Pulmonary Hypertension


Classification :

The use of a classification of pulmonary hypertension aims to individualize the categories of diseases with similarities in their pathophysiology, clinical presentation and management. A classification of pulmonary hypertension has been proposed for the first time in 1998, this classification was reviewed and amended at the World Pulmonary Arterial Hypertension we Symposium, held in Venice 2003.

Pulmonary HypertensionUnder the term of pulmonary hypertension (Htap) are grouped various diseases affecting the pulmonary arteries of small caliber, causing a gradual increase in pulmonary arterial resistance and right ventricular failure. Diseases grouped under the term PAH are separated into three main subgroups : the idiopathic PAH (formerly called primitive PAH) defined by the occurrence of the disease in the absence of an associated condition, familial PAH and PAH associated with various pathologies (connectivite, congenital heart disease, hypertension portale, Infection with HIV (VIH), toxic consumption or intake of anorectic). In the new classification, the idiopathic PAH and PAH associated with these various pathologies are now close, because these situations are characterized by pulmonary endothelial dysfunction, and similar histological changes and a similar clinical profile, justifying an identical clinical care.

To these three subgroups, must be associated veinoocclusive disease and pulmonary capillary hemangiomatosis which are characterized by a capillary venular or predominant reached. Both diseases present a risk of pulmonary edema when treated with prostacyclin. However, their numerous clinical and pathophysiological similarities with idiopathic PAH justified to include them in the PAH group.

By definition, pulmonary hypertension (HTP) called "secondary" to a well-identified cause can benefit from specific treatment such as pulmonary embolism chronic post-heart (HTP obstructive), left heart failure (post-capillary passive HTP) or chronic respiratory pathologies (HTP hypoxiques), do not belong to the group of actual PAH. Various pathologies constituting rare causes of PH are now individualized (sarcoïdose, histiocytose X, lymphangiomatose). Extensive work was interesting to variants of PH, generally disproportionate with the observed lung function abnormalities, make evoke a specific pulmonary vascular disease. Finally, HTP due to extrinsic compression of pulmonary vessels by lymphadenopathy, tumors or mediastinal fibrosis are also classified separately.

Pathological anatomy :

Our current knowledge of the lesions observed in PAH is based on histological examination of lung explants, sampling postmortem and rarely surgical lung biopsies. The evaluation and classification of venous and capillary damage are newer and integrated into the classification of pulmonary vasculopathy.

typical lesions of pulmonary arterial hypertension :

The plexiform arteriopathy is a characteristic lesion of PAH, unprecedented in our experience during HTP or pure thromboembolism (sometimes recanalization and organization of thromboembolic lesions can simulate a plexiform lesion). Histologiquement, the plexiform combines arterial medial hypertrophy, fibrosis of the intima, plexiform lesions and organized and recanalized thrombosis.

The arterial lesions may be monomorphic or variously associated in the same patient : isolated medial hypertrophy, plexiform isolated or associated with hypertrophy or thrombotic lesions, thrombotic isolated, etc. In some cases, venous or capillary damage can be observed associated with predominant arterial lesions.

The medial hypertrophy secondary to hypertrophy and hyperplasia of smooth muscle cells and increased connective tissue matrix and elastic fibers of the media.

The intimal thickening is secondary to the presence in the arterial intima fibroblasts, myofibroblasts and smooth muscle cells.

The plexiform lesions correspond to a focal proliferation of endothelial cells surrounded by myofibroblasts, of smooth muscle cells and extracellular matrix. The lesions are complicated with time and the evolution of the disease ; sometimes intertwined with interstitial lesions (associated disease, complication), to myocardial and inflammatory lesions and necrotizing small arteries (artérite).

veno-occlusive disease and pulmonary capillary hemangiomatosis :

Pulmonary veno-occlusive disease Pulmonary veno-occlusive disease is defined as diffuse and extensive blockage of small veins and the pulmonary veins by fibrous tissue. A remodeling of pulmonary arteries and arterioles is associated with achievement in venular 50 % cases, but plexiform lesions and arteritis are not classically described in veno-occlusive disease.

Pulmonary capillary hemangiomatosis :

Pulmonary capillary hemangiomatosis is characterized by a diffuse proliferation of pulmonary capillaries. These capillaries can form nodules invading the interstitium and infiltrate the vessel wall and lymph occluding their light. Sometimes the capillaries proliferating obstruct the pulmonary veins.

Distinction :

The distinction between these two diseases is by the nature of the occlusion of the pulmonary veins. This is intimal fibrosis in cases of veno-occlusive disease and proliferating capillaries in pulmonary capillary hemangiomatosis. In both diseases, there pulmonary hemosiderosis with a large amount of hemosiderin in the cytoplasm of macrophages. The bronchoalveolar lavage of these patients can regain occult alveolar hemorrhage, which is not the case in pure arterial disease.

Pathophysiology and genetics :

The pulmonary circulation is an outstanding high speed and low pressure with extensive recruitment capacity of non-perfused pulmonary vessels. It is typically recognized that vasoconstriction is an early phenomenon involved in the pathogenesis of PAH. However, the relevance of this vasoconstriction is questionable as intense vascular remodeling in pulmonary small arteries (< 500 μm) and pre-capillary arterioles leading appears in the development of arterial obstruction resulting fixed persistently elevated pulmonary arterial resistance.

This obstruction is exacerbated by thrombosis in situ favored by endothelial dysfunction and decreased blood flow in the pulmonary arteries. Endothelial dysfunction that are associated pulmonary vascular smooth muscle abnormalities is central in the development of PAH. This dysfunction is characterized by endothelial production désquilibre mediators promoting vasoconstriction and especially smooth muscle and endothelial proliferation characteristic of pulmonary arterial remodeling. Indeed, reduced production of vasodilators endothelium-derived mediators such as nitric oxide (NO) egg prostacycline, associated with endothelial overproduction vasoconstrictors such as endothelin-1 not only affects vascular tone but also causes an intense pulmonary vascular remodeling. There are no unicist mechanism to explain the occurrence of PAH, we will detail the factors possibly involved in the genesis and maintenance of PAH.

Prostacycline :

La prostacycline (prostaglandins PGI2) is an arachidonic acid metabolite synthesized by vascular endothelium. It is a potent endogenous vasodilator which causes relaxation of the smooth muscle cell by increasing cyclic AMP. Prostacyclin also inhibits proliferation of vascular smooth muscle cells and decreases platelet aggregation. It has been shown that the synthesis of prostacyclin was decreased in the endothelial cells of patients with PAH.

Endothéline-1 :

L’endothéline-1 (ET-1) probably contributes to vasoconstriction and remodeling of the pulmonary arteries characteristic of PAH. It has been shown in humans elevated plasma ET-1 in patients with PAH. ET-1 acts by binding to two types of specific receptors : AND et ETB. By binding to ETA receptor on smooth muscle cells of pulmonary arteries, ET-1 causes vasoconstriction by increase in intracellular calcium and activation of protein kinase C. Moreover, ET-1 has a proliferative action on smooth muscle cells by binding to ETA receptors and ETB.

potassium channels :

The observed pulmonary vasoconstriction in hypoxia develops through inhibition of one or more voltage-gated potassium channels (Kv) in smooth muscle cells of the pulmonary arteries. This inhibition of the Kv channel is the cause of membrane depolarization, causing an increase in intracellular calcium and contraction of smooth muscle cells of the pulmonary arteries. It was revealed a dysfunction of these potassium channels Kv in the smooth muscle cells of subjects suffering from idiopathic PAH, without clear whether these abnormalities are genetic or acquired. Moreover, Weir et coll. showed in rats that anorexics (aminorex, derivatives fenfluramine) directly inhibit the potassium channels Kv smooth muscle cells causing pulmonary vasoconstriction.

Nitrogen monoxide (NO) :

Nitric oxide is synthesized from L-arginine by the action of NO synthase, it exerts its vasodilatory and antiproliferative activity by the action of cyclic guanosine monophosphate (GMPc). The decreased expression of NO synthase observed in subjects with PAH involved in vasodilation defect related to endothelial dysfunction.

serotonin :

In PAH, circulating serotonin levels (5-hydroxy-tryptamine, 5-HT) are high, while the platelet content is reduced. The mechanism by which 5-HT interacts with the pulmonary arteries is still subject to debate. However, it was shown that the appetite suppressants lead to an increase in serotonin levels causing the release of platelet 5-HT and decreasing its reuptake. The carrier of the 5-HT (5-HTT) is encoded by a single gene which polymorphism was described. One of variants increases the activity of 5-HTT. In a French series, this variant was found in homozygous form in 65 % of patients with idiopathic PAH and only 27 % of control subjects. It has been shown that this polymorphism was also causing sensitivity to develop a PH in patients with COPD.

Superfamille of TGF-β :

Le transforming growth factor (TGF) is a growth factor and potentially involved in cell differentiation vascular remodeling. Germline mutations of genes coding for members of the family of receptors such as TGF BMPR2, ALK1, and to a lesser extent endoglin could be demonstrated in patients with PAH working in a family context but also in patients with apparently sporadic idiopathic PAH, PAH associated with the use of anorectics or complicating the evolution of a Rendu Osler.

These mutations are the cause of a decrease in receptor function superfamily TGF resulting in decreased antiproliferative effects. Current strong case for the role of a TGF receptor dysfunction in the pathogenesis of PAH through abnormal proliferation of endothelial cells and pulmonary vascular smooth muscle. We find BMPR2 mutations in about half of cases of PAH family. It is very interesting that the BMPR2 mutations are also present in 10 at 30 % seemingly non-family PAH (idiopathic or associated with anorectic intake), indicating that some sporadic PAH are actually identified the first case of an unknown familial far.

Many other growth factors are expressed in the lungs of PAH patients and are potentially involved in the development of the disease (VEGF, PDGF, basic fibroblast growth factor, insulin-like growth factor-1, epidermal growth factor). Finally, inflammatory phenomena could play a significant role in the induction or maintenance of PAH, especially in special clinical situations first and foremost the PAH associated with connective or HIV infection. In this context, certain cytokines and chemokines appear to play a role currently being analyzed.

clinical manifestations :

There are no specific clinical signs of PAH. These events do indeed reflect the impact of the disease on the right heart (Chronic cor pulmonale) or events related to the underlying disease (scleroderma, cirrhosis…).

The effort dyspnea is the most commonly found sign, present in over 95 % patients. The appearance of this dyspnea is progressive and often overlooked rule, explaining the frequent delay in care (about 2 years between onset of symptoms and diagnosis). Chest pain, lipothymies or syncope can occur especially in the effort and are major criteria of disease severity. Palpitations are common to the effort and can sometimes prove true heart rhythm disorders.

hemoptysis can complicate PAH, they are minimal rule, but sometimes require bronchial artery embolization, due to frequent bronchial arterial hypertrophy in these patients. Dysphonia is sometimes observed, indicating a secondary left recurrent laryngeal paralysis recurrent nerve compression by the trunk of the pulmonary artery dilated left (syndrome d’Ortner).

The search for signs of right ventricular failure should be systematic. Jugular turgor, Hepatojugular the ebb and hepatalgia are the most common signs. edema of the lower limbs, ascites, hydrops underscore the severity of right heart failure. Cardiac auscultation found a B2 luster lung home (a quasi-constant), systolic murmur of tricuspid regurgitation (60 % cases), and rarely a diastolic pulmonary insufficiency murmur. The auscultation is normal and typically contrasted with the severity of breathlessness. The examination and examination must search for Raynaud's syndrome, more frequently found in PAH associated with connective, in particular systemic sclerosis.

Explorations :

Orienting elements diagnosis :

The chest radiograph most often found hypertrophy of the trunk and proximal branches of the pulmonary arteries and increased cardiothoracic index. It also allows searching for parenchymal abnormalities indicating an associated respiratory disease. The presence of interstitial syndrome should suggest some forms of pulmonary hypertension (post-capillary origin, ILD, maladie veino-occlusive, pulmonary capillary hemangiomatosis).

The electrocardiogram typically found signs of hypertrophy right at the atrial level (where P width in DII-DIII et bifide V1) and ventricular (where big R in V1, where R < S and V6, dextrorotation with S1Q3 appearance, disorders of repolarization in the right derivations).

Echocardiography transthoracic Doppler is coupled to the reference examination for detection of PAH, it allows to estimate pulmonary artery pressure (PAP) Systolic by measuring the velocity of tricuspid regurgitation flow. Ultrasound generally find dilated right cavities associated with a paradoxical movement of the interventricular septum. Under optimal conditions, it measures the diastolic PAP and cardiac output, but these conditions are rarely collected in routine practice. The existence of pericardial effusion is an element of poor prognosis. The review also allows searching congenital heart disease or a right-left shunt through the foramen ovale opening. The technique may be improved by injection of microbubbles in search of an early passage of the contrast in the left cavities. A transesophageal echocardiogram is sometimes necessary for the detection of cardiac abnormalities, particularly in atrial septal.

diagnostic elements :

The right catheterization is the only examination to confirm the diagnosis of PAH. The pre-capillary damage is defined by a mean PAP greater than 25 mm Hg at rest or greater 30 mmHg to the effort in the absence of elevation in PAP occlusion, reflect the capillary pressure (< 15 mmHg). This measurement can be refined by performing a filling test to unmask a left diastolic dysfunction. In the case of a confirmed PAH, it is necessary to perform a vasodilator testing with inhaled nitric oxide or prostacyclin intravenously. Indeed, this test is positive when vasodilation (decrease in mean PAP more 10 mmHg with a mean PAP below 40 mmHg and a normal heart rate and high) can characterize a subgroup of patients with a better prognosis and may benefit from prolonged treatment with calcium antagonists.

Pulmonary CT angiography with research elements for a chronic pulmonary heart postembolic (organized thrombus into the pulmonary arteries proximal, defects eccentric, mosaic pattern). However, Current data point to the limitations of pulmonary CT in the diagnosis of this disease is best detected by pulmonary ventilation-perfusion scintigraphy. Achieving millimeter cuts to search for suggestive of pulmonary veno-occlusive disease or pulmonary capillary elements hemangiomatosis (thickening of the septa, fuzzy nodules, mediastinal lymphadenopathy). It also can detect a respiratory disease originally a hypoxic PH (emphysema, Pulmonary Fibrosis ...).

The lung scan ventilation and perfusion research elements for a thromboembolism. On suspicion of chronic pulmonary heart postembolic (even in the absence of proximal thrombus visible on CT angiography), pulmonary angiography is essential to confirm the diagnosis and determine the possibilities of surgery by thrombo-endarterectomy. The lung scan can also reveal a true shunt when switching extrapulmonary marker.

Pulmonary function tests found volumes and substantially normal rates, but a decrease in the diffusion of carbon monoxide is substantially constant resulting pulmonary vascular disease. Associated with arterial blood gas, they track down and evaluate any associated respiratory disease. When the lines atrial pressures are high, hypoxemia can be seen by right-left shunt (reopening of the foramen ovale or shunt reversal at a cardiac malformation) confirmed by achieving blood gas with pure oxygen. A polysomnographic recording is typically recommended to search for a possible sleep apnea syndrome.

Abdominal ultrasound with Doppler of the portal vein search portal hypertension. In case of doubt left ventricular dysfunction associated, it is possible to measure the isotopic ejection fraction, or even with a left heart catheterization with coronary angiography.

Serological tests for HIV and hepatitis B and C., the autoimmunity markers and search for coagulation abnormalities are still being sought. Although it is found antinuclear factors positive in low titer 40 % idiopathic PAH, this finding requires further investigations in order to eliminate an associated connectivity. Thrombocytopenia as well as liver abnormalities type of cholestasis or cytolysis are frequent, especially during right heart decompensation.

Surgical lung biopsy or thoracoscopic have not usually indicated in the management of patients with PAH, because they are at high risk of complications and mortality, and do not alter the management. Only a pulmonary veno-occlusive disease is suspected or pulmonary capillary hemangiomatosis sometimes discuss this type of intervention.

Assessment of severity :

The importance of dyspnea is measured using the NYHA functional class suitable for patients with PAH, allowing simple and reproducible assessment during follow-up. NYHA classification is a major prognostic factor, patients functional class III or IV having a much lower survival than patients functional class I or II. The evaluation of dyspnea is complemented by a walk test 6 minutes. This is a simple and easily reproducible means of evaluating functional disability.

This test must be associated with continuous measurement oximetry, heart rate and patient assessments of dyspnea score (Borg Scale). Une de plus de DESATURATION 10 % constitute a criterion of seriousness with a mortality risk multiplied by 2,9 in the 2 years. Some authors perform stress tests to better define the patient's capacity and prognosis. However, in unstable patients, The exercise tests should be avoided, because of the risk of serious accidents (syncopations, sudden death).

During cardiac catheterization right, the measurement of right atrial pressure, cardiac index, the oxygen saturation of mixed venous blood and the calculation of total pulmonary resistance for evaluating the severity and prognosis of patients with PAH. likewise, the existence of an acute response to vasodilators is a good prognostic factor. The plasma level of certain substances is correlated with disease severity. This is the case especially brain natriuretic peptide (BNP), but also of endothelin-1, uric acid and troponin T.

Treatment :

The treatment of PAH tries to oppose the deleterious effects of vasoconstriction, pulmonary vascular obstruction by thrombosis and remodeling and right heart failure. Recent therapeutic innovations directly derived from understanding the pathophysiologic abnormalities of PAH.

conventional treatment :

The limitation of effort is the first step to explain to the patient with PAH. Any effort to cause a shortness of breath is against-indicated, dyspnea being the witness of the mismatch between cardiac output and oxygen requirements. However, to avoid excessive settlement, generally recommended to patients to limit their efforts to the symptoms experienced. likewise, all at risk to increase hypoxia is against-indicated, especially altitude stays (the threshold is not defined and depends on the severity of patients). The anti-influenza vaccinations and pneumococcal are recommended.

Diuretics in combination with salt diet help to reduce the signs of right ventricular overload and improve symptomatology. The dosage should be adjusted to the clinic (basis weight, presence of edema of the lower limbs) but can also be adjusted according to the filling pressures measured during hemodynamic balance or echocardiographic findings (size of the inferior vena cava ...). Anticoagulant therapy reduces mortality in patients with PAH, probably by reducing situ thrombosis phenomena in these patients decreased cardiac output and sedentary. It must be offered systematically when there are no cons-indication (antivitamines K, with a target INR of 1,5 at 2,5).

Oxygen therapy is prescribed when there is hypoxemia (Fo2 < 60 mmHg), The objective is mainly symptomatic. His interest in the case of true shunt is questionable. Oxygen therapy during exercise is often beneficial. General anesthesia are performed only when absolutely necessary, as much as possible with the help of a specialized team. Pregnancy is to avoid considerable risk due to worsening. It is essential to explain the importance of effective contraception to patients with PAH.

specific PAH Treatment :

Continuous intravenous prostacyclin :

The prostaglandin I2 (prostacycline) is a potent systemic and pulmonary artery vasodilator and an inhibitor of platelet aggregation.

epoprostenol (Flolan®), synthetic molecule of prostacyclin, continuously administered intravenous further has an effect on vascular remodeling and improves exercise tolerance by decreasing the slope of the pressure curve flow in the pulmonary circulation. The intravenous prostacyclin was used as treatment PAH for the first time in the early 1980 and has since proven its effectiveness.

The vasodilator testing performed during catheterization law does not determine the long-term response to epoprostenol, stressing that the action of epoprostenol is not limited in its sole acute vasodilator action. A prospective randomized study showed the efficacy of epoprostenol 81 Patients with idiopathic PAH in functional class III and IV NYHA.

After 12 weeks, a significant improvement of the distance traveled during the walk test and hemodynamics (decrease in mean PAP 5 mm Hg increase in cardiac index 0,3 l / min / m2) were observed. Moreover, survival was improved after 12 weeks in the group treated (no deaths against 8 death in the conventional treatment group). There are no randomized study analyzing developments in the longer term patients treated with epoprostenol.

However, retrospective analyzes found a clear clinical benefit in patients in functional class III or IV NYHA. In our cohort 178 Htap idiopathiques, intravenous epoprostenol improves the exercise tolerance, hemodynamics and long term survival, compared to a control group "historical" subjects treated "conventionally". The survival rate 1, 2 and 5 years were 85 %, 70 % and 55 %, respectively, against 58 %, 43 % and 28 % in the control group (p < 0,0001).

After 3 months of treatment with epoprostenol, dyspnea and distance traveled during the walk test is of prognostic clues (better survival for patients revenues in functional class I-II or browsing a greater distance 380 m 6 me). Epoprostenol is administered by continuous intravenous using a pump connected to a tunneled catheter placed in the subclavian vein. The dose of epoprostenol is gradually increased until 10 ng / Kg / min under hospital supervision, then adjusted according to clinical response and hemodynamic and its tolerance. The optimal dose is not defined, but the existence of tachyphylaxis phenomena requires a gradual increase in dose.

Side effects are common, especially pain of the jaws, headaches, diarrhea, hot flashes, the lower limb pain and episodes of nausea or vomiting. These events are dose dependent and rarely require discontinuation of treatment. The most serious complications are related to the mode of administration, continuous infusion catheter may be complicated by thrombosis or infection (incidence of sepsis in the order of 0,1 at 0,4 cases per year per patient). The discontinuation of dysfunction of the pump or rupture of the catheter may be complicated by a sudden worsening of PAH-threatening because of the very short half-life of the product.

Severe pulmonary edema have been reported of patients with PAH with predominant venular reached (veno-occlusive disease and pulmonary capillary hemangiomatosis). In PAH associated with scleroderma, continuous infusion of prostacyclin provides clinical and hemodynamic improvement, but does not seem to have such dramatic effects on survival. Non-randomized studies have also shown benefit in PAH congenital heart (syndrome d’Eisenmenger), portal hypertension or HIV infection. Epoprostenol was initially proposed as treatment waiting to lung transplantation (bridge-therapy) but epoprostenol is currently the standard treatment for severe forms and represents a real alternative to transplantation.

The prostacyclin analogues :

L’iloprost (Ventavis®) :

L’iloprost (Ventavis®) is a prostacyclin analogue inhaled requiring the use of a suitable system (particle diameter 0,5 at 3 μm).

The short iloprost Action time is the main disadvantage of this as administration mode requires achieving 6 at 12 inhalations. A randomized multicenter study analyzed the benefits of this treatment after 12 weeks in patients with idiopathic PAH, related to connective or chronic cor pulmonale postembolic unresectable functional class III or IV NYHA. A significant improvement of the distance traveled during the walk test (+ 36 m) and NYHA functional class was observed in 17 % of subjects against 4 % placebo. Coughing and symptoms related to vasodilation were the most common side effects but a significantly larger number of syncope was reported in the treated group. The long-term efficacy of inhaled iloprost requires further investigation.

treprostinil (Remodulin®) :

treprostinil (Remodulin®) is a prostacyclin analog administered subcutaneously using a mini-pump system similar to that used for the delivery of insulin in diabetics. Its effectiveness in 12 weeks was assessed idiopathic PAH in patients, related to congenital heart disease or connective, functional class II, III ou IV de la NYHA. After 12 weeks, treprostinil significantly improved distance in 6 minutes (+ 16 m), dyspnea scores, symptoms and hemodynamics.

Pain at the injection site seen in 85 % patients constituted a limiting factor in increasing doses and led to discontinuation of therapy in 8 % cases. Currently, the treprostinil is tested by continuous intravenous and nebulized in PAH.

Sodium beraprost (Berdrak®) :

Sodium beraprost (Berdrak®) is the first prostacyclin analogue orally available. A randomized placebo-controlled study evaluated efficacy in patients with idiopathic PAH, or operating in a context of CHD, of connectivity, portal hypertension or HIV infection functional class II and III NYHA. After 12 weeks, beraprost has improved the distance traveled during the walk test (+ 25 m). Analysis of subgroups found a significant treatment benefit in idiopathic PAH (+ 45 m) but no difference in associated PAH. Side effects associated with peripheral vasodilatation were commonly observed, mainly to the initial titration phase of, tolerance can become a long-term limiting factor. A randomized placebo showed a decrease in earnings of beraprost with time. Indeed, the walk test of functional class II or III patients in NYHA was significantly improved 3 and 6 month, but the difference was not significant in 9 and 12 month. Beraprost has not received authorization in the treatment of PAH in France.

Receptor antagonists of endothelin :

Le bosentan (Tracleer®) is a mixed antagonist of ETA and ETB receptors, orally active. Two randomized placebo-controlled trials have evaluated the efficacy of bosentan in patients with idiopathic PAH or PAH associated with scleroderma.

In the first study, after 12 weeks, an improvement in distance covered during walking test (+ 76 m) and hemodynamic parameters (decrease in mean PAP and increased cardiac output) was observed in patients in functional class III NYHA. The second study confirmed the benefit of bosentan in patients in functional class III or IV NYHA and showed a longer duration before clinical deterioration (defined as the occurrence of death, Lung Transplant, hospitalization, a worsening require discontinuation of treatment or the need to start treatment with epoprostenol). In this study, bosentan was started at a dose of 62,5 mg twice daily for 4 weeks and then increased at a dose of 125 mg or 250 mg twice daily. This work has not demonstrated to dose-effect relationship. On the other hand, transaminase elevation over 8 times normal were observed in 3 % patients treated at a dose of 125 mg twice daily and in 7 % patients receiving a dose of 250 mg twice daily. Treatment with bosentan is against-indicated in patients with moderate or severe hepatic impairment or in case of elevated transaminases more than three times normal. A liver enzymes must be performed before start of treatment, 2 weeks after a change in dose and every month once the maintenance dose reached.

If increased transaminases, temporary interruption or definitive treatment is necessary. A recent study showed improved survival 12 and 24 months in patients with idiopathic PAH treated with first-line bosentan. The effectiveness of bosentan has not been established for severe forms of PAH (functional class IV). Selective inhibitors of the receptor ETA (sitaxsentan, ambrisentan) are currently being evaluated in PAH.

other treatments :

The inhibitors of phosphodiesterase type 5 such as sildenafil (Viagra®) have pulmonary vasodilatory effect demonstrated in tests conducted vasodilation in patients with PAH. Numerous case reports and small series advocate of efficacy of this treatment. A blind experiment against including placebo 22 Patients with idiopathic PAH showed that sildenafil improved the exercise tolerance, cardiac index and quality of life of patients. Sildenafil has the interest of his oral (3 taken daily) and its good clinical tolerance. A randomized study evaluated the effects of idiopathic PAH terbogrel, an inhibitor of thromboxane synthetase and thromboxane A2 antagonist, orally active. The study was stopped early before the onset of disabling leg pain, representing a confounding factor for the primary objective was the walk test 6 minutes.

Non Medical Treatment :

L’atrioseptostomie :

It aims to reduce right ventricular pressure by creating a right-left shunt. This technique follows the observation of a better prognosis in patients with congenital heart disease with droitgauche shunt or a patent foramen ovale. The Atrioseptostomy probably has an interest in patients whose condition is worsening despite maximal medical treatment.

transplantation :

The double lung or heart-lung transplantation is the only curative treatment of PAH and the only alternative in case of failure of medical treatment. This technique is reserved for younger patients (< 50-55 years) with severe PAH. The results of lung transplantation show survivals 75 % at 1 year 50 % at 5 years. It is important that transplant list on the registration is not too late, the number of donors is in fact currently insufficient which causes an average waiting time of 18 months before transplant in France.

current recommendations :

Several treatments are currently approved in North America (epoprostenol, Treprostinil, bosentan) and Europe (epoprostenol, bosentan, iloprost). Except for recent data for patients receiving epoprostenol, the long-term effectiveness of these new treatments remains to be assessed. Further studies are needed to assess the long-term effectiveness of these treatments, their side effects and their cost.

In the absence of data comparing different treatments, the initial choice therefore depends as much on the experience of teams and local regulations, that the patient's condition and preferences. Most experts recommend for severe PAH in functional class IV NYHA a epoprostenol treatment in continuous intravenous infusion. Apart from this dramatic situation, Europe's processing capabilities include first-line bosentan administered orally or nebulized iloprost, begun under supervision in a specialized center for the treatment of pulmonary vascular diseases.

In the early stages of PAH, Few data are currently available. There are no registered treatment for patients in functional class I or II NYHA Europe. In the near future, new treatments such as selective inhibitors of ETA or sildenafil may be able to find their place in the therapeutic arsenal of PAH, this after having been rigorously evaluated and have been recognized by the registration agencies.

Another therapeutic approach is the combination different action mechanisms of drugs in order to potentiate their effects and thus increase their clinical benefit. Preliminary results of studies evaluating the effectiveness of combined treatment in patients with severe PAH are encouraging, but these results require further investigation.

Conclusion :

PAH is a serious illness causing a debilitating symptoms and leading to right heart failure and death in the absence of treatment. PAH's treatment progress has been considerable in recent years and the emergence of specific treatments has transformed the prognosis of this disease. A better understanding of the pathophysiological mechanisms underlying the development of PAH is required for the development of new therapeutics and the development of a cure for this orphan disease.


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