiological cause of POPH is poorly understood [1]. Previously we have reported T cell-mediated immune deficiency or compromise in patients with chronic thromboembolic pulmonary hypertension (CTEPH), idiopathic pulmonary hypertension (IPH), and acute pulmonary embolism (APE) [2, 3]. Here we report natural killer cell-mediated immune deficiency or compromise in patients with POPH. Nine patients (4 male, 5 female) diagnosed with POPH in Shanghai Tongji Hospital from year 2010 to 2011 were recruited in the present study, with a mean age of 65 ±19 years (30–82 years). The diagnosis of POPH is based on the hemodynamic criteria including portal hypertension and/or liver disease (clinical diagnosis) [4], pulmonary artery systolic pressure > 40 mm Hg at rest, pulmonary vascular resistance > 240 dynes × s × cm−5, and pulmonary artery occlusion pressure 12 [1]. We firstly detected the cluster of differentiation (CD) on the T cell surface. To our surprise, unlike the changes we previously reported in CTEPH, IPH, or APE, only slight changes of CD3+, CD4+ or CD8+ T cells were observed in POPH patients (Table I and Figures 1A–C). Interestingly, the number of CD16+CD56, which reflects the function of natural killer cell, was decreased in five patients with POPH (55.6%) (Table I and Figure 1D) [5]. Figure 1 Changes of T and NK cells of the patients enrolled in this study Table I The etiology, Child-Pugh Class, pulmonary artery systolic pressure, and the clusters of differentiation on T and NK cells of the patients enrolled in this study T cell-mediated immune deficiency or compromise has been reported in patients with CTEPH, IPH, and APE [2, 3]. In the present study, we failed to detect obvious cell-mediated immune changes. Natural killer cells, accounting for 15% of peripheral blood lymphocytes, are well-known unique effectors of the innate immune system as they can recognize stressed cells in the absence of antibodies and MHC [3]. As the role of natural killer cells is analogous to that of cytotoxic T cells [5], we detected their surface markers CD16 (FcγRIII) and CD56 in POPH patients and identified a natural killer cell-mediated immune deficiency or compromise in patients with POPH. Immune deficiency or compromise of natural killer cells is usually caused by virus infection, cancer, or immunosuppressive drugs [5]. In this study, malignant tumors or use of immunosuppressive drugs were excluded in these 9 patients; therefore the immune deficiency or compromise of natural killer cells is most likely due to virus infection. Our study indicated that the virus-killing function of natural killer cells is compromised in patients with POPH. The POPH might be a disease of acquired natural killer cell-mediated immune deficiency, and virus infection may be an important etiological factor of POPH. We also speculate that the pathogenic virus infection in POPH patients may be different from those in CTEPH, IPH, and APE.

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

Pulmonary hypertension at exercise in COPD: does it matter?

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). In these patients, the increase in pulmonary artery pressure (PAP) is usually mild, in the range of 20 to 30 mmHg mean PAP (mPAP) with little progression over the years, on average 0.4 mmHg per year, and is preventable and sometimes partially reversible with chronic oxygen therapy [1, 2]. Sharp increases in PAP may occur during sleep or episodes of acute respiratory failure, and also during exercise [1, 2]. Pulmonary hypertension in COPD is explained by the combined effects of hypoxia, inflammation, hyper-inflation of the lungs and an increase in left ventricular end-diastolic pressure [2, 3]. Increased PAP is associated with decreased survival, may be the cause of clinical right heart failure, particularly in hypoxaemic patients with associated salt and water retention, and is thought to limit exercise capacity [1, 2]. Right heart catheterisations to evaluate the pulmonary circulation used to be common practice in patients with advanced COPD. The procedure is nowadays limited to the work-up of lung transplantation or lung volume reduction surgery, or for the understanding of symptoms that appear out of proportion with the lung function impairment [2, 4]. Some rare patients with COPD, approximately 1% of those referred to expert centres, present with “out of proportion pulmonary hypertension”. This entity is defined by a particular combination of mPAP >35–40 mmHg, only moderate airflow obstruction, hypoxaemia and hypocapnia [2–5]. Whether “out of proportion pulmonary hypertension” actually represents a form of pulmonary arterial hypertension (PAH) triggered by altered blood gases or inflammation associated with COPD remains unclear [5]. But there has been no reported evidence until now that targeted therapies shown effective in the …

Is Resistance Futile?

Is Resistance Futile?

A practical and efficient cellular substrate for the generation of induced pluripotent stem cells from adults: blood-derived endothelial progenitor cells.

Induced pluripotent stem cells (iPSCs) have the potential to generate patient-specific tissues for disease modeling and regenerative medicine applications. However, before iPSC technology can progress to the translational phase, several obstacles must be overcome. These include uncertainty regarding the ideal somatic cell type for reprogramming, the low kinetics and efficiency of reprogramming, and karyotype discrepancies between iPSCs and their somatic precursors. Here we describe the use of late-outgrowth endothelial progenitor cells (L-EPCs), which possess several favorable characteristics, as a cellular substrate for the generation of iPSCs. We have developed a protocol that allows the reliable isolation of L-EPCs from peripheral blood mononuclear cell preparations, including frozen samples. As a proof-of-principle for clinical applications we generated EPC-iPSCs from both healthy individuals and patients with heritable and idiopathic forms of pulmonary arterial hypertension. L-EPCs grew clonally; were highly proliferative, passageable, and bankable; and displayed higher reprogramming kinetics and efficiencies compared with dermal fibroblasts. Unlike fibroblasts, the high efficiency of L-EPC reprogramming allowed for the reliable generation of iPSCs in a 96-well format, which is compatible with high-throughput platforms. Array comparative genome hybridization analysis of L-EPCs versus donor-matched circulating monocytes demonstrated that L-EPCs have normal karyotypes compared with their subject's reference genome. In addition, >80% of EPC-iPSC lines tested did not acquire any copy number variations during reprogramming compared with their parent L-EPC line. This work identifies L-EPCs as a practical and efficient cellular substrate for iPSC generation, with the potential to address many of the factors currently limiting the translation of this technology.

Waiting in Anticipation

Waiting in Anticipation

The Role of Target Therapies in Schistosomiasis-Associated Pulmonary Arterial Hypertension

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) may be one of the most prevalent forms of pulmonary arterial hypertension (PAH) worldwide. However, the clinical and hemodynamical response to specific PAH therapy in Sch-PAH is not known. We retrospectively analyzed the charts of all patients with Sch-PAH who initiated specific PAH treatment between June 2003 and June 2010 in a single PAH reference center in São Paulo, Brazil. Clinical and hemodynamical data were retrospectively collected and evaluated in two periods: baseline and posttreatment. The study population consisted of 12 patients with Sch-PAH. They were treated with phosphodiseterase-5 inhibitors (seven patients), endothelin receptor antagonists (four patients), or combination therapy (one patient). Mean treatment period was 34.9 ± 15.5 months. Patients with Sch-PAH presented significant improvements in terms of functional class, 6-min walk test distance (439 ± 85 to 492 ± 79 m, P = .032), cardiac index (2.66 ± 0.59 to 3.08 ± 0.68 L/min/m(2), P = .028), and indexed pulmonary vascular resistance (20.7 ± 11.6 to 15.9 ± 9 W/m(2), P = .038) with the introduction of specific PAH treatment. We conclude that specific PAH therapy may be of benefit to patients with Sch-PAH, considering clinical, functional, and hemodynamic parameters.

Gremlin plays a key role in the pathogenesis of pulmonary hypertension.

Pulmonary hypertension occurs in chronic hypoxic lung diseases, significantly worsening morbidity and mortality. The important role of altered bone morphogenetic protein (BMP) signaling in pulmonary hypertension was first suspected after the identification of heterozygous BMP receptor mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension. Subsequently, it was demonstrated that BMP signaling was also reduced in common forms of pulmonary hypertension, including hypoxic pulmonary hypertension; however, the mechanism of this reduction has not previously been elucidated. Expression of 2 BMP antagonists, gremlin 1 and gremlin 2, was higher in the lung than in other organs, and gremlin 1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic pulmonary hypertension. Hypoxia stimulated gremlin secretion from human pulmonary microvascular endothelial cells in vitro, which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced pulmonary vascular resistance by attenuating vascular remodeling. Furthermore, gremlin was increased in the walls of small intrapulmonary vessels in idiopathic pulmonary arterial hypertension and the rare heritable form of pulmonary arterial hypertension in a distribution suggesting endothelial localization. These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in pulmonary arterial hypertension.

Intracranial Vasculopathy in a Patient with Systemic Sclerosis: Atherosclerotic or Moyamoya-Like Disease?

Intracranial Vasculopathy in a Patient with Systemic Sclerosis: Atherosclerotic or Moyamoya-Like Disease?

Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension

The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 (BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 is known to interact with the cytoskeleton, and human array studies in PAH patients confirm alterations in cytoskeletal pathways. The goal of this study was to evaluate cytoskeletal defects in BMPR2-associated PAH. Expression arrays on our Bmpr2 mutant mouse lungs revealed cytoskeletal defects as a prominent molecular consequence of universal expression of a Bmpr2 mutation (Rosa26-Bmpr2(R899X)). Pulmonary microvascular endothelial cells cultured from these mice have histological and functional cytoskeletal defects. Stable transfection of different BMPR2 mutations into pulmonary microvascular endothelial cells revealed that cytoskeletal defects are common to multiple BMPR2 mutations and are associated with activation of the Rho GTPase, Rac1. Rac1 defects are corrected in cell culture and in vivo through administration of exogenous recombinant human angiotensin-converting enzyme 2 (rhACE2). rhACE2 reverses 77% of gene expression changes in Rosa26-Bmpr2(R899X) transgenic mice, in particular, correcting defects in cytoskeletal function. Administration of rhACE2 to Rosa26-Bmpr2(R899X) mice with established PAH normalizes pulmonary pressures. Together, these findings suggest that cytoskeletal function is central to the development of BMPR2-associated PAH and that intervention against cytoskeletal defects may reverse established disease.

Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females

BackgroundIdiopathic and familial forms of pulmonary arterial hypertension (PAH) occur more frequently in women than men. However, the reason for this remains unknown. Both the calcium binding protein S100A4/Mts1 (Mts1) and its endogenous receptor (receptor for advanced glycosylation end products; RAGE) have been implicated in the development of PAH. We wished to investigate if the Mts1/RAGE pathway may play a role in the gender bias associated with PAH.MethodsWe investigated the effects of gender on development of PAH in mice over-expressing Mts1 (Mts1+ mice) via measurement of pulmonary arterial remodeling, systolic right ventricular pressure (sRVP) and right ventricular hypertrophy (RVH). Gender differences in pulmonary arterial Mts1 and RAGE expression were assessed by qRT-PCR and immunohistochemistry. Western blotting and cell counts were used to investigate interactions between 17β-estradiol, Mts1 and RAGE on proliferation of human pulmonary artery smooth muscle cells (hPASMCs). Statistical analysis was by one-way analysis of variance with Dunnetts post test or two-way analysis of variance with Bonferronis post test, as appropriate.ResultsFemale Mts1+ mice developed increased sRVP and pulmonary vascular remodeling, whereas male Mts1+ mice remained unaffected. The development of plexiform-like lesions in Mts1+ mice was specific to females. These lesions stained positive for both Mts1 and RAGE in the endothelial and adventitial layers. Expression of pulmonary arterial Mts1 was greater in female than male Mts1+ mice, and was localised to the medial and adventitial layers in non plexiform-like pulmonary arteries. RAGE gene expression and immunoreactivity were similar between male and female Mts1+ mice and RAGE staining was localised to the endothelial layer in non plexiform-like pulmonary arteries adjacent to airways. In non-plexiform like pulmonary arteries not associated with airways RAGE staining was present in the medial and adventitial layers. Physiological concentrations of 17β-estradiol increased Mts1 expression in hPASMCs. 17β-estradiol-induced hPASMC proliferation was inhibited by soluble RAGE, which antagonises the membrane bound form of RAGE.ConclusionsMts1 over-expression combined with female gender is permissive to the development of experimental PAH in mice. Up-regulation of Mts1 and subsequent activation of RAGE may contribute to 17β-estradiol-induced proliferation of hPASMCs.

Ventilation/perfusion lung scan in pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD), a rare form of pulmonary arterial hypertension (PAH), requires histological proof for definitive diagnosis; however, lung biopsy is not recommended in PAH. Recent conjoint European Respiratory Society/European Society of Cardiology guidelines suggest that nonmatched perfusion defects on ventilation/perfusion (V'/Q') lung scanning in PAH patients may suggest PVOD. The aim of our study was to evaluate V'/Q' lung scans in a large cohort of PVOD and idiopathic or heritable PAH patients. V'/Q' lung scans from 70 patients with idiopathic or heritable PAH and 56 patients with confirmed or highly probable PVOD were reviewed in a double-blind manner. The vast majority of V'/Q' lung scans were normal or without significant abnormalities in both groups. No differences in ventilation or perfusion lung scans were observed between PAH and PVOD patients (all p>0.05). Furthermore, no differences were observed between confirmed (n=31) or highly probable PVOD (n=25). Nonmatched perfusion defects were found in seven (10%) idiopathic PAH patients and four (7.1%) PVOD patients (p>0.05). Nonmatched perfusion defects were rarely seen in a large cohort of idiopathic or heritable PAH and PVOD patients. Future recommendations should be amended according to these results suggesting that V'/Q' lung scanning is not useful in discriminating PVOD from idiopathic PAH.

The monocrotaline model of pulmonary hypertension in perspective

Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.

A multiple combined treatment in an adult patient with Eisenmenger's syndrome

Eisenmenger's syndrome is a left-to-right shunt caused by a congenital cardiac defect, leading to pulmonary arterial hypertension (PAH) and, in the late stage, to a reversal of the shunt right-into-left. Nevertheless, it has a better prognosis when compared to idiopathic PAH.We describe a case of woman carrying Eisenmenger's syndrome successfully treated with increasing doses of sildenafil associated to prostanoids. Themedical therapy improved her clinical condition and led to an optimal disease control till the heart transplantation. Eisenmenger's syndrome, the most advanced form of pulmonary arterial hypertension (PAH) associated with congenital heart disease, has shown a reduced survival rate when compared to general population, but appears to have a better prognosis than idiopathic PAH in comparable functional classes [1,2]. Lung transplantation with repair of the cardiac defects or combined heart–lung transplantation represents the therapeutical options for the treatment of Eisenmenger's syndrome in patients with poor prognosis. We describe the case of a young (36 years old) woman with a diagnosis of great arteries transposition, interventricular defect, hypoplastic right ventricle and persistent left superior venous cava, undergone to pulmonary artery banding on 1977. The patient arrived to our center on December 2009 presenting signs and symptoms suggestive of pulmonary hypertension: e.g. severe dyspnoea, fatigue, significant cyanosis and digital clubbing. The cardiac catheterization showed normal pulmonary venous return, persistent left vena cava draining collateral blood flow as consequence of coronary sinus subtotally occluded, intact inter-atrial septum (with no significant gradients between left and right ventricle and between ventricles and the aorta), right pulmonary artery dilatation (diameter 20 mm), 78% saturation in the aorta and 82% in the pulmonary artery, QP/QS 1.55, pulmonary arterial pressure 48/15/29 mm Hg and transpulmonary gradient 21 mm Hg (Figs. 1 and 2). The pulmonary artery banding was well placed. The mean pulmonary artery pressure dropped to 24 mm Hg after inhalation of 100% oxygen. The examination was complicated by an initial precordial pain during the catheter's insertion into the left superior vena cava, followed by an irreversible complete AV block requiring a surgical epicardial dual-chamber pacemaker insertion. Then the patient underwent atrioseptostomy. The patient was discharged on December 2009 in fairly good conditions, with a medical treatment based on sildenafil 0.5 mg/kg t.i. d., and was followed up as outpatient every 40–60 days by echocardiographic test, 6-minute walking test (6MWT), blood tests, BNP, NGAL and pacemaker control. The sildenafil dose was progressively increased to 0.5/kg q.i.d. during the following 30 days after the hospital discharge. Over few months, the patient showed a significant clinical improvement, with reduction in dyspnea and an improvement of the 6MWT from 110 m (March 2010) to 360 m (December 2010). On June 2010, the patient underwent new cardiac catheterization showing pulmonary artery pressure 33/10/22 mm Hg, transpulmonary gradient 13 mm Hg, 73% oxygen saturation in aorta and 79% in the lungs, 59% in superior vena cava, QP/QS of 1.42, intraventricular pressure 85/70/10 mm Hg and no gradient between the atria. The patient was considered a suitable candidate for heart transplantation and she was initiated into a programwith the aim to increase dosages of the vasodilator therapy by associating sildenafil to intravenous prostanoids, followed by catheterization after 5–6 months. A treatment algorithm of the Eisenmenger's syndrome, based on the case of a patient with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, is proposed. The efficacy of sildenafil therapy in patient with PAH has been described [3,4]. In our case, the combination of surgical and medical therapy has shown to be a reliable approach for the treatment of adult patients with PAH, thus limiting the heart transplant only in selected cases. We thank Natascia Crispino (Medical Dpt Pfizer Italy) for the scientific assistance. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).

Portopulmonary Hypertension

Portopulmonary hypertension (PPHT) is a respiratory complication of portal hypertension, defined as an increase in mean pulmonary artery pressure (PAP) of > 25 mmHg with an increase in pulmonary vascular resistance of > 240 dyn.s/cm(-5) and a normal pulmonary capillary wedge pressure ( < 15 mmHg), which often occurs in subjects with liver cirrhosis. Histopathological features of PPHT are endothelial and smooth-muscle cell proliferation and fibrosis leading to luminal obstruction in the resistance arteries. The pathogenesis of PPHT may result from an imbalance between vasoconstrictor and vasodilating factors. The most common pulmonary symptom is exertional dyspnea; fatigue, chest pain and syncope occur more often at an advanced stage. Edema, ascites and prominent jugular veins are signs of both decompensated hepatic cirrhosis and right ventricular failure. Right heart catheterisation is the gold standard for the diagnosis and defines PPHT in mild disease with PAP less than 35 mmHg, moderate disease with PAP between 35 and 45 mmHg, and severe disease with PAP of 45 mmHg or higher. The medical treatment of portopulmonary hypertension is based on the treatment of other forms of pulmonary arterial hypertension, including vasomodulating pharmacologic agents. Liver transplantation is accompanied by high risk of mortality, generally due to acute right ventricular failure and cardiovascular collapse. The prognosis of PPHT is poor with mean survival of 15 months.