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  • 1. Pulmonary arterial hypertension Authors: Professor Marc Humbert 1 and Professor Gérald Simonneau Creation Date: November 2004 Scientific Editor: Professor Jean-François Cordier 1 Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine-Béclère, Université Paris-Sud, Assistance Publique-Hôpitaux de Paris, 157, Rue de la Porte de Trivaux, 92140 Clamart, France. marc.humbert@abc.aphp.fr Abstract Keywords Disease name Definition/diagnostic criteria Clinical description Diagnostic methods Epidemiology Genetics Management References Abstract Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary arterial resistance leading to right heart failure. PAH can be sporadic (idiopathic PAH, or primary pulmonary hypertension), familial (caused by germline BMPR2 mutations, a type II member of the TGF beta receptor superfamily), or related to other conditions including connective tissue disease, congenital heart disease, human immunodeficiency virus infection, portal hypertension, appetite suppressant exposure. Prevalence of PAH is 15 per million in France. The lack of specificity of PAH symptoms (mostly dyspnea) presumably leads to underdiagnosis of this condition. Echocardiography is the investigation of choice for non-invasive screening. Measurement of hemodynamic parameters during right-heart catheterizing is mandatory to establish the diagnosis (mean pulmonary artery pressure > 25 mmHg and pulmonary artery wedge pressure < 12 mmHg). Acute pulmonary vasodilator testing should be performed with nitric oxide or prostacyclin during right-heart catheterization. Recent advances in the management of PAH including continuous intravenous prostacyclin infusion and endothelin receptor antagonists have improved markedly the patients’ prognosis. Novel treatments such as inhaled iloprost and type 5 phosphodiesterase inhibitors have to be further evaluated in this setting. Lung transplantation is the last option for patients deteriorating despite medical treatment. Keywords Bone morphogenetic protein receptor; Echocardiography; Endothelin; Pulmonary arterial hypertension; Prostacyclin; Right-heart catheterism; Transforming growth factor beta. Humbert M., Simonneau G. Pulmonary arterial hypertension, Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-PulmArterHypert.pdf 1
  • 2. assessment of exercise capacity and Disease name hemodynamics (see Diagnostic methods). Pulmonary arterial hypertension Clinical description Definition/diagnostic criteria Symptoms and signs of pulmonary hypertension (For references see Humbert 2004, Montani 2004, (Montani 2004) Simonneau 2004) The symptoms of PAH include of breathlessness, Pulmonary arterial hypertension (PAH) is a fatigue, weakness, angina, syncope, and disease of the small pulmonary arteries, abdominal distension. Symptoms at rest are characterized by vascular proliferation and reported only in very advanced cases. The remodeling. It results in a progressive increase in physical signs of pulmonary hypertension include pulmonary vascular resistance and, ultimately, left parasternal lift, accentuated pulmonary right ventricular failure and death. PAH is defined component of S2, pansystolic murmur of tricuspid by right-heart catheterization showing a regurgitation, diastolic murmur of pulmonary precapillary pulmonary hypertension (mean insufficiency. Jugular vein distension, pulmonary artery pressure > 25 mmHg at rest or > hepatomegaly, peripheral edema, ascites and 30 mmHg with exercise, with a normal pulmonary cool extremities characterize patients in a more artery wedge pressure <15 mmHg). advanced state. Lung sounds are usually normal. Current clinical classification of PAH comprises Finally, PAH can be suspected when abnormal apparently heterogeneous conditions, which share electrocardiographic, chest radiograph or comparable clinical and hemodynamic pictures echocardiographic findings are detected in the and virtually identical pathologic changes of the course of procedures performed for other clinical lung microcirculation. PAH includes the idiopathic reasons. (IPAH, formerly termed primary pulmonary hypertension) and familial forms (FPAH) and PAH Diagnostic methods associated with various conditions, such as scleroderma and other connective tissue diseases ECG (CTD), congenital heart defects with systemic-to- The ECG may provide suggestive or supportive pulmonary shunts, portal hypertension, human evidence of pulmonary hypertension by immunodeficiency virus infection, exposure to demonstrating right ventricular hypertrophy and drugs and toxins and other more rare settings: strain, and right atrial dilation. Right ventricular thyroid disorders, glycogen storage disease, hypertrophy on ECG is present in 87% and right Gaucher’s disease, hereditary hemorrhagic axis deviation in 79% of patients with IPAH. The telangiectasia, hemoglobinopathies (Sickle ECG has inadequate sensitivity (55%) and disease especially), myelo-proliferative disorders, specificity (70%) to be a screening tool for splenectomy. PAH is a rare condition even if detecting significant pulmonary hypertension. In appropriate prospective epidemiological data are 90% of IPAH patients the chest radiograph is lacking. abnormal at the time of diagnosis. Findings The diagnostic process of PAH requires a series include central pulmonary arterial dilatation, which of investigations that are intended to make the contrasts with ‘pruning’ (loss) of the peripheral diagnosis, to clarify the clinical class of pulmonary blood vessels. Right atrial and ventricular hypertension and the type of PAH and to evaluate enlargement may be seen and it progresses in the functional and hemodynamic impairment. more advanced cases. The chest radiograph The clinical suspicion of pulmonary hypertension allows associated moderate-to-severe lung should arise in case symptoms such as disease or pulmonary venous hypertension due to breathlessness without overt signs of specific left heart abnormalities to be sometimes identified. heart or lung disease, in cases of screening in predisposing conditions or in cases of incidental Transthoracic Doppler-echocardiography findings. The detection of pulmonary hypertension (TTE) requires investigations such as clinical TTE is an excellent non-invasive screening test examination, ECG, chest radiograph and trans- for the patient with suspected pulmonary thoracic echocardiogram. Other conditions than hypertension. TTE estimates pulmonary artery PAH which can induce pulmonary hypertension systolic pressure and can provide additional will be identified by tests such as pulmonary information about the cause and consequences of function tests, arterial blood gases, ventilation and pulmonary hypertension. According to data perfusion lung scan, high resolution computed obtained in normal subjects, mild pulmonary tomography of the chest with contrast medium hypertension can be defined as a pulmonary injection, and pulmonary angiography. Additional artery systolic pressure of approximately 36-50 investigations are required for the exact mmHg. Additional echocardiographic and Doppler identification of the type of PAH, and for the parameters are important for diagnosis confirmation and assessment of severity of 2 Humbert M., Simonneau G. Pulmonary arterial hypertension, Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-PulmArterHypert.pdf
  • 3. pulmonary hypertension, including right ventricular Assessment of Severity dimensions and function and left ventricular The variables that have been shown to predict dimensions, tricuspid, pulmonary and mitral valve prognosis in IPAH when assessed at baseline or abnormalities, right ventricular ejection and left after targeted treatments include clinical ventricular filling characteristics, inferior vena cava parameters (baseline NYHA functional dimensions and pericardial effusion size. classification, NYHA functional class on chronic Besides identification of pulmonary hypertension, epoprostenol treatment, history of right heart TTE also allows a differential diagnosis of failure), exercise capacity (baseline six-minute possible causes. In fact, TTE can recognize left walk distance, six-minute walk distance on chronic heart valvular and myocardial diseases epoprostenol treatment, baseline peak VO2), responsible for post-capillary pulmonary echocardiographic parameter (pericardial effusion, hypertension; congenital heart diseases with right atrial size), hemodynamics (right atrial systemic-to-pulmonary shunts can be easily pressure, cardiac output, mixed venous identified. The venous injection of agitated saline saturation, pulmonary vascular resistance, as contrast medium can help the identification of positive acute response to vasoreactivity test, fall patent foramen ovale or small sinus venosus type in pulmonary vascular resistance after 3 months atrial septal defects that can be overlooked on the of intravenous epoprostenol), and blood tests standard TTE examination. Transesophageal (hyperuricemia, baseline brain natriuretic peptide, echocardiography is rarely required. troponin). Very little information is available in other conditions such as PAH associated with Hemodynamics CTD, congenital systemic to pulmonary shunts, Right heart catheterization (RHC) is required to HIV infection or portal hypertension. In these confirm the diagnosis of PAH, to assess the circumstances, additional factors may contribute severity of the hemodynamic impairment and to to the overall outcome. In fact, PAH associated test the vasoreactivity of the pulmonary with CTD tissue disorders has a worse prognosis circulation. PAH is defined by a mean PAP > 25 than IPAH patients, whereas patients with PAH mmHg at rest or > 30 mmHg with exercise, by a associated with congenital systemic to pulmonary pulmonary wedge (occluded) pressure (PWP) ≤ shunts have a more slowly progressive course 15 mmHg (demonstrating pre-capillary pulmonary than IPAH patients. In clinical practice, the hypertension) and by PVR > 3 mmHg/l/min (Wood prognostic value of a single variable in the units). Left heart catheterization is required in the individual patient may be less than the value of rare circumstances in which a reliable pulmonary multiple concordant variables. wedge pressure cannot be measured. The assessment of pulmonary wedge pressure may Epidemiology allow the distinction between arterial and venous The prevalence of PAH is 15 per million in adult pulmonary hypertension in patients with individuals in France with higher values in the concomitant left heart diseases. RHC is important Paris area (30 per million). The prevalence of also in patients with definite moderate-to-severe IPAH is of 6 per million. In the 1990’s, the IPPHS PAH because the hemodynamic variables have results demonstrated that the incidence of IPAH is prognostic relevance. Elevated mean right atrial 1.7 per million in Belgium (Abenhaim 1996). pressure, mean pulmonary artery pressure and reduced cardiac output and central venous O2 Genetics saturation identify IPAH patients with the worst (For reference see Humbert 2002) prognosis. An acute vasodilator challenge PAH can be either sporadic or clustered in performed during RHC can identify patients who families. The first detailed description of familial may benefit from long-term calcium channel PAH by Dresdale in 1954 included a description of blocker treatment (CCB) (see below). Acute related subjects with severe pulmonary vascular vasodilator testing should only be done using disease of unknown etiology. Later, it became short-acting pulmonary vasodilators at the time of apparent that this familial condition was less rare the initial RHC in experienced centers to minimize than initially believed, in part because of patient the potential risks. Currently the agents used in and physician unawareness of the familial acute testing are intravenous prostacyclin or occurrence of the disease, but also because of adenosine and inhaled nitric oxide. A positive the markedly reduced penetrance of the genetic acute vasoreactive response (positive acute defects. A pioneer report by Loyd and colleagues responders) is defined as a reduction of mean in 1984 clearly supported the concept that a pulmonary artery pressure ≥ 10 mmHg to reach proportion of cases of so-called sporadic PAH an absolute value of mean pulmonary artery were in fact mislabelled as non-familial when the pressure ≤ 40 mmHg with an increase or family histories were incomplete, suggesting that unchanged cardiac output. Generally, only about the incidence of familial PAH is higher than 10% of IPAH will meet these criteria. previously reported. Because of the lack of data, the true incidence of familial PAH is unknown. The 3 Humbert M., Simonneau G. Pulmonary arterial hypertension, Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-PulmArterHypert.pdf
  • 4. NIH Registry has provided the best estimate of failure. However a diagnosis of PAH does not this condition. This prospective analysis of 187 preclude an active and fulfilling lifestyle, and patients from 32 North American medical centers patients are usually advised to engage in activities identified 12 cases with familial history affecting a appropriate to their physical capabilities in order to first-blood relative. In consequence, it has been prevent deconditioning and attendant worsening widely accepted that at least 6% of individuals of overall function. Extreme caution concerning diagnosed with PAH have a family history of the physical activity is advised for those patients with disorder, and thereby identifying relatives as being advanced PAH and symptoms of dizziness, at additional risk of developing the disorder. lightheadness, or severe dyspnea because of a Familial PAH segregates as an autosomal risk of life-threatening syncope. Chronic dominant trait but with markedly reduced hypoxemia due to impaired cardiac output, right- penetrance. Defects within bone morphogenetic to-left shunting through a patent foramen ovale or protein receptor type II gene (BMPR2), coding for a congenital heart defect results in desaturation of a type II receptor member of the transforming mixed venous blood. When chronic hypoxemia growth factor beta (TGF-β) family, have been develops, supplemental oxygen including shown to underlie familial PPH. Germline BMPR2 ambulatory oxygen therapy is indicated. mutations have been detected in at least 60% of The value of cardiac glycosides in treating the families studied to date. Disease-associated isolated right heart dysfunction is controversial. mutations are predicted to interrupt the BMP These agents are most useful in cor pulmonale, mediated signalling pathway, predisposing to when left ventricular failure is also present. proliferation rather than apoptosis of cells within However, since neurohormonal activation has small pulmonary arteries. Several lines of been demonstrated in pulmonary hypertension, evidence point to the potential requirement of digoxin might be considered because of its additional factors, either environmental or genetic, sympatholytic properties. Digoxin may be most in the pathogenesis of the disease. In addition, a beneficial in PAH with concomitant intermittent or proportion of so-called idiopathic PAH as well as chronic atrial fibrillation. No prospective, appetite-suppressant-associated PAH turn out to randomized, double-blind, placebo-controlled have an inherited basis, as demonstrated by trials are available to provide clear treatment detection of germline BMPR2 mutations. guidelines. Dramatic clinical improvements in Analysis of other genes encoding TGF-β receptor patients with right heart failure can be achieved by proteins, led to the demonstration that PAH in instituting diuretic therapy including anti- association with hereditary hemorrhagic aldosteron diuretics, which reduces the right telangiectasia, an autosomal dominant vascular ventricular preload. dysplasia, can involve ALK-1 mutations, a type I As pregnancy and labor increase the demand on TGF-β receptor. The relevance of the TGF-β the heart-pulmonary system, they should be superfamily in the etiology of PAH is further contraindicated in patients with pulmonary supported by a recent report of endoglin germline hypertension. Consequently, safe and effective mutation in a patient who had hereditary contraception is always recommended in women hemorrhagic telangiectasia and dexfenfluramine- of childbearing age. Intrauterine devices or associated PAH. These observations support the surgical sterilization have been proposed but hypothesis that mutations in the TGF-β since these procedures can promote bleeding, it superfamily may be a trigger for pulmonary may be impossible to perform in severely vascular remodeling. While this achievement has compromised patients. Many centers treating generated extreme interest, the pathobiology of patients with PAH recommend oral contraception severe PAH remains unclear and genomic with progesterone derivatives or low dose approaches to pulmonary hypertension research estrogens, when there is no history of may identify additional molecular determinants for thromboembolic disease or thrombophilia. this disorder. Finally, there is an urgent need to The rationale for anticoagulant therapy in PAH is develop guidelines for genetic counselling to based on the presence of well-recognized risk assist patients, their relatives and pulmonary factors for venous thromboembolism such as vascular specialists. Such guidelines do not exist heart failure, sedentary lifestyle, and thrombophilic yet. predisposition. Indeed, the identification of thrombosis in post-mortem examinations of Management patients with IPAH further supports this strategy. (For references see Humbert 2004, Klepetko However, no data exist to support anticoagulants 2004, Montani 2004, Sandoval 2002) use specifically in PAH. Warfarin has been evaluated in only two studies with small numbers Basic therapy of patients (one retrospective and one prospective Patients with PAH have a restricted pulmonary but non-randomized). On the basis of these circulation. Increased oxygen demand may limited studies, aiming for an International worsen pulmonary hypertension and right heart 4 Humbert M., Simonneau G. Pulmonary arterial hypertension, Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-PulmArterHypert.pdf
  • 5. Normalized Ratio between 1.5 and 2.5 is veno-occlusive disease and pulmonary capillary recommended. hemangiomatosis, severe pulmonary edema and death may occur, presumably because of Calcium channel blockers (CCB) increased pulmonary perfusion in the presence of Pulmonary artery vasoconstriction may contribute downstream vascular obstruction. to the pathogenesis of PAH. Uncontrolled studies Subcutaneous Treprostinil suggest that long-term administration of high-dose The potential complications related to the central CCB prolong survival in responsive patients venous catheter required for intravenous (approximately 10 percent of all patients referred prostacyclin administration have led to the to pulmonary vascular units). Patients who may development of treprostinil, a stable prostacyclin benefit from long-term CCB are identified by analogue amenable to continuous subcutaneous performing an acute vasodilator challenge during infusion. Local pain at the infusion site was a right-heart catheterization (see above). The significant side effect, occurring in 85% of occurrence of severe life-threatening subjects. Infusion site pain precluded dose hemodynamic compromise during acute increase in a significant proportion of patients and vasodilator challenge with CCB is well led to discontinuation in 8%. Despite these documented, and these agents should not be limitations, patients with PAH who developed life- used as first-line vasodilators for acute testing. threatening complications with intravenous Rather, short-acting agents such as intravenous epoprostenol have been safely transitioned to prostacyclin, adenosine, or inhaled nitric oxide subcutaneous treprostinil. should be employed. Chronic treatment with oral Oral Beraprost CCB should then be considered for those who Beraprost sodium, the first biologically stable and respond to one of these three drugs. orally active prostacyclin analogue, is absorbed rapidly in fasting conditions. It reaches a peak Prostacyclin therapy concentration after 30 minutes and has an Intravenous Prostacyclin (Epoprostenol) elimination half-life of 35-40 minutes. Present Prostaglandin I2 (prostacyclin), the main product clinical results with this therapy are disappointing. of arachidonic acid metabolism in the vascular Inhaled Iloprost endothelium, induces vascular smooth muscle Iloprost is a chemically stable prostacyclin relaxation by stimulating cyclic adenosine analogue that may be delivered via inhalation in monophosphate production and inhibiting smooth patients with PAH. The delivery system produces muscle cell growth. In addition, it is a powerful aerosol particles of appropriate size to ensure inhibitor of platelet aggregation. Intravenous alveolar deposition, improving pulmonary prostacyclin (epoprostenol) was first used to treat selectivity. Iloprost has a disadvantageous primary pulmonary hypertension (IPAH) in the relatively short duration of action requiring up to 6 early 1980s giving substantial long-term to 12 inhalations a day. Side-effects included hemodynamic and symptomatic improvement. A cough and symptoms linked to systemic prospective, randomized open trial in 81 patients vasodilatation. In addition, syncope was more with severe IPAH has demonstrated significant frequent in the iloprost-treated group. Although efficacy on survival, exercise capacity, uncontrolled data are encouraging, long-term hemodynamics and survival. There is no long- efficacy of inhaled iloprost remains to be term randomized trial with epoprostenol in PAH. established. Nevertheless, cohort analysis of IPAH patients receiving continuous intravenous epoprostenol as Endothelin receptor antagonists compared to historical control groups clearly Bosentan (dual endothelin receptor antagonist) demonstrated clinical benefits in NYHA functional In addition to its direct vasoconstrictor effect, class III and IV patients. Despite these endothelin-1 (ET-1) stimulates vascular smooth improvements approximately one-third of primary muscle cell proliferation, acts as a co-mitogen, pulmonary hypertension patients succumb within induces fibrosis, and is a pro-inflammatory three years of diagnosis. Common side-effects mediator via stimulation of leukocytes and attributable to epoprostenol include jaw pain, adhesion molecules. The effects of ET-1 are headache, diarrhea, flushing, leg pain, and mediated through ETA and ETB receptors. nausea, though generally mild and dose-related. Activation of ETA receptors causes sustained More serious complications are usually related to vasoconstriction and proliferation of vascular the delivery system. The incidence of catheter- smooth muscular cells, while ETB receptors related sepsis ranges from 0.1 to 0.6 per patient- mediate pulmonary endothelin clearance and year. Pump failure or dislocation of the central induce endothelial cell production of nitric oxide venous catheter leading to interruption in drug and prostacyclin. Bosentan is an orally active dual infusion may be life-threatening. In patients with (ETA and ETB) endothelin receptor antagonist. pulmonary hypertension with prominent Two double-blind, randomized, placebo-controlled pulmonary vein involvement such as pulmonary trials have supported the efficacy of oral bosentan 5 Humbert M., Simonneau G. Pulmonary arterial hypertension, Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-PulmArterHypert.pdf
  • 6. in patients with PAH (primary or associated with Adjunctive sildenafil or bosentan therapy have scleroderma). No dose response for efficacy could produced favorable outcomes in some patients be ascertained. Bosentan is metabolized by the already receiving oral, inhaled or intravenous liver and may increase hepatic aminotransferase prostacyclin analogues. Conversely, recent report levels. This also applies to other endothelin on thirteen patients already receiving vasodilators receptor antagonists, such as ambrisentan and for PAH (including calcium channel blockers, sitaxsentan. In the bosentan trial, development of epoprostenol, or bosentan) indicated that adding abnormal hepatic function appeared dose- long-term sildenafil had unsubstantial results on dependent, providing a rationale for the approved functional status and right-heart function. Further dose of 125mg bid. Elevations to more than eight adequately powered, prospective, randomized, times the upper limit of normal occurred in 3% and double-blind, placebo-controlled studies are 7% of patients receiving 125 mg and 250 mg needed to conclusively determine the effect of bosentan bid, respectively. The drug is combination therapy in PAH. contraindicated during pregnancy due to its teratogenic potential. Atrioseptostomy Selective ETA blockers The prognosis of patients with severe PAH is Sitaxsentan and ambrisentan are currently being heavily dependent on the function of the right investigated for efficacy in PAH. ventricle. Early experimental trials have shown that performing an atrial septal defect is Potential future therapies associated with decreased right ventricular Nitric oxide pressure and increased systemic blood flow. In Nitric oxide is a potent endogenous, endothelium- addition, patients with a right-to-left cardiac shunt derived vasodilator that directly relaxes vascular due to congenital heart defect or patent foramen smooth muscle through stimulation of soluble ovale have a better prognosis than those without guanylate cyclase and increased intracellular intracardiac shunting. Blade balloon atrial cyclic guanosine monophosphate (cGMP). septostomy in refractory PAH has been Chronic inhaled nitric oxide, while showing benefit successfully applied in several studies. in small series and case reports, is very Unfortunately, the procedure-related mortality cumbersome to use, and because of this, unlikely remains high, especially if patients have already a to be given to a large number of patients. It can low arterial oxygen saturation or evidence of right cause hemodynamic deterioration when the ventricular failure. Atrial septostomy may be an inhalation is interrupted. interesting alternative for selected patients with Sildenafil severe disease, particularly if a transplantation Another strategy for increasing the activity of candidate deteriorates despite maximal medical endogenous nitric oxide in PAH would be to therapy. enhance the nitric oxide-dependent, cGMP- mediated pulmonary vasodilatation by inhibition of Lung transplantation phosphodiesterase type 5, responsible for cGMP- Lung transplantation is the ultimate alternative for breakdown. Phosphodiesterase type 5 inhibitors severe PAH cases that cannot be managed such as sildenafil have an acute pulmonary medically. Many patients with PAH have had a vasodilator effect. In patients with PAH, short-term single lung transplant with good long-term results. intravenous application of sildenafil during right- However, nearly all transplant centers currently heart catheterization reduced pulmonary vascular prefer to transplant both lungs (double-lung resistance in a dose-dependent manner. In transplant), in part because there are generally combination with inhaled iloprost, augmentation of less postoperative complications. Heart-lung the pulmonary vasodilator effect of each single transplantation may be needed in some patients agent was noted. In patients deteriorating despite with end-stage heart failure or complex congenital ongoing iloprost therapy, long-term adjunctive oral heart disease. Patients with severe PAH who sildenafil improved exercise capacity and have undergone lung transplantation show an pulmonary hemodynamics. Although promising, overall 1- and 5-year survival of about 75% and there are few data on long-term sildenafil 50%, respectively. Long-term survival and quality treatment in PAH apart from case reports and of life is limited by the high prevalence of chronic short series. The experience with sildenafil is thus allograft rejection. The optimal timing to make the preliminary and controlled studies are ongoing to initial referral to a transplant center is the crucial determine efficacy, side effects and safety. initial step in the transplantation process, and the Combination therapy long waiting time before transplantation due to the Combination therapy using drugs with different shortage of organ donors must be integrated into mechanisms of action to maximize the clinical this decision. benefit is an emerging therapeutic option in PAH. Long-term combination therapies have been recently evaluated in patients with severe disease. 6 Humbert M., Simonneau G. Pulmonary arterial hypertension, Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-PulmArterHypert.pdf
  • 7. Treatment algorithms Barst RJ, McGoon M, Torbicki A, Sitbon O, Several treatments for PAH are now approved in Krowka MJ, Olchewski H, Gaine S. Diagnosis and North America (epoprostenol, treprostinil, differential diagnosis of pulmonary arterial bosentan) and Europe (epoprostenol, iloprost, hypertension. J Am Coll Cardiol 2004; 43:S40-7. bosentan). With the exception of recent data from Dresdale DT, Michtom RJ, Schultz M. Recent patients receiving prolonged epoprostenol studies in primary pulmonary hypertension, therapy, the long-term effects of novel treatments including pharmacodynamic observations on are still unknown. There is a substantial need for pulmonary vascular resistance. Bull N Y Acad long-term observational studies evaluating the Med. 1954 Mar;30:195-207. different treatments in terms of survival, side- Humbert M, Trembath RC. Genetics of effects, quality of life and costs. As head-to-head pulmonary hypertension: from bench to bedside. comparisons of currently approved therapies are Eur Respir J 2002; 20:741-9. not available, the choice of optimal treatment will Humbert M, Sitbon O, Simonneau G. Treatment be dictated by clinical experience and drug of pulmonary arterial hypertension. N Engl J Med availability, as well as patient preference. 2004; 351:1425-36. The treatment of PAH has historically been Klepetko W, Mayer E, Sandoval J. Interventional restricted due to limited therapeutic options. and Surgical Modalities of Treatment for Recent advances in our understanding of the Pulmonary Arterial Hypertension. J Am Coll pathophysiological and molecular mechanisms Cardiol 2004; 43:S73-80. that may underlie PAH, with the subsequent Loyd JE, Primm RK, Newman JH. Familial availability of novel pharmacological therapies, primary pulmonary hypertension: clinical patterns. provide renewed hope for both patients and their Am Rev Respir Dis. 1984 Jan;129:194-7. physicians. Advancing knowledge of this Montani D, Hamid A, Yaici A, Sztrymf B, Humbert devastating disease may ultimately lead to the M. Hypertension artérielle pulmonaire. Rev Prat development of therapies that ensure a better 2004; 54:5-13. prognosis. Sandoval J, Rothman A, Pulido T. Atrial septostomy for pulmonary hypertension. Clin References Chest Med 2001; 22:547-60. Abenhaim L, Moride Y, Brenot F, Rich S, Simonneau G, Galie N, Rubin L. Clinical Benichou J, Kurz X, Higenbottam T, Oakley C, Classification of Pulmonary Arterial Hypertension. Wouters E, Aubier M, Simonneau G, Bégaud B. J Am Coll Cardiol 2004; 43:S5-12. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335:609-16. 7 Humbert M., Simonneau G. Pulmonary arterial hypertension, Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-PulmArterHypert.pdf