European Respiratory Society
Pulmonary Vascular Pathology: A Clinical Update

Pulmonary vascular pathology forms an important challenge in daily clinical practice; pulmonary embolism (PE) is the third leading cause of cardiovascular mortality in North America and is responsible for 5–10% of all in-hospital deaths. Furthermore, the diagnosis of PE remains one of the most difficult problems confronting clinicians. Timely diagnostic testing must be performed to enable the initiation of antithrombotic therapy for patients proven to have this condition while avoiding the risks of anticoagulation for patients without PE. The widespread adoption of right heart catherisation in the 1950s, for the study of heart and lung disease in humans, allows identification of patients suffering from pulmonary hypertension (PH). In case of exclusion of other causes of PH, this unexplained PH is designated as primary. Although descriptions of young people dying of right heart failure for unexplained reasons existed in the literature, it was not until 1951 that R. Dresdale published findings on a small series of patients and used the appellation “primary pulmonary hypertension”. The present monograph reviews the current knowledge in this field of pulmonary medicine. In particular, a better understanding of the actual pathogenesis of these pathologies offers perspectives of optimism in the future management of these patients. This monograph provides an informative and authoritative review on pulmonary vascular pathology for the respiratory physician.

  • European Respiratory Society Monographs
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    Correspondence: R. Verhaeghe, Centre for Vascular Diseases, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

    Current knowledge on risk factors for venous thromboembolism (VTE) can still be largely explained within the framework of Virchow's classical concept on the pathogenesis of thrombosis. Genetic risk manifests as either a decrease in anticoagulant activity (deficiency of antithrombin, protein C or S) or an increase in procoagulant activity (factor V Leiden, prothrombin G20210A). The clinical impact of these factors is determined by their prevalence in the population and by the relative risk associated with each defect. The mutations in factor V and prothrombin are rather mild enhancers of thrombotic risk but are more common. The role of genetic variation in levels of some coagulation proteins as a risk factor for thrombosis needs further clarification.

    Antiphospholipid antibodies are directed against phospholipid-binding proteins and enhance their affinity for phospholipid surfaces. They are detected as anticardiolipins or as lupus anticoagulants. Multiple effects may contribute to their thrombogenic character. Cancer cells also interact with several processes to shift the haemostatic balance towards a prothrombotic state; therapeutic intervention further augments the thrombotic risk. The need to search for occult malignancy in VTE is an open clinical debate. Epidemiological studies have clearly established the thrombotic risk in females on hormonal contraception or replacement.

    Several studies argue for a lower risk of pulmonary embolism than of deep vein thrombosis in carriers of the factor V Leiden mutation, while the data on prothrombin G20210A are still less convincing. The observation is intriguing but unexplained.

    Counselling patients and their family on thrombophilia testing is a delicate issue. Approaches may vary from almost unrestricted screening to tailoring to the individual's specific need.

  4. Page 15
    Correspondence: R. Verhaeghe, Centre for Vascular Diseases, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

    Clinical signs and symptoms are but the starting point for a correct diagnosis of pulmonary embolism (PE). They evoke suspicion and allow a classification of patients into categories of clinical probability of PE. This can be achieved either empirically or with the aid of formal prediction rules. Further diagnostic testing confirms or excludes PE.

    Over the last few decades, ventilation/perfusion scintigraphy was the most commonly used test. A perfusion scan is very sensitive to detect emboli and a high-probability scan calls for treatment, but the majority of patients have a nondiagnostic scan that requires further testing. Angiography, the gold standard, has well-established and reliable criteria to start or withhold treatment in suspected patients but is used reluctantly by many physicians. More recent tests are leg ultrasonography, D‐dimer, helical computed tomography (CT) and echocardiography.

    D‐dimer is a sensitive but poorly specific indicator of thromboembolism. Numerous assays for D‐dimer exist that are difficult to standardise. A normal D‐dimer (alone or in combination with other tests) virtually rules out clinically important PE in patients with a nonhigh clinical probability. The accuracy of helical CT is best for central pulmonary vessels and decreases towards peripheral vessels. The main question is to what extent are negative CT findings reliable, in order to withhold treatment. Echocardiography may be useful in patients with massive PE; it mainly shows signs of right ventricular overload, but visualises emboli less frequently. The latter two tests are likely to have a major impact on diagnostic strategies in the near future.

  5. Page 25
    Correspondence: R. Verhaeghe, Dept of Vascular Pathology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

    Treatment of pulmonary embolism (PE) aims to prevent death and recurrent thromboembolism. This is primarily achieved with standard anticoagulation, heparin relayed with oral anticoagulants. In the initial phase of treatment unfractionated heparin could be replaced by low molecular weight heparin in stable patients. The optimal duration of anticoagulant treatment is uncertain since current evidence suggests that prolonged anticoagulation delays rather than suppresses the recurrence risk.

    Initial thrombolytic treatment for acute PE is a debated issue. It is fairly well accepted for massive PE but controversial for submassive PE. A definite impact on mortality was never demonstrated and there is an increased bleeding risk. Current clinical practice prefers short-duration dosage schemes of thrombolytic agents. Embolectomy, if carried out, is a last resort intervention in a life-threatening situation.

    Venous filters aim at preventing recurrent embolism when anticoagulation fails or is impractical. In general, the insertion of a filter should not modify the anticoagulant management. Filters favour the recurrence of deep vein thrombosis and may have additional drawbacks and therefore their use should remain restrictive.

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    Correspondence: M. Delcroix, Dept of Pneumology, University Hospital Gasthuisberg, Herestraat 49, 3000, Leuven, Belgium.

    Pulmonary arterial hypertension is an infrequent and severe disorder, either idiopathic (primary pulmonary hypertension; PPH) or related to systemic connective tissue disease, congenital heart disease, portal hypertension, and human immunodeficiency virus infection, or to the use of drugs such as anorexigens. A genetic predisposition together with a precipitating factor is probably responsible for the development of the disease. A family history has been identified in >6% of all cases with PPH. The disease may be transmitted as an autosomal trait with a low penetrance of 10–20%. Heterozygous germline mutations in bone morphogenetic protein receptor (BMPR)‐II have been identified in 60% of the cases with familial PPH, and in 25% of the sporadic cases. Bone morphogenetic protein (BMP) molecules exert their effects by binding to a type‐II receptor, which results in recruitment and phosphorylation of a type‐I receptor, which in turn activates downstream signalling via several Smad transcription factor molecules, or via mitogen-activated protein kinases. A possible involved mechanism is a failure of the growth inhibitory effects of BMPs in PPH smooth muscle cells. Since the majority of PPH cases have no detectable BMPR2 mutation, it is likely that inherited susceptibility may result from a combination of several independently inherited genetic variants. Targeted prevention of pulmonary hypertension (PH) is expected from the identification of the gene responsible for familial PPH. Genetic testing in relatives of BMPR2 mutation carriers with familial or sporadic PPH should be performed within controlled studies or on specific request of patients or relatives adequately counselled and fully informed in the frame of genetic-counselling clinics.

    In order to determine the therapeutical options for individual patients, the reversibility of the PH has to be tested. The working group recommends the use of classical agents such as adenosine, epoprostenol and inhaled nitric oxide, and classical criteria (20% decrease in pulmonary arterial pressure and in pulmonary vascular resistance) because they have been validated as predictive for a long-term response to calcium-channel blocker (CCB) therapy. CCB are very cost-effective and should still be recommended as first-line therapy for responders even if they do not have antiproliferative properties.

    For the monitoring of treatment effects, the most frequently used parameters have been haemodynamics measured by right heart catheterisation and exercise capacity evaluated by the 6‐min walk test. Haemodynamics correlate well with survival, but the relevance of therapy-induced changes is questioned. Cardiopulmonary exercise testing is safe and sensitive to treatment effects, but a walking test is easier to perform and also very sensitive to treatment effects. Noninvasive evaluation through Echo-Doppler and magnetic resonance imaging needs further validation. These techniques can show significant improvement in morphology and function for both right and left ventricles. The working group advises repeat catheterisation only in the case of clinical deterioration. Pericardial effusion, right ventricular to left ventricular area ratio, tricuspid pressure gradient, pulmonary acceleration time, and right ventricular performance index seem to be the most valuable Echo-Doppler indexes. Quality of life has never been a primary end-point for the evaluation of patients with PPH.

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    Correspondence: M. Delcroix, Dept of Pneumology, University Hospital Gasthuisberg, Herestraat 49, 3000, Leuven, Belgium.

    Pulmonary arterial hypertension (PAH) is a life-threatening disease for which continuous intravenous prostaglandin (PG)I2 or epoprostenol has been proven effective in significantly improving functional class, exercise capacity, haemodynamics and survival. When the functional class and haemodynamics are significantly improved after 3 months of therapy, which happens in one-third of the patients, the 5‐yr survival is excellent (90%). However, this treatment requires a permanent central venous catheter with the associated risk of serious complications, such as sepsis, thromboembolism or syncope and it is extremely expensive. As a consequence new derivatives have been developed that are more stable and easier to administer. Treprostinil was the first PGI2 analogue developed for subcutaneous use. It has been shown to improve functionality, exercise capacity, and haemodynamics, but not survival over a 3‐month period. The most common side-effect is pain at the infusion site that can impair uptitration of the medication. Transition from intravenous epoprostenol to subcutaneous treprostinil can be safely achieved over a brief time period. Iloprost is the first PGI2 analogue developed for intermittent aerosolisation. Again it has been proven effective and safe. However, transition from intravenous epoprostenol to inhaled iloprost seems to be much more difficult. Finally, beraprost is the first PGI2 developed for enteral administration. It is relatively well tolerated, and has also been shown to improve exercise capacity.

    Endothelin-receptor antagonists have also been developed recently. Bosentan is the first one that has demonstrated efficacy in patients with PAH. It is well tolerated and induces a reversible dose-related increase in liver enzymes in a minority of the patients. Combination of PGI2 and anti-endothelins is currently under investigation.

    Atrial septostomy has been shown to improve functionality, exercise capacity, haemodynamics and survival in patients with terminal pulmonary hypertension (PH). The working group recommends that it is performed in patients with persistent poor functionality under maximal medical therapy.

    Single-, bilateral- and heart-lung transplantation (LTx) have been performed successfully in patients with primary PH. Right ventricular contractility seems intrinsically preserved as assessed by good recovery of systolic function after LTx, but the early postoperative period is often characterised by haemodynamic instability. There is no strong evidence to specify which is the optimal lung transplant procedure for PH. The choice largely depends on the local situation with organ donors and the experience of the transplant team. Single LTx is the preferred procedure in many US centres, while bilateral LTx is preferred at most European centres.

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    Correspondence: M. Delcroix, Dept of Pneumology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

    Even though prostaglandin I2 agonists and endothelin (ET) antagonists have been proven effective to improve quality of life and survival in patients with pulmonary arterial hypertension (PAH), there is still no cure for the disease. Further investigation towards new drugs is underway, exploring other metabolic pathways.

    Nitric oxide (NO) has been shown to be a very potent pulmonary vasodilator. The reduced production of NO observed in pulmonary hypertension (PH) can be compensated for in four different ways: 1) administration of inhaled NO, which necessitates sophisticated and clumsy devices; 2) nitric oxide synthase (NOS) gene transfer, which is limited by the short duration of gene expression in vivo and is still at a preclinical experimental stage; 3) use of oral inhibitors of the cyclic guanosine monophosphate, phosphodiesterase (PDE)5, which seems very promising in human pilot studies; and 4) oral supplementation of l-arginine, the substrate of NOS, also currently being investigated in patients with PAH.

    Serotonin (5‐HT) is a potent vasoconstrictor and is also involved in the smooth muscle proliferation. Both 5‐HT-receptor antagonists and 5‐HT-transporter inhibitors, respectively targeting these two aspects, are currently being investigated.

    The role of corticosteroids and immunosuppressants is probably limited to patients with PAH related to connective tissue disease clearly responding to this therapy. However, there is evidence of inflammatory involvement even in patients with primary PH and this supports present preclinical works on cytokines and anticytokines. Pharmacological synergism has been described between different pathways emphasising the role for combination therapies. Synergisms are described between 5‐HT-receptor blockers and PDE5 inhibitors, between 5‐HT transport and receptor activity, and between NO administration and ET antagonism.

    Some of the current therapeutic approaches of PAH are applicable, with certain restrictions, to PH secondary to pulmonary veno-occlusive disease, inoperable chronic thromboembolism and interstitial lung disease. Selective pulmonary vasodilation with preservation of the ventilation/perfusion adequacy is a key issue. This seems achievable through the inhalational route of application and perhaps also through vasodilators with some form of intrapulmonary selectivity as the PDE5 inhibitors. PH in chronic obstructive pulmonary disease, new physiopathological aspects of smoking-related vascular remodelling, and some treatment perspectives are also discussed in this chapter.

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    Correspondence: E.J.R. van Beek, Unit of Academic Radiology, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK.

    Pulmonary embolism is one of the most frequently encountered indications for diagnostic imaging. Standard techniques, such as chest radiology, lung scintigraphy and pulmonary angiography have been employed for many years. More recent developments have included helical computed tomography (CT) angiography and magnetic resonance imaging (MRI) techniques. However, the exact roles of these diagnostic modalities are still cause for debate, as these technical innovations have not yet been fully assessed.

    The current chapter adresses the evidence for use of pulmonary angiography, lung scintigraphy and MRI. It briefly describes their techniques and their diagnostic accuracy. The topic of helical CT is discussed elsewhere, but the recent developments and the future use of MRI techniques that are currently undergoing clinical trials are discussed in this chapter. Finally, several possible diagnostic algorithms are outlined that may be at the heart of diagnostic work-up in the future.

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    Correspondence: M. Remy-Jardin, Dept of Radiology, Hospital Calmette, University Centre of Lille, Blvd Jules Leclerq, 59037 Lille, France.

    Over the past 10 yrs, spiral computed tomography (CT) angiography of the pulmonary arteries has reached a high accuracy in the evaluation of pulmonary embolism (PE). The advantages of CT angiography compared with ventilation/perfusion scintigraphy and pulmonary angiography are related to the possibility of direct visualistion of clots within pulmonary arteries and the ability to provide alternative diagnoses when no abnormalities are found within the pulmonary circulation. The recent introduction of multislice CT technology has considerably improved the evaluation of peripheral pulmonary arteries, enabling high-resolution CT examinations of the entire thorax during short breath-hold periods. Since spiral CT is becoming more readily available, this chapter focuses on spiral CT angiography and discusses imaging technique, image interpretation, and the role of CT angiography in the diagnosis of PE.

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    Correspondence: A. Torbicki, Dept of Chest Medicine, Institute of Tuberculosis and Lung Diseases, 01-138, Warsaw, Poland.

    The diagnostic and prognostic value of echocardiography in pulmonary embolism (PE) is increasingly recognised. Indeed, there are specific Doppler echocardiographic signs of acute PE. Direct visualisation of thrombi in systemic veins, the right heart and proximal pulmonary arteries is possible, which by itself justifies initiation of treatment. Indirect signs of PE and of the severity of it are those of right ventricular (RV) overload. The association with moderate elevation of velocity of the tricuspid insufficiency jet indicates a worse prognosis up to 1 yr; this is even more so if a patent foramen ovale with right-to-left shunting is documented. Conversely, a normal RV echogram consistently indicates a good prognosis in patients with PE treated with anticoagulants. To conclude, current data strongly indicate that echocardiography provides clinically relevant information both in patients with suspected or with confirmed PE.

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    Correspondence: G. Agnelli, Sezione di Medicina Interna e Cardiovascolare, Dipartimento di Medicina Interna, Università di Perugia, Via Enrico dal Pozzo, 06123, Perugia, Italy.

    A number of issues on prophylaxis and treatment of venous thromboembolism (VTE) are still unresolved. Currently ongoing trials on primary prophylaxis of VTE are searching for more effective and safer anticoagulant agents and more practical regimens for extending prophylaxis after hospital discharge. The results of studies evaluating the efficacy and safety of new antithrombotic agents for the prophylaxis of VTE will be available in the next few months. Anticoagulants currently used for the treatment of VTE need close laboratory monitoring. Consensus exists concerning the need to identify simple, safe, effective, and widely applicable strategies for the long-term prevention of recurrent VTE. New oral anticoagulant agents that do not require laboratory monitoring are under investigation in clinical trials. The use of these new agents will simplify the treatment of VTE. A safer and easier thrombolytic regimen is needed to improve the clinical outcome of patients with acute pulmonary embolism and right ventricular dysfunction.

    To conclude, it is hoped that the new pharmacological agents currently under investigation will contribute to the solutions of these clinical problems making the prevention and treatment of VTE more effective, safer and easier.

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    Correspondence: A. Perrier, Medical Clinics 1 and 2, Dept of Internal Medicine, University Hospital, 24 Rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.

    Diagnosis of pulmonary embolism (PE) has undergone a major paradigm shift in recent years. No single noninvasive test has sufficient diagnostic accuracy to be used alone for diagnosing or ruling out PE. Even pulmonary angiography, a gold standard presently challenged by helical computed tomography (CT) scan, does not possess ideal diagnostic accuracy. Hence, modern diagnostic strategies for PE consist of combinations of non- or minimally invasive tests such as plasma D‐dimer measurement, lower limb venous compression ultrasonography, ventilation/perfusion lung scan and helical CT; pulmonary angiography being used only in rare cases of inconclusive noninvasive work-up. The value of clinical assessment in order to refine the interpretation of diagnostic tests is increasingly recognised and clinical probability of PE can be assessed with fair accuracy, either implicitly or by clinical prediction rules. Management studies in which patients deemed not to have PE are left untreated and followed up to assess their 3‐month thromboembolic risk have become the benchmark for the validation of diagnostic algorithms. Cost-effectiveness analysis allows the evaluation and comparison of the various diagnostic sequences. Finally, preliminary evidence shows that the implementation of evidence-based diagnostic algorithms is feasible and may increase the quality of care.

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    Correspondence: I.A. Greer, Dept of Obstetrics and Gynaecology, University of Glasgow, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow, G31 2ER, UK.

    Pulmonary thromboembolism is the major cause of maternal death in the UK. The major risk factors are increasing age particularly >35 yrs, operative vaginal delivery, Caesarean section and especially emergency Caesarean section in labour, high body mass index, previous venous thromboembolism (VTE) especially if idiopathic or thrombophilia associated, thrombophilia, and a family history of thrombosis suggestive of an underlying thrombophilia. Objective diagnosis is essential in the subject with signs or symptoms suggestive of thromboembolism. Ultrasound venography and ventilation/perfusion lung scans are the most common investigations but other techniques, such as helical computed tomography and magnetic resonance imaging can also be employed. Low molecular weight heparin is usually the treatment of choice for the acute and maintenance therapy of VTE in pregnancy because of a superior side-effect profile compared with unfractionated heparin, a good safety record for mother and foetus, and convenient dosing.

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    Correspondence: R. Naeije, Dept of Physiology, Erasme Campus of the Free University of Brussels, CP 604, 808, Lennik road, B-1070, Brussels, Belgium.

    Pulmonary arterial hypertension (PAH) is a syndrome of dyspnoea, fatigue, chest pain and syncope defined by an increase in pulmonary vascular resistance of unknown cause. The clinical presentation of PAH is explained by the inability of the excessively afterloaded right ventricle to increase output in response to peripheral oxygen demand. This is related to the steepness of the pulmonary artery pressure/flow relationship, and increased right ventricular systolic pressure by the combined effects of increased pulmonary arterial resistance, elastance, and wave reflection. The pathobiological understanding of PAH is making rapid progress. The gene of the purely primary form of PAH has been located on chromosome 2, and shown to present in approximately one-third of patients' mutations of a sequence that encodes for a transforming growth factor receptor, bone morphogenetic protein receptor‐II. How this mutation accounts for the disease remains presently unclear. Biological abnormalities have been identified in all pulmonary arterial wall compartments. The endothelium produces an excess of endothelin (ET), a potent vasoconstrictor and mitogen, while synthesis and release of antagonistic prostaglandin (PG)I2 and nitric oxide (NO) is decreased. Pulmonary vascular smooth muscle cells present with an increased expression of a serotonin transporter (5‐HTT), allowing for vasoconstrictive and mitogenic effects of circulating serotonin, and also show dysfunctional voltage-dependent potassium channels, which promote vasoreactivity and proliferation. The adventitial matrix-bound metalloproteases appear to be activated in relation to increased serine elastase, leading to increased production of tenascin, a potent mitogen. While none of these abnormalities solely explains PAH, their identification has already led to efficient therapeutic interventions, including the administration of PGI2 derivatives and anti‐ET compounds. Studies are underway to test the possible benefit of NO, 5‐HTT inhibitors, and matrix metalloproteinase or serine elastase antagonists. Lack of complete understanding of the pathobiology of PAH explains why current therapeutic approaches remain palliative.

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    Correspondence: G. Simonneau, Service de Pneumologie et Réanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140, Clamart, France.

    Several risk factors for pulmonary arterial hypertension have been recognised including drugs and toxins, demographic and medical conditions, and diseases. Conclusions regarding the causal relationship between risk factors and the development of pulmonary hypertension (PH) relate to the magnitude of the association, the temporality of the association, and consistency of the observations. The exact mechanism(s) by which the risk factors produce PH has not been established as yet. Given the fact that the absolute risk is generally low, factors of individual susceptibility are likely to play an important role.

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    Correspondence: A.J. Peacock, Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, G11 6NT, UK.

    There is no sphygmomanometer for the pulmonary circulation. The consequence of this lack of a simple test to make the measurement of pulmonary artery blood pressure means that the diagnosis is often made late at a time where there is already structural remodelling of the pulmonary circulation. This in turn means that the circulation is already resistant to the effects of vasodilators. In the past there have been few treatments for severe pulmonary arterial hypertension (PAH) and therefore no pressure to make the diagnosis earlier. However, with the advent of prostaglandin (PG)I2 and more recently a number of other drugs such as the PGI2 analogues, endothelin antagonists and other compounds, it is clear that effective treatments are now available. It is also clear that these treatments are likely to be more effective if given earlier in the course of the disease, before the structural changes have occurred and hence there is greater pressure to make the diagnosis earlier and give the patients a greater chance of survival. An enormous leap forward was the discovery of the gene for familial primary pulmonary hypertension (PPH), which also appears to be present in a proportion of those with so-called sporadic pulmonary hypertension (PH). Furthermore, it is now known that in many other causes of PH, such as human immunodeficiency virus, portopulmonary hypertension, connective tissue disease-associated hypertension and anorectic drug-associated PH, the histology is similar to so-called unexplained PPH. This suggests a common biological path that is in the process of being unravelled by basic scientists. The understanding of this pathobiology will of course lead to the developments of new therapies, which are aimed not so much at the consequences of the biological process but at the fundamental causes of that process. New drugs would be expected to interfere with cellular transduction, cell-signalling systems and genetic transcription factors. Once again, however, it is likely that these compounds will only be effective if given early. The knowledge of the genetic basis of the disease with the possibility of genetic screening and new techniques for noninvasive assessment in the pulmonary circulation, in particular, amplified echocardiography, magnetic resonance imaging and sophisticated cardiopulmonary exercise testing, means that there is a greater possibility for screening the population without needing a right heart catheter. At present it is not clear who should be screened; neither is it clear whether those screened and found to have mild PH would benefit from early therapy. The author believes that the answers to these tricky ethical and medical questions will come in the next few years. Researchers are on the threshold of a golden era of the management of PAH.

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    Correspondence: I.M Lang, Dept of Internal Medicine II, Division of Cardiology, University of Vienna, Währinger Gürtel 18–20, 1090, Vienna, Austria.

    Chronic thromboembolic pulmonary hypertension (CTEPH) is an enigmatic disorder characterised by a failure to resolve extensive pulmonary thromboemboli that results in severe pulmonary hypertension. Although CTEPH is believed to be a thromboembolic disease, the classical risk factors for venous thromboembolism are absent. The present chapter provides recent information on CTEPH-associated disorders that may provide new insights into the pathophysiology of this disease. Furthermore, the cell biology of pulmonary vascular occlusions are discussed, as well as typical diagnostic findings and a survey on traditional treatment strategies and prognostic factors.