Maria Klara Frey, Irene Lang
Clinical Cardiology Department, University Internal Medicine Clinic II,
Vienna Medical University, Austria
Although the disease “pulmonary hypertension” (PH) was described as long as 100 years ago, even today there is no comprehensive explanation of its pathogenesis, and nor are there currently any prospects of a cure for this disease. Despite growing awareness of this rare but serious disease, there is an average of two years between the initial consultation of a doctor and a diagnosis being made . If untreated, the idiopathic form (iPAH) results in death within 3 years .
The term PH is used if the average pressure in the pulmonary arterial system is ≥ 25 mmHg. Values below 20 mmHg are regarded as normal, values of between 21 and 24 mmHg are described as borderline (“borderline PH”). The supplementary definition of PH used to date – an increase in mPAP to values > 30 mmHg on exertion – has been dropped. Older people, in particular, reach high levels such as this relatively often on exertion, without suffering from pulmonary hypertension . The criterion of increased pulmonary vascular resistance of 2-3 Wood units is no longer part of the current definition either. Precapillary, pulmonary arterial hypertension is characterised by a pulmonary capillary wedge pressure of <15 mmHg.
Pulmonary arterial hypertension (PAH) covers a group of diseases characterised by the proliferation and remodelling of the distal pulmonary arteries. Loss of the pulmonary vasculature leads to an increase in right ventricular afterload and right heart insufficiency .
The prototype PH, idiopathic pulmonary arterial hypertension (iPAH), is an extremely rare disease with an incidence of 1 – 2 per million . The prevalence of PAH is about 15 per million . Idiopathic PAH affects women more often than men. The heritable forms of PAH (hPAH) are statistically linked to mutations in the “bone morphogenetic protein receptor II” (BMPR II) gene. Secondary forms of PAH (aPAH) are far more common; they include PAH secondary to connective tissue diseases, HIV infection, portal hypertension, congenital heart diseases, schistosomiasis and chronic haemolytic anaemia. All forms are diagnosed at a late stage because of their gradual onset and nonspecific symptoms.
PH is characterised by an increase in pulmonary arterial pressure and progressive obliteration of the vasculature. This results in right ventricular hypertrophy and/or dilatation, subsequently to right heart insufficiency and death from right heart failure. The focus of recent research has been the decoding of a large number of pathogenetic mechanisms at both a molecular and a genetic level. The basis for current treatment approaches is the imbalance between vasoconstriction and vasodilation, with the imbalance observed between proliferation and apoptosis in the vascular wall in affected patients becoming increasingly important. The concept of reverse remodelling is increasingly being picked up for the future development of treatments.
In histological terms, changes are observed in all three layers of the pulmonary arteria vascular wall: concentric intimal proliferation, hypertrophy of the tunica media and adventitial fibroblast proliferation. “Plexiform lesions” (endothelial cell proliferation resembling glomeruli) and blood clots in situ are also typical findings. This “pan-vasculopathy” chiefly affects small pulmonary vessels, known as the resistance vessels.
At a genetic level, various mutations have been detected in the “bone morphogenetic protein receptor II” (BMPR II) gene in heritable PH. These mutations occur in heritable PAH (in 60% of cases) but also in the sporadic form of PAH (in 25% of cases) . The ligands for this receptor are members of the TGF-beta family and are important for the differentiation, proliferation and apoptosis of many types of cell. Activin-like kinase 1 (ALK 1) mutations which have been described in patients with hereditary haemorrhagic telangiectasia and PAH also appear to play a decisive role in the differentiation and stabilisation of blood vessels.
In the past, a distinction was made between primary (idiopathic) pulmonary hypertension of unknown cause and a secondary form resulting from underlying diseases. However, this concept was dropped at the WHO 3rd Symposium on Pulmonary Hypertension in 2003 in Venice as a result of new scientific findings about the pathophysiology, molecular biology and clinical symptoms. The “Venice classification” distinguishes between 5 major groups, with primary PH (PPH) today being described as idiopathic PAH (iPAH). During the 4th World Symposium on PH, in 2008 in Dana Point, California, an international conference of experts decided to retain the general philosophy and organisation of this “Venice Classification” (Table 1). However, on the basis of recent publications, slight modifications were made, affecting Group 1 of the Venice Classification, pulmonary arterial hypertension, in particular.
An accurate diagnosis assigning patients affected to one of the PH groups is important because of the different therapy strategies. While patients assigned to Group 1 of the Dana Point Classification are given specific vasodilatory therapies, the main focus of treatment in Groups 2, 3 and 5 is geared to treating the underlying cardiac or pulmonary disease. The differential diagnosis of chronic, thromboembolic pulmonary hypertension (CTEPH) (Group 4 of the Dana Point Classification) is of particular importance because this is the only form of pulmonary hypertension that is curable by means of pulmonary endarterectomy (PEA) and lifetime oral anticoagulation.
1. Pulmonary arterial hypertension
1.1. Idiopathic pulmonary arterial hypertension (iPAH)
iPAH is a sporadic disease with neither a family predisposition nor definite risk factors. However, mutations were found in the BMPR II gene in between 11 and 40% of supposedly idiopathic forms with no family background, so that a clear distinction between idiopathic and family BMPR II mutations is problematic and would appear to be artificial .
1.2. Heritable pulmonary arterial hypertension
A hereditary disease is involved in all patients with BMPR II mutations, regardless of whether the mutation is occurring for the first time (de novo mutation) or has already been present in family members. For this reason, the new classification should no longer refer to “familial PAH” but to a “heritable” form. Genetic testing as a result of the new category of “heritable PAH” is, however, not generally necessary for all patients with iPAH or familial cases of PAH. The gene has very low penetration so that manifestation of the disease occurs in only 20% of all carriers of the mutation. If genetic testing is desired, this should be undertaken only after a detailed discussion of the risks, possibilities and consequences of this testing.
1.3. PAH associated with drugs and toxins
An epidemic occurrence of PAH was seen in Austria, Germany and Switzerland in the 1960s in connection with patients taking aminorex. Thirty years later, fenfluramine and dexfenfluramine, two appetite suppressants authorised in the USA, were taken off the market as a result of increased numbers of cases of PAH. Chronic cocaine or amphetamine abuse also increases the risk of developing PAH. According to a recent case-control study, selective serotonin receptor inhibitors taken by pregnant women increase the risk of persistent PH in the neonate (1.5 in the Dana Point classification) .
1.4. Pulmonary arterial hypertension secondary to diseases such as:
1.4.1. Connective tissue diseases
Pulmonary hypertension may develop as a complication of various connective tissue diseases. Patients with progressive systemic sclerosis are particularly frequently affected, prospective studies having demonstrated a prevalence of about 12% . It is interesting to note that PAH is not the only form of PH found with systemic sclerosis. Interstitial lung disease (PH with interstitial lung disease, 3.2.) and diastolic dysfunction (2.2. of the Dana Point classification) in the context of systemic sclerosis may also result in increased pressure in the small circulatory system . If pulmonary hypertension is suspected, these patients should therefore be assessed precisely so as to allow for accurate classification and hence the relevant treatment. Several studies have shown that the prognosis for PAH secondary to systemic sclerosis is less good, despite modern treatment, than in patients with iPAH.
1.4.2. HIV infection
In cases of HIV infection with unclear dyspnoea on exertion, the possibility of pulmonary hypertension should always be considered after ruling out typical secondary disorders. The incidence of pulmonary hypertension in the HIV population is some 1,000 times higher than in the general population (approximately 0.5% of all patients infected with HIV develop PAH). Here, again, the molecular mechanisms that lead to the disease have not been clarified but there appears to be an unequivocal correlation between the number of CD4-positive lymphocytes and disease activity. Because neither the virus itself nor viral DNA has been found in endothelial cells of the pulmonary vessels, secondary messengers, such as cytokines, growth factors, endothelin and viral proteins have been discussed.
1.4.3. Portal hypertension (= portopulmonary hypertension = PPHT)
Between 2 and 6% of all patients with portal hypertension develop PAH, and far greater numbers must be assumed for patients with advanced cirrhosis of the liver and ascites . The underlying pathomechanisms are speculative. It is possible that increased pulmonary blood flow and microthrombi are involved. The severity of the liver disease does not correlate with the prevalence of PPHT, whereas female gender and autoimmune diseases are linked to increased prevalence .
1.4.4. Congenital heart diseases
Between 5 and 10% of all patients with congenital shunts develop PAH. Morbidity and mortality in these patients depend on the heart defect involved. Increased pressure / volume load and shear stress on pulmonary endothelial cells are potential mechanisms, as is a genetic susceptibility. A shunt reversal (Eisenmenger syndrome) may develop as a result of the increased pulmonary vascular resistance.
One major change in the new classification involves PH secondary to schistosomiasis. This form was previously considered one of the thromboembolic and/or embolic diseases based on an assumption of the pulmonary arteries being obstructed by Schistosoma eggs. However, recent publications show that both the clinical symptoms and the histopathology (plexiform lesions) exhibit major similarities to iPAH. Local inflammation triggered by parasitic antigens is being discussed as the pathomechanism. Migration of the parasites causes portopulmonary hypertension, a common complication of the disease that further encourages the development of pulmonary hypertension . Over 200 million people globally are infected with schistosomiasis, about 1% of the chronically ill patients developing PH. PAH secondary to schistosomiasis is thus probably the most common form of PH, but clinical trials rarely include this group. Unfortunately, those affected seldom have access to specific treatments.
1.4.6. Chronic haemolytic anaemia
PAH may occur as a complication of chronic hereditary and acquired haemolytic anaemia, including sickle cell anaemia, thalassaemia, hereditary spherocytosis, acquired spherocytosis and microangiopathic haemolytic anaemia. The pathomechanism under discussion is increased NO consumption by free haemoglobin but chronic inflammatory processes and microthromboses are probably also involved in the development of the disease.
1.5. Persistent pulmonary hypertension of the newborn
Absent or delayed postnatal adaptation of the pulmonary vascular system causes the development of PPHN. PPHN has an incidence of 0.43 to 6.8 cases per 1,000 live births and has a mortality rate of between 10 and 20%. In the event of response to therapy, PPHN has a favourable prognosis and generally results in complete recovery.
1. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary haemangiomatosis (PCH)
These very rare diseases have been classed in PH Group I since the Venice Classification (2003). Previously they were assigned to Group II, pulmonary venous hypertension. The initial categorisation in Group II was made on the basis of detection of fibrous intimal lesions in the region of the pulmonary venous vascular bed as an indication of pulmonary occlusive venopathy. But, in addition to the venous intimal fibrosis, PVOD also involves capillary and arterial damage to the pulmonary vasculature. In clinical terms, patients with PVOD/PCH often present with very similar symptoms to those of patients with iPAH. “Drumstick fingers” and bilateral basal crackles on auscultation of the lungs may be indications of the presence of PVOD. The detection, in high-resolution computed tomography of the lung, of accentuated septal lines, mediastinal adenopathy and ground-glass opacity of the parenchyma of the lung, particularly in a centrilobular position, should arouse suspicion of the existence of PVOD in cases of PH of unclear origin. Aggressive progress with poor therapeutic response is typical of these forms of the disease. Administering prostacyclins may cause potentially fatal pulmonary oedema.
2. Pulmonary hypertension secondary to left heart diseases
PH with left heart disease is one of the most important differential diagnoses for PAH. In contrast to PAH, the increased pulmonary pressure is not the result of pathology of the precapillary pulmonary circulation but develops as a result of left atrial or left ventricular pressure increase. Pulmonary vascular resistance is normal or only slightly increased (<3.0 Wood units) and there is no gradient between mean PAP and wedge pressure (trans-pulmonary gradient <12 mmHg). A number of valvular and/or myocardial diseases, such as mitral and aortic valve pathologies or cardiomyopathies, for example, may be responsible. The new classification distinguishes between 3 sub-groups (systolic and diastolic left ventricular dysfunction and left heart valve diseases).
3. Pulmonary hypertension secondary to lung diseases and/or hypoxaemia
Patients with chronic lung diseases and/or hypoxaemia may develop increased pulmonary vascular resistance as a result of hypoxic vasoconstriction of the pulmonary arteries. The mean pulmonary arterial pressure is usually only slightly raised (mPAP <35 mmHg). In the case of higher pressure values and only minor damage to the lung parenchyma, reference is made again here to “out-of-proportion PH”. The prevalence of PH with lung diseases is unclear. A retrospective study diagnosed PH on right heart catheterisation in only 1% of just under 1,000 patients with COPD . The survival of the patients is determined not by the pulmonary vessel disease but by the severity of the lung disease.
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
Chronic thromboembolic pulmonary hypertension develops as a reaction to single or recurrent pulmonary embolisms if thrombi lead to fibrotic remodelling processes in the vascular walls and obstruction of the pulmonary blood vessels. Any resulting increase in pulmonary vessel resistance causes chronic right heart stress. It is estimated that up to 4% of all patients with acute pulmonary embolism develop CTEPH . An early pulmonary embolism, young age, major perfusion defect and idiopathic presentation are linked to an increased probability of developing CTEPH in this context. The true incidence of CTEPH might even be higher since no history of a thromboembolic event can be ascertained in one third of those affected . Factors linked to an increased risk of developing CTEPH are status post-splenectomy, ventriculo-atrial (VA) shunt for the treatment of hydrocephalus, osteomyelitis, chronic inflammatory bowel diseases, malignancies and thyroid replacement therapy . Antiphospholipid antibodies were diagnosed in 10 to 20% of all patients and increased plasma factor VIII in 25% .
A positive segmental ventilation/perfusion scan is diagnostic for CTEPH. Computed tomography and pulmonary angiography can be used to determine the anatomical position of the blood clots within the pulmonary vascular tree, which is an essential criterion for operability.
The treatment of choice is surgical endarterectomy of the pulmonary obstructions, which results in a functional cure for 80 per cent of patients. The surgical risk depends not only on the experience of the surgical team but also on the selection of patients. Thus, patients with no CTEPH risk disease have a surgical mortality rate of about 4%; patients with splenectomy, VA shunt, osteomyelitis or chronic inflammatory bowel disease, on the other hand, have a 20% of dying during surgery .
In inoperable cases or cases of persistent PAH, it may be possible to improve symptoms and long-term survival with drug therapy. Lifetime oral anticoagulation is indicated for patients with CTEPH even after successful surgery.
5. Pulmonary hypertension with other diseases
This category includes diseases that may cause pulmonary hypertension as a result of inflammatory processes or mechanical obstruction (haematological diseases, sarcoidosis, storage diseases, tumours, etc.). Treatment is restricted to treatment of the underlying disease.
The keys to diagnosis are a detailed history and thorough clinical examination of the patient. The affected person should be transferred to a specialist centre for clarification. Only those patients in whom the risk of developing PH is substantially raised should undergo screening. This includes patients with a known BMPR II mutation, scleroderma and patients with portal hypertension who are being assessed for a liver transplant.
International specialist associations differentiate between 4 diagnostic steps: suspicion, detection, categorisation in the Dana Point classification system, evaluation of the severity. Functional classification is undertaken on the basis of NYHA Classes I-IV (Table 2). Patients in NYHA classes I or II at the time of diagnosis have a mean survival of 6 years in comparison with a mean survival of 2.5 years and 6 months respectively in NYHA classes III and IV where the disease is already at an advanced stage. Another option for assessing severity is provided by the 6-minute walk test (6-minute walk distance, 6MWD), in which the distance covered by a patient in 6 minutes is measured. The 6MWD has good prognostic value and is therefore used as a primary endpoint in many studies. It also constitutes a good parameter for progress during treatment. The maximum oxygen uptake (peak VO2) measured during a bicycle ergometer test is also an independent predictor of mortality .
Symptoms usually develop gradually and only manifest at a loss of more than 60% of pulmonary vasculature. Although dyspnoea (particularly breathlessness caused by activity) is a common early symptom, it is not a cardinal symptom. Fatigue, reduced performance, chest pain, recurring syncope on activity and after attacks of coughing, haemoptysis (which may occur with all forms of pulmonary hypertension) and dizziness are other symptoms.
Tachycardia and left parasternal or epigastric heaves of the right ventricle are observed. The second heart sound is emphasised and a pansystolic heart murmur can be heard, suggesting tricuspid insufficiency. Pulmonary insufficiency can occasionally be heard on auscultation. In the advanced stage, oedema of the legs, ascites, distention of the veins of the neck, hepatomegaly and cyanosis are also present as signs of right heart decompensation. Findings from auscultation of the lungs are usually normal.
Blood gas analysis is normal in the early stages, later pO2 is reduced, pCO2 increased, later reduced and HCO3 increased. The red blood count in advanced stages of PH secondary to congenital heart disease or hypoxaemia presents polycythaemia and haematocrit > 50%. In cases of iPAH, both atrial natriuretic peptide (ANP) and “brain natriuretic peptide” (BNP) correlate with survival, and BNP and NT-BNP are independent predictors of mortality . Increased uric acid (resulting from compromised oxidative metabolism) and increased troponin T levels (resulting from right ventricular ischaemia) correlate with a poor prognosis  . At present, proBNP levels are the most commonly used biomarkers. They correlate with enlargement, compressive stress and reduced function of the right ventricle.
ECG has specificity of 70% and sensitivity of 55% in the diagnosis of PH . The ECG signs of right ventricular dysfunction are right bundle branch block, rotation of the electrical cardiac axis to the right, right heart hypertrophy (R>S in V1), right ventricular repolarisation dysfunction (“right ventricular strain” RVS) and a “P pulmonale” indicating an enlarged right atrium (Figure 1) .
New algorithm with ECG and NT-proBNP
In the event of clinical and echocardiographic suspicion of PAH, the ECG is first checked for the presence of T wave inversions/ ST segment depressions in the chest leads (V2–V4) (“right ventricular strain pattern” – RVS). If RVS is found, the patient should always be referred for RHC. If RVS is not present, the serum concentration of NT-proBNP decides whether RHC should be performed. PAH can be ruled out with a probability verging on certainty in patients with no RVS and NT-proBNP levels ≤ 80 pg/ml. RHC is therefore not required. Thus, by using an electrocardiogram and serum values of n-terminal natriuretic peptide, 90% of all exclusion catheterisations can be avoided without overlooking a single case of genuine pulmonary arterial hypertension .
Typical findings involve abrupt changes in diameter in pulmonary blood vessels with dilated central pulmonary arteries and a loss of peripheral blood vessels. Enlargement of the right atrium and/or ventricle can also be seen. A normal chest x-ray does not rule out PH.
Transthoracic echocardiography (TTE)
The importance of echocardiography as a screening method in cases of clinical suspicion of PAH is undisputed. However, it is not possible to use it to distinguish between pre- and post-capillary pulmonary hypertension. A further limitation is the fact that the pressure in the small circulation system estimated using echocardiography is under- or overestimated by over 20% in more than 50% of cases. If the systolic pulmonary pressure estimated with echocardiography is between 37 and 50 mmHg, PAH is a possibility and the European guidelines currently in force provide for a Class IIa indication for carrying out right heart catheterisation (RHC). If the systolic pulmonary pressure in the echocardiogram is more than 50 mmHg, PAH is likely and RHC should always be performed (Class I indication).
Parameters for assessment of the pulmonary circulation are: systolic pulmonary arterial pressure, right heart dimensions, right ventricular function, right ventricular mass and tricuspid regurgitation. Prognostic parameters that can be ascertained using echocardiography are pericardial effusion, the size of the right atrium and the size ratio between right and left end-diastolic diameter. TAPSE (Tricuspid Annular Plane Systolic Excursion) can also be used to draw conclusions about mean survival. A TAPSE <1.8cm is linked to greater right ventricular systolic dysfunction. In addition, TTE allows the diagnosis of a potential underlying cause (e.g. shunt defect, valvular or myocardial disease).
Ventilation/perfusion scintigraphy of the lung (V/Q scan)
The V/Q scan is important for the diagnosis of CTEPH. A segmentally positive V/Q scan is diagnostic for CTEPH if at least one major defect is present .
A spiral CT investigation with intravenously administered contrast medium is an informative option for diagnosis. CT is particularly suitable for assessment of the lung parenchyma and the vessels around the heart.
For patients with CTEPH, surgical thrombendarterectomy is a possible cure. Pulmonary angiography is a valuable method for planning the operation. It provides accurate information about the location of intraluminal filling defects, stenosis and occlusions.
Right heart catheter and haemodynamic testing
A diagnosis of PH can only be made with a positive right heart catheterisation finding. Measurement of the pulmonary vascular resistance (PVR), cardiac index (CI) and mean right atrial pressure (mRAP) allows statements to be made regarding the severity and hence the prognosis for the patient. On the basis of current data, the CI, mRAP and mPAP parameters are independent predictors of survival, although it must be borne in mind that mPAP also falls with decreased right ventricular function.
A complete right heart catheter examination should include measurement of the pulmonary capillary wedge pressure (PCWP) using a balloon catheter in various sections of the pulmonary vascular system. This permits differentiation between pre- and post-capillary PH. If optimal measurement of the PCWP is not possible or is in doubt, left ventricular end-diastolic pressure (LVEDP) may also be determined. A primary measurement of LVEDP is also recommended in patients in whom there is a high probability of a left ventricular cause of the symptoms (e.g. orthopnoea).
A test of pulmonary vasoreactivity is recommended in principle for all patients with documented pulmonary hypertension. The acute response to vasodilators correlates well with the underlying vascular morphology and thus constitutes a good prognostic parameter. Those patients in whom the mean pulmonary arterial pressure (mPAP) drops by at least 10 mmHg below an absolute value of 40 mmHg are described as responders. Cardiac output should increase or at least remain unchanged at the same time. The vasoreactivity test should only be performed using substances with a short half-life. Test substances recommended by the European Society of Cardiology (ESC) are epoprostenol, adenosine and nitric oxide (NO). Approximately 10% of all adults with idiopathic PAH are haemodynamic responders. High-dose calcium channel blocker therapy is indicated for these patients. Genuine responders have an excellent prognosis with a 5-year survival rate of almost 95% .
Therapy goals are an improvement in symptoms, quality of life and survival. Changes in functional capacity (6-minute walk test, ergometry, etc.) and haemodynamics are used to assess therapeutic success. In principle, PH patients should always be managed by specialist centres.
In general, patients affected by this condition should avoid physical exertion since this may lead to dramatic increases in pulmonary vascular pressure. Efficient infection prophylaxis and aggressive treatment of infections should also be ensured. Since 50% of all pregnancies in PH women have a fatal outcome, strict contraception is recommended.
1. Oral anticoagulation
Blood clots in the small resistance vessels of the lung are a common phenomenon in PH. On the basis of one prospective and two retrospective trials, oral anticoagulation is recommended for all patients with iPAH. The European Society of Cardiology (ESC) recommends an INR of between 1.5 and 2.5 as the target value. Few data are available regarding anticoagulation in associated forms of PAH. The international expert consensus is that anticoagulation is recommended for these patients only at an advanced stage of the disease (e.g. patients receiving continuous i.v. therapy). For patients with CTEPH, oral anticoagulation with a target INR of 2.5–3.5 is indicated in order to prevent any further thrombotic event.
Diuretics are used to treat right heart failure, which may result in ascites and peripheral oedema at an advanced stage of the disease. Calcium-sparing diuretics are preferred because of their aldosterone-antagonising action and are given once daily. However no clinical trials are available in this patient population so that the selection of substance class and dosage is left to the experience of the physician treating the patient.
The majority of patients with PAH has only mild arterial hypoxaemia. Patients with a patent foramen ovale may develop considerable hypoxaemia. Although no consistent trial data are currently available, the ESC recommends oxygen therapy for all patients.
4. Digitalis and dobutamine
It has been demonstrated that short-term intravenous administration of digoxin in cases of iPAH causes a slight improvement in cardiac output and a significant reduction in circulating norepinephrine . However, since no data are available proving the effect of long-term treatment with positive inotropic agents, the use of these substances is left to the doctor treating the patient.
5. Specific vasodilators
A number of specific vasodilators are currently available for the treatment of PAH. The substances listed are recommended by international professional associations on the basis of positive trial results.
5.1. Calcium channel antagonists. The use of calcium channel blockers is only justified in cases of genuine haemodynamic responders with idiopathic PAH. The success of the treatment must be documented consistently. If patients who are described by definition as “acute responders” do not achieve functional stages I or II under calcium channel blocker therapy, an alternative or additional PAH treatment should be considered. The substances used in trials are nifedipine (120–240 mg/day) or diltiazem (240–720 mg/day). Arterial hypotension and oedema of the legs are particular limiting factors for this treatment.
5.2. Beta-blockers. According to the recommendation of the Guidelines, beta-blockers are contraindicated in PH because of their negative inotropic action. Recent data contradict this dogma: the favourable effect of beta-blockers has in fact been illustrated in an animal model .
5.3. Synthetic prostacyclin and prostacyclin analogues. Prostanoids have a vasodilatory, anti-proliferative, anti-inflammatory and anticoagulant action. The current treatment algorithm provides for prostanoids only once patients have reached NYHA stages III and IV and for patients with right ventricular decompensation. This recommendation is arbitrary and tends to correspond more to patient desires than to evidence-based medicine. No trial exists that proves that what is known as a “goal-oriented” approach is better than a “hit-hard-and-early” strategy. In practice, the former results in significant time losses .
5.3.1. Epoprostenol (Flolan®, Dynovas®) is given intravenously. It is given on an outpatient basis using a portable infusion pump linked to a permanent central venous catheter (Hickman line) because of its short half-life (3 to 5 minutes). The dose may be altered according to requirement and tolerability, with one limiting factor here being the development of side effects, such as gastrointestinal symptoms, headache, jaw pain, diarrhoea, flush, nausea, joint pain or hypotension. The conventional starting dose under inpatient conditions is 2 ng/kg/min, gradually increased as a function of the PAH symptoms and the side effects. Most experts believe that the optimum dose for chronic treatment is 25-40 ng/kg/min, with customised adjustment being undertaken.
5.3.2. Treprostinil (Remodulin®) is given subcutaneously. The action is just as good as that of its benzidine analogue epoprostenol, but with treprostinil it is pain at the injection site that is the main limiting factor. Subcutaneous treprostinil has been authorised since 2002 for functional classes NYHA II, III and IV. The TRIUMPH trial was able to demonstrate the efficacy of inhaled treprostinil , while oral pharmaceutical forms were unable to demonstrate any benefit for patients with PAH in trials that have not yet been published.
5.3.3. Inhaled iloprost (Ventavis®) is well established in trials but almost exclusively used as a supplementary therapy in practice. One reason for this might be the fact that, because of its short half-life, iloprost has to be taken every 90 minutes. It has been authorised since 2004 for functional classes NYHA III and IV. Improvements in terms of performance efficiency, NYHA class and haemodynamics have been observed in randomised trials .
5.3.4. Selexipag is the first selective, orally administered prostacyclin receptor agonist. This class of substances is unique and new. A placebo-controlled double-blind trial was able to demonstrate a statistically significant reduction in pulmonary vascular resistance (PVR – as primary endpoint of the trial) after 17 weeks. With a reduction of 30% in PVR, this primary endpoint was therefore achieved with a high level of statistical significance.
5.4. Endothelin receptor antagonists (ERA). Endothelin (ET) is a strong vasoconstrictor which is created in increased amounts in PH patients and leads to vasoconstriction and remodelling. Endothelin also stimulates the proliferation of smooth muscle cells in the pulmonary blood vessels. Two endothelin receptors are known (ET-A and ET-B), blockade of which results in vasodilation without reflex tachycardia and in improvement of endothelial function. Endothelin-1 plasma levels correlate with the severity and prognosis of the disease.
5.4.1 Bosentan (Tracleer®) is a “dual ERA”, i.e. it blocks both endothelin A and B receptors. Trials have shown that bosentan improves physical capacity, haemodynamics and possibly also the survival of patients with PH. However, 6% of patients developed a reversible increase in liver enzyme levels, so that monthly monitoring of transaminases is recommended. An improvement in haemodynamics and functional capacity was also achieved in patients with Eisenmenger syndrome (BREATHE 5 trial) . The initial data from an open-label trial in HIV patients show a clinical improvement with bosentan  and preliminary data for patients with CTEPH also provide evidence of improvement with bosentan .
5.4.2 Ambrisentan (Volibris®). Ambrisentan also selectively inhibits the endothelin A receptor. The ARIES trial demonstrated the efficacy of ambrisentan with an improvement in 6-minute walk distance and with a longer “time to clinical worsening” . Ambrisentan has been authorised for PAH patients in NYHA functional classes II and III since June 2007.
5.5. Phosphodiesterase (PDE-)inhibitors.
5.5.1. Sildenafil (Revatio®) is a PDE5 inhibitor that was developed for the treatment of erectile dysfunction (Viagra®). By increasing the intracellular concentration of cyclic GMP (cGMP), it reduces the tone of smooth vascular musculature. Clinical trials demonstrated improved performance capacity and haemodynamics during treatment . Sildenafil has been authorised for the treatment of PAH in Austria since February 2006.
5.5.2. Tadalafil (Adcirca®) is also a PDE5 inhibitor developed, like sildenafil, for the treatment of erectile dysfunction (Cialis®). Its advantage over sildenafil is the longer half-life requiring tablets to be taken only once daily (in comparison with the three times daily dosage of sildenafil) and the absence of interaction with ERAs.
5.5.3. Stimulators of soluble guanylate cyclase. The prototype of this new group of drugs is riociguat, which is currently being tested in randomised trials. A Phase 2 trial demonstrated improvements in 6MWD .
5.6. Combined therapies. In cases of lack of response or clinical deterioration with a single treatment, combined therapies are being increasingly publicised that take advantage of the various pathobiological mechanisms of the treatments available. However, care must be taken to avoid drug-drug interactions. For example, interactions have been reported between sildenafil and bosentan (increase in bosentan plasma levels and decrease in sildenafil plasma levels), although the clinical relevance of these observations is not yet clear. The ERAs bosentan and sitaxentan and the PDE5 inhibitor sildenafil act in particular on various CYP enzymes, whereas this is not the case with prostanoids and the ERA ambrisentan. Combination trials currently in progress should create greater clarity regarding the risks and benefits of different combinations of PAH-specific therapies.
5.7. Start of treatment. Since the World Symposium on Pulmonary Hypertension at Dana Point in 2008, targeted therapy is recommended even for patients who are at an early stage of the disease. The basis of this recommendation is findings from three randomised, placebo-controlled trials, in which patients in NYHA stages II and III were included. Early therapy with bosentan, ambrisentan and/or sildenafil was found to be of benefit to these patients. In Europe, the endothelin receptor antagonists bosentan and ambrisentan are the only substances authorised for the treatment of Stage II PAH  [38, 39].
5.8. Treatment of “non-PAH pulmonary hypertension” (non – PAH PH). The post-capillary form, i.e. pulmonary hypertension linked to increased left ventricular filling pressure, is the most common form of PH (post-capillary PH). It includes all the diseases that lead to an increased left ventricular end-diastolic pressure (LVEDP), i.e. reduced systolic function, diastolic dysfunction and valvular disease. The aim here is to cure or treat the underlying disease. But a specific therapy may be indicated in very rare cases if the underlying disease is being optimally treated, the PCWP is normal or minimally increased, pulmonary vascular resistance is significantly increased and an improvement of the clinical condition of the patient appears possible with a PAH-specific therapy. This form of PH is described as “out of proportion PH”, in other words greater than would be assumed from the raised left ventricular filling pressure or the lung disease. However, caution should be exercised before generally treating these patients with PAH-specific therapy until clinical trials have proved a benefit for these patients. Potential side effects of PAH-specific treatment for these patients are fluid retention, pulmonary oedema and a ventilation/perfusion mismatch .
1. Atrial septostomy
The creation of this right-left shunt is indicated in cases of right heart failure and syncope despite maximum conservative therapy. The aim is to reduce the right ventricular end-diastolic pressure. This procedure may also be used as a bridging measure before other forms of treatment.
2. Pulmonary thrombendarterectomy (PEA)
PEA is the treatment of choice for patients with CTEPH. In this operation, the blood clot and some of the vascular media are dissected out of the pulmonary vessel. The indication is based on functional restriction, haemodynamics and location of the blood clots (more central or more peripheral). Whether thromboembolic lesions can be reached depends very much on the experience of the surgical team. In the ideal case, thrombotic material can be removed even from subsegmental vascular sections. The prerequisite for PEA is oral anticoagulation for at least 3 months. Perioperative mortality is reported as between 5 and 24% depending on the centre. With a 5-year survival rate of 75–80%, PEA is clearly superior to drug therapy and also to lung transplant and should therefore be undertaken in all patients who meet the criteria for surgery.
3. Lung transplant
If the condition of a patient does not improve despite the maximum drug therapy, lung transplant constitutes a further option. The 5-year survival rate for this procedure is about 45%.
Because of the complexity of both the disease and the treatment, patients with PAH should be very closely monitored. For patients in the early stages of the disease, being given oral therapy, six-monthly check-ups are recommended. Patients at an advanced stage of the disease, particularly those receiving parenteral or combined therapy, should be observed in specialist centres at three-monthly intervals.
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Correspondence: Prof. Dr. Irene Lang, Klinische Abteilung für Kardiologie, Universitätsklinik für Innere Medizin II, Medizinische Universität Wien, Währinger Gürtel 18–20, 1090 Wien, Austria, e-mail: firstname.lastname@example.org
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