[Update pulmonary arterial hypertension : Definitions, diagnosis, therapy]. / Update pulmonalarterielle Hypertonie : Definitionen, Diagnose, Therapie.

The term pulmonary arterial hypertension comprises a group of pulmonary vascular diseases of different etiologies that are characterized by similar precapillary vascular remodeling processes and result in exertional dyspnea and right heart insufficiency. The specific pharmacological treatment approach considers the risk of mortality and phenotypical properties and includes treatment with phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostanoids, as well as with more novel substances, such as a soluble guanylyl cyclase stimulator and an oral prostacyclin receptor agonist. The prognosis of the disease is mainly determined by the right heart insufficiency for which there is currently no specific pharmacological treatment. Lung transplantation may be offered as a last option. This review provides an overview of the current European guidelines from 2015 and the recommendations of the Cologne Consensus Conference for pulmonary hypertension from 2016.

[Riociguat: stimulator of soluble guanylate-cyclase. New mode of action for the treatment of pulmonary arterial and non operable chronic thromboembolic pulmonary hypertension]. / Riociguat: Stimulation der löslichen Guanylatzyklase. Neuer Wirkmechanismus zur Behandlung der pulmonal-arteriellen und der nicht operablen chronisch thromboembolischen pulmonalen Hypertonie.

Riociguat is the first clinically available soluble Guanylate-cyclase stimulator (sGC) and representative of a completely new class of drugs. Riociguat is approved for pulmonary arterial hypertension (PAH) and non-operable or recurrent/persistent chronic thromboembolic pulmonary hypertension (CTEPH). Moreover, Riociguat is currently under investigation for a wider spectrum of diseases. This article focusses on its mode of action and clinical trial data. Finally, based on these data, the status of approval, as well as the costs a proposal is given how Riociguat can be integrated in the current treatment of PAH and CTEPH.

[Medical treatment of pulmonary hypertension: what's new?]. / Medikamentöse Therapie der pulmonalen Hypertonie: Was ist neu?

Pulmonary hypertension (PH) is a chronic progressive disease of the pulmonary circulation of multifactorial causes. The current diagnostic classification of PH distinguishes five main groups, which have as a common feature an increased pulmonary arterial pressure and pulmonary resistance. The classification differentiates pulmonary arterial hypertension (PAH), PH due to left heart disease, PH in lung diseases and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), and PH with unclear/multifactorial mechanisms. Recent advances in basic research with the approval of new drugs and the establishment of therapeutic strategies, mainly in PAH and CTEPH, require a differentiated view of the disease, a careful diagnosis and initiation of therapy, and regular follow-ups. In this article, we provide an overview of the complex drug therapy currently available for PAH patients.

[Early diagnosis and therapy in pulmonary hypertension--aspects of a vision]. / Die frühe Diagnose und Therapie der pulmonalen Hypertonie--Aspekte einer Vision.

In patients with pulmonary hypertension progressive vascular changes in the lung precede the clinical and hemodynamic manifestations of the disease. Therefore, early diagnosis and timely treatment of the disease are crucial. This has been the topic of an expert meeting in Greifswald, Germany in June 2012. The current definition of pulmonary hypertension requires a mean pulmonary artery pressure ≥ 25 mmHg at rest, a hemodynamic abnormality already reflecting pulmonary vascular changes beyond early disease. There is increasing evidence supporting the concept that a lower pressure threshold at rest or an abnormal pressure response with exercise better characterize early disease. While right heart catheterization at rest remains the diagnostic gold standard other methods for detecting early disease are explored with echocardiography being the most frequently used technique. Targeted therapy has been approved for patients with pulmonary arterial hypertension (PAH, WHO-group I) in functional class II-IV. Preliminary data in functional class I patients suggest therapeutic potential of theses drugs in early disease as well. Current guidelines propose therapeutic goals based on parameters with prognostic importance. However, these recommendations are based on mostly retrospective analyses of pre-treatment data obtained in patients with pulmonary hypertension in functional class II-IV. Therefore, evidence-based therapeutic goals for early interventions in functional class I patients are lacking.

[Dynamic hyperinflation in pulmonary arterial hypertension: "hyperinflator" and "non-hyperinflator"]. / Dynamische Hyperinflation bei der pulmonal arteriellen Hypertonie: "Hyperinflator" und "Non-Hyperinflator".

BACKGROUND: The dynamic decrease in inspiratory capacity (IC) during exercise with restriction of tidal volume (VT) is known as dynamic hyperinflation (DH) and is described mostly in patients with COPD differentiating between a "hyperinflator" and a "non-hyperinflator". Recent studies have revealed DH in patients with idiopathic pulmonary arterial hypertension (iPAH), but the influence of the DH on the reduced exercise capacity with exertional dyspnoae is still being debated. METHODS: We analysed flow-volume curves during cardiopulmonary exercise testing (CPET) in idiopathic PAH (n = 19), in COPD (n = 17), in idiopathic pulmonary fibrosis (IPF) (n = 19) and a control group (n = 30). We measured IC at rest and during maximal exercise and furthermore ventilation, VT and oxygen uptake (VO2 peak). In iPAH a right heart catheter test and a 6-minute walk test (6MWT) were performed, also the B-type naturetic peptide (BNP) and the NYHA/WHO functional class were determined. RESULTS: The IC decreased significantly in 11 PAH "hyperinflators" (PAH-H) (Δ IC: - 0.34 ± 0.14 L, p < 0.001) compared to 8 PAH "non-hyperinflators" (PAH-NH) (Δ IC: 0.08 ± 0.2 L). COPD patients exhibited a characteristic hyperinflation pattern with a decrease in IC throughout exercise (Δ IC: - 0.61 ± 0.3 L, p < 0.001), while patients with IPF (Δ IC: 0.03 ± 0.15 L) and the control group responsed to exercise with a non-hyperinflator pattern (Δ IC: 0.1 ± 0.2 L). Both PAH collectives showed a reduced IC/TLC, while VT/IC was elevated with a decreased peak VO2 and max. performance compared to the control group. Correlations of the IC rest/max (L) were shown in PAH-H and PAH-NH with the VO2 peak, max. performance and VT. CONCLUSION: The analysis of flow-volume curves during CPET can indentify DH in a subgroup of patients with iPAH. The DH contributes significantly but slightly to the development of exertional limitations and dyspnoe in a subgroup of iPAH. Further studies with a larger sample size will be required to definitively measure the impact of the DH seen in these patients.

Diagnosis of CTEPH versus IPAH using capillary to end-tidal carbon dioxide gradients.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents an important differential diagnosis to idiopathic pulmonary arterial hypertension (IPAH). We hypothesised that the capillary to end-tidal carbon dioxide gradient at rest and during exercise might help differentiate CTEPH from IPAH. Patients who presented with unequivocal IPAH or CTEPH according to ventilation/perfusion scanning, pulmonary angiography, computed tomography and right heart catheterisation were included in this retrospective study and compared with healthy controls. 21 IPAH patients and 16 CTEPH patients fulfilled the inclusion criteria. Haemodynamics and peak oxygen uptake were comparable, but respiratory rates at rest and during exercise were significantly higher in CTEPH than in IPAH. End-tidal carbon dioxide was significantly lower in CTEPH versus IPAH at rest and during exercise, while capillary carbon dioxide values were similar. Correspondingly, capillary to end-tidal carbon dioxide gradients were significantly increased in CTEPH versus IPAH at rest and during exercise (median (range) 8.6 (3.0-13.7) versus 4.4 (0.9-9.0) (p<0.001) and 9.3 (3.3-13.1) versus 4.1 (0.0-8.8) mmHg (p<0.001), respectively). Although these values were closer to normal in IPAH they were still significantly elevated compared with healthy controls (2.3 (-4.8-8.1) and -1.9 (-5.7-6.2) mmHg, respectively). Capillary to end-tidal carbon dioxide gradients may help to distinguish CTEPH from IPAH based on resting and exercise values.

[Right heart failure in chronic pulmonary hypertension and acute pulmonary embolism]. / Rechtsherzversagen bei chronischer pulmonaler Hypertonie und akuter Lungenembolie.

Right-sided heart failure is a severe and often life-threatening complication of chronic pulmonary hypertension. The detection of trigger factors that induce right heart failure in previously stable patients is important to initiate a causal therapeutic strategy. Pulmonary embolism (PE) is a frequent cause of acute right heart failure and therapeutic strategies for PE are well documented in the current guidelines. Treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is surgical pulmonary endarterectomy (PEA) and patients with possible CTEPH should be referred to an experienced PEA surgeon without delay. Intensive care management for overt right heart failure is complex and includes the use of pulmonary vasodilators, individual adjustment of diuretic or volume therapy, augmentation of myocardial contractility and left ventricular afterload. Therapeutic regimens aim at optimized filling of the right ventricle, improvement of myocardial perfusion by avoiding tachycardia, elevating systemic pressure and reducing right ventricular afterload. Early communication with a specialized center for pulmonary hypertension is recommended.

Stem cell-mediated natural tissue engineering.

Recently, we demonstrated that a fully differentiated tissue developed on a ventricular septal occluder that had been implanted due to infarct-related septum rupture. We suggested that this tissue originated from circulating stem cells. The aim of the present study was to evaluate this hypothesis and to investigate the physiological differentiation and transdifferentiation potential of circulating stem cells. We developed an animal model in which a freely floating membrane was inserted into each the left ventricle and the descending aorta. Membranes were removed after pre-specified intervals of 3 days, and 2, 6 and 12 weeks; the newly developed tissue was evaluated using quantitative RT-PCR, immunohistochemistry and in situ hybridization. The contribution of stem cells was directly evaluated in another group of animals that were by treated with granulocyte macrophage colony-stimulating factor (GM-CSF) early after implantation. We demonstrated the time-dependent generation of a fully differentiated tissue composed of fibroblasts, myofibroblasts, smooth muscle cells, endothelial cells and new blood vessels. Cells differentiated into early cardiomyocytes on membranes implanted in the left ventricles but not on those implanted in the aortas. Stem cell mobilization with GM-CSF led to more rapid tissue growth and differentiation. The GM-CSF effect on cell proliferation outlasted the treat ment period by several weeks. Circulating stem cells contributed to the development of a fully differentiated tissue on membranes placed within the left ventricle or descending aorta under physiological conditions. Early cardiomyocyte generation was identified only on membranes positioned within the left ventricle.

Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(2A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR(2B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen. Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Endotoxin "priming" potentiates lung vascular abnormalities in response to Escherichia coli hemolysin: an example of synergism between endo- and exotoxin.

The pore-forming hemolysin of Escherichia coli (HlyA), an important virulence factor in extraintestinal E. coli infections, causes thromboxane generation and related vasoconstriction in perfused rabbit lungs (Seeger, W., H. Walter, N. Suttorp, M. Muhly, and S. Bhakdi. 1989. J. Clin. Invest. 84:220). We investigated the influence of pulmonary vascular "priming" with endotoxin on the responsiveness of the lung to a low-dose HlyA challenge. Rabbit lungs were perfused with Krebs Henseleit buffer containing 0.1-100 ng/ml Salmonella abortus equii lipopolysaccharide (LPS) for 60-180 min. This treatment caused protracted release of tumor necrosis factor into the recirculating medium, but did not induce significant alterations of pulmonary hemodynamics and fluid balance. At a dose of 1 ng/ml, HlyA elicited only moderate thromboxane release (< 200 pg/ml) and pulmonary artery pressure increase (< or = 6 mmHg) in control lungs. Acceleration and potentiation of both the metabolic and vasoconstrictor response occurred in lungs primed with LPS. This priming effect displayed dose (threshold integral of 0.1-1 ng/ml LPS) and time dependencies (threshold integral of 60-90 min LPS incubation). Maximum thromboxane release and pulmonary artery pressure increase surpassed the responses to HlyA in nonprimed lungs by more than 15-fold. Cyclooxygenase inhibition and thromboxane-receptor antagonism blocked these effects. These data demonstrate that LPS priming synergizes with HlyA challenge to provoke vascular abnormalities that are possibly relevant to the pathogenesis of organ failure in severe local and systemic infections.

Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.

Mitochondrial cytochrome redox states and respiration in acute pulmonary oxygen sensing.

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism to optimise lung gas exchange. We aimed to decipher the proposed oxygen sensing mechanism of mitochondria in HPV. Cytochrome redox state was assessed by remission spectrophotometry in intact lungs and isolated pulmonary artery smooth muscle cells (PASMC). Mitochondrial respiration was quantified by high-resolution respirometry. Alterations were compared with HPV and hypoxia-induced functional and molecular readouts on the cellular level. Aortic and renal arterial smooth muscle cells (ASMC and RASMC, respectively) served as controls. The hypoxia-induced decrease of mitochondrial respiration paralleled HPV in isolated lungs. In PASMC, reduction of respiration and mitochondrial cytochrome c and aa3 (complex IV), but not of cytochrome b (complex III) matched an increase in matrix superoxide levels as well as mitochondrial membrane hyperpolarisation with subsequent cytosolic calcium increase. In contrast to PASMC, RASMC displayed a lower decrease in respiration and no rise in superoxide, membrane potential or intracellular calcium. Pharmacological inhibition of mitochondria revealed analogous kinetics of cytochrome redox state and strength of HPV. Our data suggest inhibition of complex IV as an essential step in mitochondrial oxygen sensing of HPV. Concomitantly, increased superoxide release from complex III and mitochondrial membrane hyperpolarisation may initiate the cytosolic calcium increase underlying HPV.

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension.

An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH. This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH. Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells. Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.

First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.

Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease). The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability. Riociguat had a favourable safety profile at single doses < or =2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg. The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.

Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia.

Bronchopulmonary dysplasia (BPD) is characterised by impaired alveolarisation, inflammation and aberrant vascular development. Phosphodiesterase (PDE) inhibitors can influence cell proliferation, antagonise inflammation and restore vascular development and homeostasis, suggesting a therapeutic potential in BPD. The aim of the present study was to investigate PDE expression in the lung of hyperoxia-exposed mice, and to assess the viability of PDE4 as a therapeutic target in BPD. Newborn C57BL/6N mice were exposed to normoxia or 85% oxygen for 28 days. Animal growth and dynamic respiratory compliance were reduced in animals exposed to hyperoxia, paralleled by decreased septation, airspace enlargement and increased septal wall thickness. Changes were evident after 14 days and were more pronounced after 28 days of hyperoxic exposure. At the mRNA level, PDE1A and PDE4A were upregulated while PDE5A was downregulated under hyperoxia. Immunoblotting confirmed these trends in PDE4A and PDE5A at the protein expression level. Treatment with cilomilast (PDE4 inhibitor, 5 mg.kg(-1).day(-1)) between days 14 and 28 significantly decreased the mean intra-alveolar distance, septal wall thickness and total airspace area and improved dynamic lung compliance. Pharmacological inhibition of phosphodiesterase improved lung alveolarisation in hyperoxia-induced bronchopulmonary dysplasia, and thus may offer a new therapeutic modality in the clinical management of bronchopulmonary dysplasia.

Long-term outcome with intravenous iloprost in pulmonary arterial hypertension.

There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn x s x cm(-5) at the time of diagnosis and of 1,858 dyn x s x cm(-5) at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studies.

Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ET(A) or nonselective ET(A)/ET(B) blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease.

[Pulmonary hypertension in hereditary haemorrhagic teleangiectasia]. / Pulmonalvaskuläre Beteiligung bei Morbus Osler.

BACKGROUND: In hereditary haemorrhagic teleangiectasia (HHT) can be accompanied by pulmonary arteriovenous vascular malformations (PAVM). Pulmonary hypertension (PH) is regarded as a rare pulmonary manifestation. METHODS AND PATIENTS: We non-invasively assessed the pulmonary circulation in 20 patients with HHT using standard resting echocardiography including contrast studies. In 14 patients a mutation in the endoglin gene was present. The other 6 patients carried a mutation in the Alk-1 gene. RESULTS: We identified 4 patients with manifest PH, among them 2 patients (both with endoglin mutations) with concurrent thromboembolism, and 2 patients (both with Alk-1 mutations) with hepatic manifestations of HHT. Two patients required specific pulmonary vasoactive therapy with sildenafil and bosentan, respectively. Another patient received embolisation therapy for hypercirculatory PH due to hepatic arteriovenous malformations. Pulmonary arteriovenous malformations were found in 8 patients (7 with endoglin, and 1 with Alk-1 mutations), among them were 2 patients with PH. CONCLUSIONS: Patients with HHT should undergo echocardiographic screening for PAVM as well as PH. When PH is detected, other conditions such as hepatic or thromboembolic diseases should be considered, regardless of the underlying genetic defect.

[Therapy of pulmonary arterial hypertension]. / Therapie der pulmonalarteriellen Hypertonie.

Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e. g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e. g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.