where PAH can complicate the clinical course in 15 \200\22320% of patients, in the absence of interstitial lung disease. Other associated conditions include mixed connective tissue d isease and systemic lupus erythematosis, and more rarely, rheumatoid arthritis, dermatopoly myositis and primary Sjogrens \200\231 sysndrome. There is a well recognized associa- tion of PAH with congenital heart disease causing left to right shunts. Overall the prevalence o f PAH is 15 \200\22330%, but varies depending on the nature of the underlying cardiac defec t. Portal hypertension, usually associated with cirrho- sis, is associated with PAH in less than 5% of patients. There is an unusually high prevalence of PAH (0.5%) in patients with HIV infection. Epidemiological studies have con \201 rmed the association of PAH with amph etamine-like diet pills. In the 1970s increased numbers of patients with PAH were found to have been exposed to Aminorex. In the 1990s, further studies confirmed an assocation of 1.3.1. Collagen vascular disease 1.3.2. Congenital systemic-to-pulmonary shunts** 1.3.3. Po rtal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. Other (thyroid disord ers, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemo globinopathies, myeloproliferative disorders, splenectomy) 1.4. Associated with signi \201 cant venous or capillary involvement 1.4.1. Pulmonary veno-occlusive disease (PVOD) 1.4.2. Pulmonary capillary hemangiomatosis ( PCH) 1.5. Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension with left heart disease 2.1. Left-sided atrial or ventricular hea rt disease 2.2. Left-sided valvular heart disease 3. Pulmonary hypertension associated with lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disord ered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitu de 3.6. Developmental abnormalities 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease 4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruct ion of distal pulmonary arteries 4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material) CHAPTER 12.2 Pulmonary hypertension 265 PAH with appetetite suppressant drugs of the fen \202 uramine and dexen \202 uramine grou p. An epidemic of PAH also oc- curred in Spain in 1980s following the ingestion of con- tam inated rape seed oil. Other more rarely associated conditions are listed in Table 12.2.1. T he classi \201 cation of PAH includes two other rare pulmonary vascular diseases, pulmonar y veno-occlusive disease and pulmonary capillary haemangiomatosis. Both are more rare than idiopathic PAH, though the true prevalence is unknown. Persistent pulmonary hypertension of the newborn is a disorder characterized by a failure of vascular transition from fetal to a neonatal circulation and is estimated to affect 0.2% of live-born term infants. Pulmonary and pleural lymphatics are dilated and long- standing venous hypertension may lea d to oedema and \201 brosis. A further distinct pathological entity is pulmonary capillar y haemangiomatosis (PCH), characterized by the presence of numerous foci of proliferating, congested, thin- walled capillaries, which invade alveolar tissue, as well as pleura, bronc hial and vascular tissue. Clinical features Symptoms The three main presenting symptoms are dyspnoea, chest pain and syncope. The severity of symptoms is related to prognosis. Unexplained breathlessness on ex ertion should always raise the possibility of pulmonary arterial hyperten- sion, particular ly in the setting of conditions known to be associated with pulmonary hypertension (Table 1 2.2.1). The condition may have an insidious onset. Frequently there is a delay of up to thr ee years between the \201 rst symptoms and diagnosis. Syncope is an ominous sign, usu- al ly re \202 ecting severe right ventricular dysfunction. Other symptoms include lassitude, abdominal swelling from ascites and ankle swelling. Small haemoptysis may occur at later st ages. Genetic factors Familial PAH is a rare autosomal dominant condition with reduced penetrance . It is indistinguishable on clinical or pathological grounds from idiopathic PAH. In 2000, hetero- zygous germline mutations were identi \201 ed in the gene encoding the bone morph ogenetic protein type II receptor (BMPR-II), located on the long arm of chromosome 2 (2q33) . BMPR-II is a receptor for bone morphogenetic pro- teins (BMPs). BMPs are members of the t ransforming growth factor- (TGF- ) superfamily. Mutations in BMPR- II have now been iden ti \201 ed in over 70% of cases of familial PAH. Similar mutations are also found in 15 \200\22326% of patients thought to have sporadic or idiopathic disease. BMPR-II mutations h ave been identi \201 ed in most of the 13 exons of the BMPR2 gene. The majority (70%) of m utations are non- sense or frameshift mutations. Approximately 30% of the mutations are mis sense mutations. These cause retention of mutant protein within the endoplasmic reticulum o r affect important functional domains of the receptor, such as the ligand binding domain or the kinase domain. Muta- tions in BMPR-II have also been found in a small proportion (10%) of patients with PAH associated with appetite sup- pressants and in children with complica ted PAH associated with congenital heart disease. Mutations in another TGF- receptor, ALK -1, have also been reported is association with PAH. ALK-1 mutations are usually found in f amilies with hereditary haemorrhagic telangiectasia, though occa- sionally some family memb ers develop severe PAH. These \201 ndings have highlighted the central role of the TGF- signaling pathway in the pathogenesis of PAH. Clinical signs Tachypnoea may be present, even at rest. Peripheral cyano- sis is common due to a low cardiac output. Central cyano- sis occurs later as pulmonary gas exchange deterio rates or right to left shunting occurs through a patent foramen ovale. The jugular venous p ulse may be elevated with a prominent \200\230a \200\231 wave, re \202 ecting the increas ed force of atrial contraction, or, if tricuspid regurgitation is present, there may be a l arge \200\230V \200\231 wave. There may be a right ventricular heave and a pulsatile liver . On auscultation, forceful closure of the pulmonary valve leads to an accentuated pulmonar y arterial component of the second heart sound. There is often a third and fourth right hea rt sound. The murmurs of tricuspid regurgitation (systolic) or pulmonary regurgita- tion (d iastolic) may be heard. Jaundice, ascites and periph- eral oedema may be present at advance d stages of the disease. Cyanosis may be present, though profound cyano- sis may indicate t he presence of a right to left shunt. Differential diagnosis If the symptoms and clinical signs suggest pulmonary hy- pertension, the differential diagnosis should be considered with reference to the classi \201 cation in Table 12.2.1. Most importantly the presence of left heart disease, parenchy- mal lung di sease or congenital heart disease should be excluded. Pulmonary hypertension due to chronic throm- boembolic disease is important to detect because speci \201 c surgical treatment i s available. Idiopathic PAH remains a diagnosis of exclusion. Pathology Typical morphological appearances include increased mus- cularisation of small (< 200 M diameter) arteries and thickening or \201 brosis of the intima, referred to as con cen- tric intimal \201 brosis. In severe cases dilatation of small pul- monary arterioles is seen and sometimes \201 brinoid necro- sis. In the larger elastic arteries, aneurysma l dilatation may occur and atherosclerotic change, the latter being other- wise extremely u nusual in the normotensive pulmonary artery. The term plexogenic arteriopathy is used to de - scribe the presence of plexiform lesions (200 \200\223400 M), which are tangles of capil lary-like channels adjacent to small pulmonary arteries. Plexiform changes are found in som e 50% of cases of idiopathic PAH but also in other causes of severe pulmonary hypertension, such as that due to congenital heart disease. Pathologically, in some cases of idiopathic PAH there are changes in the pulmonary venous circulation as well as the arterial. If the v enous changes dominate the pathology the diagnosis is pulmonary veno- occlusive disease (PV OD), which has some distinct clinical features (see later in this chapter). Accompanying ar terial changes, particularly muscular hypertrophy, often co-exist. Clinical investigation The investigation of a patient with suspected pulmonary hypertension involves (i) the exclusion of other underlying causes and (ii) an assessment of severity o f pulmonary hyper- tension and right heart failure for prognosis and treatment. Blood tests A thrombophilia screen may reveal clotting abnormalities predisposing to chroni c thromboembolic pulmonary hy- pertension. This should include antithrombin III, protein C and S, factor V Leiden, anti-cardiolipin antibodies, and lupus anticoagulant. Thyroid funct ion should be measured since both hypo- and especially hyperthyroidism are commonly reporte d associations. An autoantibody screen should N MORRELL 266 be performed to exclude underlying connective tissue disease. Positive antinuclear antibodi es can be found in 30 \200\22340% of patients with idiopathic PAH. A primary vasculi- tis i s an uncommon cause of pulmonary hypertension, but measurement of antineutrophil cytoplasmi c antibodies (ANCA) should be requested. Since there is an increased incidence of unexplain ed pulmonary hypertension in HIV positive patients, this diagnosis should be considered in all patients. small arterioles reducing local perfusion. Additional \201 nd- ings in the pulmonary func tion tests such as marked air- \202 ow obstruction (e.g. severe chronic obstructive pulmo - nary disease), or a restrictive defect (e.g. pulmonary \201 brosis) would indicate the presence of an underlying cause for the pulmonary hypertension. However, subtle changes in lung volumes and mild air \202 ow obstruction have been reported in a proportion of patien ts with PAH. In some groups of patients at high risk of developing PAH, for example in scle roderma, the Kco can be monitored at in- tervals. A fall in the Kco, accompanied by breathl essness, may be the \201 rst sign of PAH complicating scleroderma. Imaging The plain CXR shows enlargement of the proximal pulmo- nary arteries, which may be dramatic. The proximal right and left main pulmonary arteries are enlarged and periph- eral pruning of the pulmonary vascular pattern occurs, giving rise to increased peripheral radi olucency. If heart failure is present the heart may be enlarged and enlarge- ment of the ri ght atrium is seen. The CXR may also give clues to underlying diagnoses such as interstitia l lung disease. A spiral contrast enhanced CT will detect proximal pulmo- nary arterial obs truction suggestive of acute or chronic thromboembolic disease. A pattern of mosaic perfusi on of the lung parenchyma may is also a feature of chronic thromboembolic pulmonary hyperte nsion, and may be the only sign in predominantly distal disease. A high resolution CT scan will pick up unsuspected parenchymal abnormalities, such as \201 brosis. CT scanning is a lso useful to indicate more uncommon forms of PAH, such as PVOD. In PVOD the CT may show a degree of mediastinal lymphadenopathy and septal lines in the lung periphery, presumably in dicating lymphatic and venous obstruction. On the ventilation-perfusion lung scan the patte rn of ventila- tion is usually normal in idiopathic PAH, and uneven venti- lation should su ggest underlying lung disease. The pattern of perfusion is also virtually normal though sma ll patchy perfusion defects may be present. This is in contrast to the appearance in chroni c thromboembolic pulmonary hyper- tension when segmental or larger perfusion defects persis t, often indistinguishable from the pattern of acute pulmonary embolism. Pulmonary artery a ngiography is only required if the diagno- sis is likely to be chronic thromboembolic pulmo nary hypertension. In this situation angiography will provide pre- cise anatomical informat ion regarding the location of vas- cular obstruction, indicated by abrupt cut-off of vessel s or intravascular webs, which may be of great use if surgical endarterectomy is being cont emplated. The main contribution of magnetic resonance imaging (MRI) is in the assessment of patients with suspected intracardiac shunts or with anomalous vascular anatomy; for exampl e, if a shunt is suspected on the basis of right heart catheterisation, but cannot be demon strated by echocardiography. In addition, MRI can provide further pulmonary angiographic im ages. Exercise testing Signi \201 cant PAH is always associated with a reduced exer- cise capaci ty. One of the most useful tests of exercise capacity in PAH patients is the 6MWT. A normal distance is greater than 500m. Heart rate and oxygen saturation should be monitored during the test. A low 6MW is pre- dictive of a poor survival. Full cardiopulmonary exercise test ing is technically more demanding to perform and is only recommended if the diagnosis is in doubt, for example if there was a need to document cardiovascular limitation on exercise. Peak oxygen uptake on exercise is low and the anaerobic threshold is reduced to about 40% o f nor- mal. There is excessive ventilation for a given degree of oxygen consumption or carb on dioxide output, even at rest. There is no ventilatory impairment when underlying lung di sease is absent. There is often a pronounced tachy- cardia at submaximal exercise, and usua lly arterial oxygen desaturation. Cardiac function tests In symptomatic PAH the electrocardiogram (ECG) is abnor- mal in 80 \200\22390% of established cases. However, the ECG has inadequate sensitivity (55%) and spe ci \201 city (70%) as a screening tool for detecting pulmonary hypertension. The ECG typic ally shows right axis deviation (more than +120 ) in the limb leads. A dominant R wave and T wave inversion in the right precordial leads accompanied by a dominant S wave in the lef t precordial leads suggests right ventricular hypertrophy. Tall peaked P waves in the right precordial and inferior leads denotes right atrial enlargement. Right bundle branch block is common. Echocardiography remains the best screening test for sig- ni \201 cant pulmonar y hypertension. It detects the presence and direction of intracardiac shunts. Usually this is possible using conventional transthoracic techniques, but if visu- alisation is poor or a small shunt is still suspected, then transoesophageal echocardiography may be necessary. In addition, the left ventricle can be reliably assessed to determine whether there is a co ntribution from left ven- tricular systolic or diastolic dysfunction to the elevated pulmon ary arterial pressure. The function of the right ven- tricle can also be assessed qualitati vely and quantitatively, in terms of atrial and ventricular dimensions and wall thickness. Paradoxical bowing of the intraventricular septum into the left ventricular cavity may be s een during systole, as a con- sequence of greatly elevated right sided pressures. Newer ech ocardiography techniques such as 3-D echo and tissue Doppler are being evaluated. Continuou s wave Doppler echocardiography is used to measure high \202 ow velocities across cardiac valves. One of the most commonly derived indices in the right heart is the pulmonary arter y systolic pressure measured by Doppler echocardiography. The measurement is made from meas urement of the velocity of the tricuspid regurgitant jet. About 80% of patients with Pulmonary function tests The typical pattern for standard pulmonary function test for disea se con \201 ned to the pulmonary circulation is \200 Normal lung volumes. \200 Normal FEV1/VC ratio (>0.75), indicating no air \202 ow obstruction. Low transfer factor (diffusing capacity, TLco) and low transfer coef \201 cient (Kco). The low diffusing capacity probably results from a combina- tion of a reduced cardiac outpu t and disease affecting the CHAPTER 12.2 Pulmonary hypertension 267 PAH and 60% of normal subjects have measurable tricuspid regurgitation. The maximum \202 ow velocity (v) of the regur- gitant jet is measured and inserted into the modi \201 ed Be r- nouilli equation for convective acceleration pressure change, giving an estimate of righ t ventricular systolic pressure (RVSP): to successfully adjust to the demands of their illness and its treatment. The overall aims are to improve symptoms and quality of life, increase exercise capacity and improve prognos is. Supportive medical therapy Patients with right heart failure and \202 uid retention may r equire diuretics. Decreasing cardiac preload with diuretics is often enough to alleviate ep isodes of right heart failure. Caution should be exercised though, because faced with a red uction in vascular \201 lling pressures patients with severe PAH will not be able to incr ease cardiac output effectively. This may result in systemic hypotension and syncope. Antia rrhythmics may be required for sustained or paroxys- mal atrial \201 brillation. Patients with severe PAH are prone to this complication because of stretching of the over- loaded r ight atrium. The presence of atrial \201 brillation can significantly compromise the alre ady reduced cardiac output in patients with PAH and should be treated aggressively. Rate co ntrol with digoxin is possible, but if not contraindicated, pharmacological cardioversion w ith amio- darone is preferable. Electrophysiological mapping of arrhythmias and ablation of arrhythmogenic pathways may be indicated in selected patients. RVSP = 4.v2 + RAP Where RAP is right atrial pressure. In the absence of pul- monary valve s tenosis, the RVSP is equal to the pulmonary artery systolic pressure (PASP). RAP can be est imated clinically from the height of the jugular venous pressure. There is a reasonable cor relation between Doppler esti- mates of PASP and catheter measurements. Right heart cathete risation remains the best technique for con \201 rming the diagnosis of pulmonary hyperten sion and for providing important prognostic information. An ele- vated mean pulmonary arter ial pressure of greater than 25mmHg at rest is the accepted de \201 nition, or 30mmHg on e xercise. In patients with idiopathic PAH the mean pulmo- nary arterial pressure may exceed 60mmHg. The pulmo- nary capillary wedge pressure (PCWP) can also be deter- mined at cathete risation, which is an approximation of left atrial pressure. An elevated PCWP (>15mmHg) gen erally indicates left heart disease, but can also be elevated in pul- monary veno-occlusive disease. Measurement of the PCWP is often unreliable in the presence of chronic thromboemb olic pulmonary hypertension. Sampling of ve- nous blood oxygen saturation as one passes the catheter down from the right atrium to right ventricle may detect a sudden \200\230step-u p \200\231 in oxygenation, which would indicate the presence of a left-to-right shunt. Most important is the de- termination of right ventricular function, which provides important p rognostic information. Cardiac output can be determined by thermodilution or the Fick metho d. Indica- tors of right heart failure, and hence poorer prognosis, include: i) an elevated right atrial pressure (>10mmHg), ii) an elevated right ventricular end diastolic pressure (>10mmHg), iii) a reduced mixed venous oxygen satura- tion (SvO2 <63%) and iv) a reduced ca rdiac output (<2.5liter/min). Calcium channel blockers Patients with idiopathic PAH and a documented acute vasodilator re sponse at cardiac catheterisation, as de \201 ned above, should be offered long term treat ment with a cal- cium channel blocker. This is associated with very signi \201 - cant impr ovement in symptoms and prognosis in this subset of patients. Nevertheless, only 50% of tho se who respond in the cardiac catheterisation laboratory will main- tain a long-term respon se to calcium channel blockers. Calcium channel blockers should be avoided in any patient w ith signi \201 cant signs of right ventricular failure, or until this is controlled, becau se of their negative inotropic effects. For this reason, and the risk of systemic hypotensi on calcium channel blockers should not be prescribed without con \201 r- mation of a vasod ilator response at cardiac catheterisation. Indiscriminate prescribing will lead to increas ed mortality in the PAH population. Treatment should be started in hospi- tal, using diltia zem, amlodipine or nifedipine, and carefully titrated against systemic blood pressure. The aim is to increase the dose to the maximum tolerated. Vasoreactivity studies A subgroup (10 \200\22315%) of patients with idiopathic PAH, and ano rexigen-associated PAH, demonstrate a marked reduc- tion in pulmonary vascular resistance f ollowing the admin- istration of a vasodilator. These patients are the only group that resp ond favorably to long-term treatment with vasodilator therapy in the form of calcium channe l block- ers (see later in this chapter), and are thus an important group to identify. Vaso dilator studies are undertaken at the time of right heart catheterisation. The preferred ag ent is inhaled nitric oxide, or an intravenous infusion of prostacyclin or adenosine. A pos itive response is de \201 ned as a fall in mean pulmonary arterial pressure of at least 10 mmHg to below 40mmHg, accompanied by an increase or no change in cardiac output. Anticoagulation Warfarin therapy to maintain the INR between 2 and 3 is recommended in all patients with idiopathic and familial PAH. Two retrospective and one small prospective stud y have demonstrated a survival bene \201 t of anticoagulation. Warfarin therapy was shown to almost double survival rate in idiopathic PAH over a 3-year period. The consensus is tha t patients with PAH associated with connective tissue disease should also receive warfarin, unless contraindi- cated. The risk-bene \201 t ratio of anticoagulation in other forms of PAH is undetermined. Oxygen therapy Oxygen therapy is indicated for symptomatic relief of breathlessness. There are no published trials of the bene \201 t of long-term oxygen therapy in hypoxaemic patie nts with PAH. Nocturnal oxygen was shown to be of no bene \201 t in Eisenmenger \200\231s syndrome. Ambulatory oxygen may be ben- e \201 cial if there is evidence of correctable de saturation of >4% to less than 90% during a 6MWT. Consideration should be given to in- \202 ight supplemental oxygen for air travel. Treatment All patients with suspected severe PAH are best referred to a specialist center f or initial assessment and treatment. A multidisciplinary team approach to planning treatmen t is preferred with input from respiratory physicians and cardi- ologists, transplant physi cians and cardiothoracic surgeons, radiologists, specialist nurses, and palliative care spe cialists. Assisting patients to adapt to the uncertainty associated with chronic, life-shor tening disease is essential if they are N MORRELL 268 Disease-targeted therapies Over the last 10 years, remarkable advances have been made in th e availability of therapeutic agents for PAH. Clinical trails have almost exclusively recru ited patients with idiopathic PAH and anorexigen associated PAH, though often include a sub set of patients with PAH associ- ated with systemic sclerosis. There are limited published data in other forms of PAH. These agents are used to reduce pulmonary vascular resistance a nd improve cardiac output. They all improve exercise performance and data support extended survival times for some. Figure. 12.2.1 presents an algorithm summarizing the pharmacologic al approach to treating PAH, based on current recommenda- tions. Disease-targeted therapy i s usually only licensed for treatment of patients in NYHA class III and IV. Prostanoids Pro stacyclin has a half-life in the circulation of less than 2 minutes and thus must be given by continuous intrave- nous infusion. Although prostacyclin produces acute hemo- dynamic ef fects in some patients, most patients experience a fall in pulmonary vascular resistance wi th long-term use even in the absence of acute improvements. Prostacyclin has been shown to improve haemodynamics, exercise tol- erance, quality of life and survival in patients in NY HA class III and IV. Side effects are usually experienced when start- ing prostacyclin or w hen escalating the dose. These include jaw pain, cutaneous \202 ushing, nausea and diarrh ea, as well as myalgias. Acute withdrawal of prostacyclin, for example if the infusion pump fails, can cause severe rebound pulmonary hypertension, which can be fatal. Recurrent seps is due to line infection can also be problematic. Although prostacyclin remains a proven therapy in PAH, the complexity of its administration, and the availability of newer oral agents, means that this approach tends to be reserved for patients with seve re haemodynamic compromise. Stable analogs of prostacyclin have been developed with longer half lives and improved bioavailability. Iloprost can be given by the intravenous or inhale d route. Treprostinil can be given subcutaneously or intravenously and is approved for use in patients in NYHA class II, III, and IV. Beraprost is an orally available prostacyclin an alog, though the dose may be limited by gastrointestinal side effects. It is presently only available in Japan. Endothelin receptor antagonists The orally active, dual selective ETA/ETB receptor antago- nist, bosentan, has been shown to improve exercise capacity, functional class, haemodynamic s, echocardiographic and Doppler variables, and time to clinical worsening in idio- pathic PAH. The most signi \201 cant side effect of bosentan is elevation of the hepatic transami nases, which is usually reversible on stopping the drug. Sitaxsentan and ambrisen- tan are newer ETA selective agents with similar ef \201 cacy to bosentan in short term studies, an d favorable safety pro- \201 les. All patients on these agents require monthly monitoring of liver function tests. Phosphodiesterase inhibitors Sildena \201 l is an orally active selective inhibitor of cGM P- phosphodiesterase type 5. It acts by inhibiting the break- down of cyclic GMP, with vaso relaxant and antiproliferative effects in pulmonary vascular smooth muscle. Sildena \201 l improves exercise tolerance and pulmonary haemodynamics Pulmonary arterial hypertension (NYHA functional class III or IV) Conventional therapy (oral anticoagulant diuretics oxygen) Acute vasodilator response YES NO Oral calcium-channel blockers Class III Class IV Sustained response Intravenous prostacyclin or endothelin-receptor antagonist or prostacyclin analogs Endothelin-receptor antagonist or prostacyclin analogs or intravenous prostacyclin NO YES No improvement or deterioration Atrial septostomy or lung transplantation PDE5 inhibitors Continue calcium- channel blockers Fig. 12.2.1 Algorithm summarizing the pharmacological approach to treating PAH. CHAPTER 12.2 Pulmonary hypertension 269 in short term studies in PAH. Longer acting PDE5 inhibi- tors, such as tadala \201 l, also show promise. for patients with underlying systemic sclerosis, connective tissue disease, HIV disease, an d anorexigen-associated PAH. The prognosis for patients surviving to adulthood with PAH ass ociated with a congenital intracardiac defect is substantially better than patients with id iopathic PAH. At least in patients with idiopathic PAH targeted therapies seem to improve s urvival to some extent, though de \201 nitive studies are awaited. Females with severe PAH should be advised that pregnancy carries a very high mortality because of the associated i ncreased burden on the right heart. Combination therapy There is considerable theoretical and experimental evi- dence to suppor t the use of combinations of the above disease-targeted therapies in PAH. Since PAH is a pr ogres- sive disease most patients eventually deteriorate on mono- therapy. The addition of further agents has been shown to provide clinical bene \201 t, although the evidence for p recise recommendations is lacking at present. Atrial septostomy Atrial septostomy involves creating a right to left shunt between the atr ia. The preferred technique is by percuta- neous graded balloon dilatation. The rationale f or this pro- cedure is that patients with PAH and a patent foramen ovale have improved surv ival. Creating the shunt reduces right ventricular preload which relieves the failing right ventricle and can increase cardiac output and improve exercise capacity. This increase in cardiac output is at the expense of a reduction in systemic arterial oxygen saturation, but systemic oxygen delivery is usually improved. The procedure is usually reserved for patien ts who are failing on maximal medical therapy or as a bridge to transplantation. Miscellaneous Pulmonary hypertension is detectable in some 5% of patients with sarcoidosis. This may develop in the context of end stage pulmonary \201 brosis due to sarcoid, but a lso may present as an isolated sarcoid vasculopathy in patients with relatively little pare nchymal lung involvement. A falling diffusion co-ef \201 cient for carbon monoxide in the face of preserved lung volumes may the \201 rst clue to this in a sar- coid patient with worsening dyspnoea. In patients with vasculopathy there may be a marked response to immuno- suppression with prednisolone, which is worth trying before embarking on targeted PAH ther apy. The commonest world-wide cause of pulmonary hyper- tension is said to be schistosomias is. When one considers how many patients are infected with schistosomiasis this may be true , but true prevalence \201 gures are hard to come by. The clinical picture in schistosomi asis is usually domi- nated by the effect on the urinary tract (Schistosoma hae- matobium) or liver (Schistosoma mansoni and japonica). Pulmonary hypertension is thought to be due to granulo- mata in or adjacent to pulmonary arterioles caused by the reaction to the presenc e of Schistosome eggs. One of the commonest causes of pulmonary hypertension is that which occurs as a complication of COPD. The pul- monary hyper tension is due to a combination of hypoxic pulmonary vasoconstriction, hypoxia-driven pulmonary vascular remodeling and a redu ction in capillary cross sectional area in emphysema. Lung hyperin \202 ation and polycyth aemia may also contribute. The prevalence of pul- monary hypertension in patients with seve re COPD may be as high as 50%. However, the average mean pulmonary arterial pressure is of the order of 25mmHg and progresses slowly (less than 1mmHg/year). It is likely that ventila tory impairment due to obstructed airways contributes to the majority of the exercise limit ation in these patients. Nevertheless, there are relatively unusual cases of COPD in which the pulmonary hypertension dominates. These patients are often profoundly hypoxic, have emp hysema on CT scanning and demonstrate a low diffusion coef \201 - cient for carbon monoxid e. The level of pulmonary hyper- tension is similar to that seen in idiopathic PAH and thes e patients warrant targeted therapy for PAH in addition to optimization of their COPD medic ation. Transplantation Transplantation of the lungs or heart and lungs was devel- oped as a treatm ent for end-stage PAH during the 1980s. The advent of modern targeted therapies has reduced the number of patients referred for transplantation. However, the long-term outcome of pat ients who remain in NYHA functional class III or IV remains poor. Lung or heart lung transp lantation therefore remains an important mode of treatment for patients failing medical the rapy. Patients with pulmonary veno-occlusive disease and pulmonary capillary haemangiomatos is have a particularly poor outlook and respond poorly to available medical therapies and s hould be referred early for transplantation assessment. In gen- eral, patients presenting w ith NHYA class IV symptoms should be referred for transplant assessment at the time of pres entation, because their prognosis is poor. Additional indicators of poor prognosis include: i) a six minute walking distance <332 meters, ii) a peak oxygen consumption <10.4 ml/min/ kg, iii) a cardiac index <2 l/min/m2, iv) a right atrial pressure >20mmHg, v) a mean pulmon ary arterial pressure >55mmHg, vi) a mixed venous oxygen saturation of <63%. Those with sig ni \201 cant improvement after three months medical therapy can be removed or suspended fr om listing for transplant. The choice of procedure varies between centers but single lung ( SLT), bilateral lung (BLT) and heart lung transplantation (HLT) are used in patients with P AH. International Registry \201 gures show that the one- year mortality post-transplantat ion is highest in patients with idiopathic PAH compared with any other indication. Median s urvival post-transplantation for idiopathic PAH is between 4 and 5 years. Chronic thromboembolic pulmonary hypertension (CTEPH) Pathogenesis CTEPH occurs when a clot fails to resolve completely after an acute pulmonary embolic event. The rate of resolution of clots after acute pulmonary embolism varies and is longer in patients with pre-existing cardiopulmonary disease, but nor- mal perfusion should be restored by 4 \200\2236 weeks af ter the acute event. To some extent, the rate of resolution depends Prognosis The prognosis of PAH varies depending on the underlying association or cause. Pro gnosis is most closely linked to indices of cardiac function, especially cardiac index. His torical data in the period prior to the availability of modern targeted therapies suggest a n expected median survival for idiopathic PAH between 2.5 and 4 years, and a 3 year surviva l of about 60%. The prognosis is worse N MORRELL 270 the presence of peripheral disease. Ventilation-perfusion lung scans also usually show mult iple segmental perfusion defects not matched by defects in ventilation, even in distal dise ase. Computed tomography can also reveal the extent of right ventricular hypertrophy and di latation, although this is probably best seen by MRI. Three-dimensional reconstruc- tion of the two-dimensional CT and MR images can help decide whether the distribution of disease i s suitable for PEA. The use of a combination of these techniques means that the more invasi ve traditional pulmonary angiogram can be avoided in most patients. Approximately 60% of ca ses of CTEPH are potentially suitable for surgery. Of the patients who are not suitable for surgical management, many may be suitable for targeted therapy with the new pharmacologica l agents described above. on the initial clot burden or the size of the acute pulmonary embolism. If the clot fails t o resolve, it becomes organized before it can be completely \201 brinolysed. The organize d thrombus is incorporated into the wall of the pulmonary artery, becomes covered by endoth elial cells and forms a false intima. The organized material occludes the vascular lumen, w hich increases pulmonary vascular resistance and leads to pulmonary hypertension. The true prevalence of CTEPH is hard to ascertain, because it is not usually sought in patients who are recovering from acute pulmonary embo- lism (PE), but it almost certainly is underdiagno sed. One well-designed study found that 4% of patients with a history of acute PE had a per sistent elevation of pulmonary arterial pressure after two years. Evidence also shows that those with a higher initial clot burden (massive PE) are more likely to develop CTEPH than those with minor PE. The more widespread use of thrombolysis for acute PE is often assumed to reduce the prevalence of CTEPH, but no data at present support this view. It is of note that some of the classic risk factors for acute deep vein thrombosis (DVT)/PE are not found with increased frequency in the population that develops CTEPH. For example, the factor V Leiden polymorphism, which leads to activated protein C resistance and is found with high p revalence in the population of patients with acute DVT, is not overrepresented in patients with CTEPH. The prevalence of protein C and S de \201 ciency is increased in patients with CTEPH, although these conditions account for a small minority of patients. In addition, so me 10% of patients with CTEPH may have circulating antiphospholipid antibodies. Recent rese arch points to a de \201 ciency in the abil- ity to \201 brinolyse established clots as a predisposing factor. Other important predisposing factors include previous splenectomy an d in \202 ammatory bowel disease. Treatment Pulmonary endarterectomy (PEA) is a surgical procedure during which organized thr ombi are removed from the proximal pulmonary arteries. The procedure is a major operation t hat usually requires the patient to undergo repeated cycles of cardiopulmonary bypass with cerebral cooling. This ensures a bloodless \201 eld of view for the sur- geon, who can th en enter the left and right main pulmo- nary arteries via an arteriotomy. The aim is to ide ntify a dissection plane along the base of the false intima and to dissect distally as far as possible. It is often possible to remove organized material as far distally as segmental pul- monary arteries. With successful clearance of proximal clots, the pulmonary vascular resistance can fall dramati- cally post-operatively, and near normalization of resistance c an be achieved in the long term. Patients are maintained on life-long warfarin and have an inferior vena cava \201 lter sited prior to the operation. Long-term survival is often ex cellent after a successful procedure with marked improvements in exercise capacity, NYHA fu nctional status and quality of life. The operation itself carries some risk, and perioperat ive mortality varies between 7 \200\22320% depending on the experience of the center. There are two main aspects to patient selection for this procedure. Comorbidities are important predictors of perioperative mortality and require careful assessment. A further important c onsideration is the distribution of the disease, as organized clots need to be anatomically acces- sible to the surgeon. If the organized material is predomi- nantly of a distal dist ribution within the pulmonary arter- ies, that is involves subsegmental vessels, there is a high risk that pulmonary vascular resistance will not decrease after the procedure and tha t the patient will be left with signi \201 - cant pulmonary hypertension. Patients with pe rsistent PAH following PEA may bene \201 t from the targeted pharma- cological therapies d etailed above. Clinical presentation Clinically, patients often present with persistent symptoms of dyspno ea after an acute embolic event and despite the recommended period of anticoagulation. Up t o 60% of patients with CTEPH will have a prior documented epi- sode of previous venous thro mboembolism, although some patients may present with gradually worsening dys- pnoea in the absence of acute events. A further important \201 nding may be pulmonary \202 ow murmur s, resulting from turbulent \202 ow across partially obstructed large pulmonary arteries, which may be audible on chest auscultation in up to 30% of patients with CTEPH. Otherwise the clinical presentation is similar to that described above for PAH.