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Year : 2009  |  Volume : 10  |  Issue : 4  |  Page : 162-173 Table of Contents     

Pulmonary hypertension insights from experience of the last decade and highlights from the guidelines1

1 M.D, Department of Cardiology and Cardiothoracic Surgery, Hamad Medical Corporation, Doha, Qatar
2 Consultant Cardiologist, Department of Cardiology and Cardiothoracic Surgery, Hamad Medical Corporation, Doha, Qatar

Date of Web Publication17-Jun-2010

Correspondence Address:
Awad Alqahtani
M.D., Department of Cardiology and Cardiothoracic Surgery, Hamad Medical Corporation, P.O. Box 3050, Doha
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Source of Support: None, Conflict of Interest: None

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Pulmonary-arterial hypertension (PAH) from any cause is more prevalent than previously believed and significant uncertainties remain regarding the diagnosis and optimal treatment of PAH. It is now recognized that effective treatment for one cause of PAH may not necessarily be useful for PAH from a different cause. This article reviews the contemporary definition, classification, and diagnosis of PAH, with a focus on recent developments in its treatment.

Keywords: Pulmonary arterial hypertension, Pulmonary vascular resistance, pulmonary artery pressure

How to cite this article:
Al-Aqeedi RF, Alqahtani A. Pulmonary hypertension insights from experience of the last decade and highlights from the guidelines1. Heart Views 2009;10:162-73

How to cite this URL:
Al-Aqeedi RF, Alqahtani A. Pulmonary hypertension insights from experience of the last decade and highlights from the guidelines1. Heart Views [serial online] 2009 [cited 2020 Aug 12];10:162-73. Available from: http://www.heartviews.org/text.asp?2009/10/4/162/63682

   I.Definition Top

PAH is a devastating disease, characterized by progressive increases in pulmonary-vascular resistance (PVR) and pulmonary-artery pressure (PAP). PAH has been defined as an increase in mean PAP ≥ 25 mmHg at rest as assessed by right heart catheterization (RHC). Recent data has shown that the normal mean PAP at rest is 14 ±3 mmHg, with an upper limit of normal of 20mmHg2 . Different hemodynamic definitions of pulmonary hypertension (PH) are according to various combinations of values of pulmonary wedge pressure (PWP), PVR, and cardiac output (CO). Pre-capillary PH includes the clinical groups 1, 3, 4 and 5 while post-capillary PH includes the clinical group 2 [Table 1],[Table 2].

   II. Classification of pulmonary hypertension Top

While the worldwide experts' consensus in the fourth World Symposium on PH held in 2008 in Dana Point, California agreed to maintain the general philosophy and organization of the World Health Organization 1973, Evian-Venice 1998 and 2003 classifications respectively, a new clinical classification was adapted to classify PH into six groups according to pathological, pathophysiological, and therapeutic characteristics attempting to avoid possible confusion among the terms PH and pulmonary arterial hypertension (PAH). Compared with the previous version of the clinical classification the changes are as follows:

Group 1, PAH:

The term familial PAH has been replaced by heritable PAH because specific gene mutations have been identified in sporadic cases with no family history.

The classification of congenital heart disease (CHD) causing PAH has been updated to include a clinical and an anatomical-pathophysiological version in order to better define each individual patient. Associated PAH (APAH) includes conditions which can have a similar clinical presentation to that seen in IPAH with identical histological findings including the development of plexiform lesions. APAH accounts for approximately half of the PAH patients followed at specialized centres and includes schistosomiasis, chronic hemolytic anemia such as sickle cell disease, thalassemia, hereditary spherocytosis, stomatocytosis, and micro­angiopathic haemolytic anemia.

Group 1': Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangio­matosis remain difficult disorders to classify since they share some characteristics with IPAH but also demonstrate a number of differences.

Group 2: PH due to left heart disease.

Group 3: PH due to lung diseases and hypoxia, are not substantially changed.

Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH) is maintained as a single category as there are no well-defined criteria to discriminate proximal from distal CTEPH obstructive lesions.

Group 5: PH with unclear and/or multifactorial mechanisms: this group comprises a heterogeneous collection of diseases with uncertain pathogenetic mechanisms.

   III.Epidemiology of pulmonary hypertension Top

In a survey performed in an echocardiography laboratory, the prevalence of PH (PA systolic pressure > 40 mmHg) was 10.5%. Among them 78.7% had left heart disease (group 2), 9.7% had lung diseases and hypoxia (group 3), 4.2% had PAH (group 1), 0.6% had CTEPH (group 4), and in 6.8% it was not possible to define a diagnosis. Recent data from Scotland and other countries have confirmed that PAH (Group 1) prevalence is in the range 15-50 subjects per million population in Europe [3] .

IPAH corresponds to sporadic disease, without any familial history of PAH or known triggering factor. When PAH occurs in a familial context, germline mutations in the bone morphogenetic protein receptor 2 gene are detected in at least 70% of cases [4].

PH due to left heart disease (Group 2): Up to 60% of patients with severe left ventricular (LV) systolic dysfunction and up to 70% of patients with isolated LV diastolic dysfunction may present with PH. PH can be found in virtually all patients with severe symptomatic mitral valve disease and in up to 65% of those with symptomatic aortic stenosis [2] .

PH due to lung diseases and/or hypoxemia (Group 3): One study has shown that serotonin gene polymorphism appears to determine the severity of PH in hypoxemic patients with chronic obstructive pulmonary disease (COPD). Based on published series, the incidence of significant PH in COPD patients with at least one previous hospitalization for exacerbation of respiratory failure is 20%. In interstitial lung disease, the prevalence of PH is between 32 and 39% [5] .

Group 4, CTEPH: The incidence after acute pulmonary embolism is 0.5-2%. It can be found in patients without any previous clinical episode of acute pulmonary embolism or deep venous thrombosis (up to 50% in different series) [6] .

Group 5, PH is multifactorial and there is heterogeneity of risk factors in this group.

   IV.Pathology of pulmonary hypertension Top

Different pathological features characterize the diverse clinical PH groups.

Group1 - affects distal pulmonary arteries (<500mcm) causing medial hypertrophy, intimal proliferative and fibrotic changes, adventitial thickening with moderate perivascular infla­mmatory infiltrates, complex lesions (plexiform, dilated lesions), and thrombotic lesions. Pulmonary veins are classically unaffected.

Group 1' - involves septal veins and preseptal venules with occlusive fibrotic lesions, venous muscularization, frequent capillary proliferation, pulmonary oedema, occult alveolar haemorrhage, lymphatic dilatation and lymph node enlargement, and inflammatory infiltrates.

Group 2 - causing thickening and enlarge­ment of pulmonary veins, pulmonary capillary dilatation, interstitial edema, alveolar hemorrhage, and lymphatic vessel and lymph node enlargement. Distal pulmonary arteries may be affected by medial hypertrophy and intimal fibrosis.

Group 3 - changes includes medial hypertrophy and intimal obstructive proliferation of the distal pulmonary arteries. There is a variable degree of destruction of the vascular bed in emphysematous or fibrotic areas.

Group 4 - an organized thrombi are tightly attached to pulmonary arterial medial layer in the elastic pulmonary arteries, replacing the normal intima.

Group 5 - includes heterogeneous conditions with different pathological pictures.

   V. Pulmonary arterial hypertension (Group 1) Top

PAH is a clinical condition characterized by the presence of pre-capillary PH in the absence of other causes of pre-capillary PH such as lung diseases, chronic thromboembolic PH, or other rare diseases [Table 1].

The exact interactions between pathobiological mechanisms in the initiation and progression of the pathological processes are not well understood. The consequent increase in PVR leads to right ventricular (RV) overload, hypertrophy, and dilatation, and eventually to RV failure and death.

   VI. Diagnostic algorithm Top

The evaluation process of a patient with suspected PH requires a series of investigations intended to confirm the diagnosis, clarify the clinical group of PH and the specific etiology within the PAH group, and evaluate the functional and hemodynamic impairment.

For objective assessment of exercise capacity, the 6-minute walking test (6MWT) and cardiopulmonary exercise testing are commonly used in patients with PAH. The 6 MWT is technically simple, inexpensive, reproducible, and well standardized. In addition to distance walked, dyspnea on exertion (Borg scale) and finger O2 saturation are recorded. Since PAH, and particularly IPAH, is a diagnosis of exclusion, the algorithm in [Figure 1] can be useful as a starting point in any case of suspected PH. It starts with the identification of the more common clinical groups such group 2 left heart disease and group 3 lung diseases, then distinguishes group 4 CTEPH and finally makes the diagnosis and recognizes the different types in group 1 PAH and the rarer conditions in group 5.

PAH should be considered in the differential diagnosis of exertional dyspnea, syncope, angina, and/or progressive limitation of exercise capacity, particularly in patients without apparent risk factors, symptoms or signs of common cardiovascular and respiratory disorders. Special awareness should be directed towards patients with associated conditions and/or risk factors for development of PAH, such as family history, CTD, CHD, HIV infection, portal hypertension, hemolytic anemia, or a history of intake of drugs and toxins known to induce PAH [Table 3].

If the clinical assessment is compatible with PH, ECG, chest radiograph, transthoracic echocardiogram, pulmonary function tests, and high-resolution CT of the chest are requested to identify the presence of group 2 left heart disease or group 3 lung diseases. If these are not found or if PH seems 'out of proportion' to their severity, less common causes of PH should be looked for. Ventilation/perfusion lung scan should be considered; the presence of multiple segmental perfusion defects suggests a diagnosis of group 4 CTEPH. The CT scan may also show signs suggestive of group 1' PVOD. If a ventilation/perfusion scan is normal or shows only subsegmental 'patchy' perfusion defects, a tentative diagnosis of group 1 PAH or the rarer conditions of group 5 is made. Additional specific diagnostic tests including hematology, biochemistry, immunology, serology, and ultrasonography will allow the final diagnosis to be refined. Open or thoracoscopic lung biopsy entails substantial risk of morbidity and mortality. Because of the low likelihood of altering the diagnosis and treatment, routine biopsy is discouraged in PAH patients.

   VII. Therapy Top

Over the last decade eight drugs with different routes of administration were approved by regulatory agencies. Modern drug therapy leads to a significant improvement in patients' symptomatic status and a slower rate of clinical deterioration. A meta-analysis performed on 23 RCTs in PAH patients reports a 43% decrease in mortality and a 61% reduction in hospitalizations in patients treated with specific drug therapies vs. patients randomized to placebo [7] . Despite that, PAH remains a chronic disease without a cure. A treatment algorithm for patients with PAH shown in [Figure 2].


Patients should be encouraged to be active within symptom limits and avoiding exertion that leads to severe breathlessness, exertional dizziness, or chest pain. While pregnancy is associated with 30-50% mortality, it is a considered contraindication in patients with PAH. The known physiological effects of hypoxia suggest that in-flight O 2 administration should be considered for patients in WHO-FC III and IV and those with arterial blood O 2 pressure consistently 8 kPa (60 mmHg). Patients with PAH are susceptible to developing pneumonia, which is the cause of death in 7% of cases [8] . While there are no controlled trials, it is recommended to vaccinate against influenza and pneumococcal pneumonia. Elective surgery is expected to have an increased risk in patients with PAH. It is not clear as to which form of anesthesia is preferable but epidural is probably better tolerated than general anesthesia.

VII.2. Supportive therapy

Evidence in favor of oral anticoagulation is confined to patients with IPAH, heritable PAH, and PAH due to anorexigens. The potential benefits of oral anticoagulation should be weighed against the risk of bleeding such as portopulmonary hypertension with severe esophageal varices. The target international normalized ratio (INR) in patients with IPAH varies from 1.5-2.5 in North America to 2.0-3.0 in European centers. Clinical experience shows clear symptomatic benefit in fluid-overloaded patients treated with diuretics therapy. In patients with COPD, when arterial blood O 2 pressure is consistently less than 8 kPa (60 mmHg) patients are advised to take O 2 to achieve a arterial blood O 2 pressure of 8 kPa for at least 15 h/day. Ambulatory O 2 may be considered when there is evidence of symptomatic benefit and correctable desaturation on exercise. Digoxin may be given to slow ventricular rate in patients with PAH who develop atrial tachyarrhythmias.

VII.3. Specific drug therapy

VII.3a. Calcium channel blockers

Only a small number of patients with IPAH who demonstrate a favourable response to acute vasodilator testing at the time of RHC do well with CCBs. The choice of CCB is based upon the patient's heart rate at baseline. The effective daily doses are relatively high, 120-240mg for nifedipine, 240-720mg for diltiazem, and up to 20 mg for amlodipine cases [9].

VII.3b. Prostanoids

1. Epoprostenol:
A synthetic prostacycline has a short half-life (3-5 min), administered continuously by an infusion pump and a permanent tunnelled catheter. It improves symptoms, exercise capacity, and hemodynamics in patients with IPAH and in PAH associated with scleroderma and is the only treatment shown to improve survival in IPAH in a randomized study [10].

Treatment with epoprostenol is initiated at a dose of 2-4 ng/kg/min, with doses increasing at a rate limited by side effects. The optimal dose varies between 20 and 40 ng/kg/min. Abrupt interruption of the epoprostenol infusion should be avoided as, in some patients, this may lead to a rebound PH with symptomatic deterioration and even death.

2. Iloprost: A prostacyclin analogue available for I.V., oral, and aerosol administration. The inhaled daily iloprost (6-9 times, 2.5-5 mg/inhalation) increase exercise capacity and improve symptoms, PVR, and clinical events. A study (STEP) on 60 patients already treated with bosentan has shown increase in exercise capacity (P, 0.051) in the subjects randomized to the addition of inhaled iloprost in comparison with placebo [11].

Continuous I.V. administration of iloprost appears to be as effective as epoprostenol in patients with PAH and CTEPH. The effects of oral iloprost have not been assessed in PAH.

3. Treprostinil: An analogue of epoprostenol administrated by I.V. and S.C. route. The S.C. administration can be accomplished by a microinfusion pump and a small subcutaneous catheter. The effects showed improvement in exercise capacity and hemodynamics. The optimal dose varies between 20 and 80 ng/kg/min. Survival appeared to be improved among patients who continued to receive S.C. treprostinil.

A phase III RCT (TRIUMPH) of inhaled treprostinil in patients on background therapy with either bosentan or sildenafil was recently completed, and preliminary data show improve­ments in exercise capacity [12] . Oral treprostinil is currently being evaluated in RCTs in PAH.

4. Beraprost: The first orally active prostacyclin analogue shown an improvement in exercise capacity up to 3-6 months with no haemodynamic benefits.

VII.3c. Endothelin receptor antagonists

1. Bosentan:
An oral endothelin receptor antagonist evaluated in PAH (idiopathic, associated with CTD, and Eisenmenger's syndrome. It has been shown to improve exercise capacity, functional class, hemo­dynamics, echocardiographic and Doppler variables, and time to clinical worsening [13] . Bosentan treatment is started at the dose of 62.5 mg twice daily and uptitrated to 125 mg twice daily after 4 weeks.

Increases in hepatic aminotransferases occurred in 10% of the subjects but were found to be dose dependent and reversible so liver function test should be performed monthly. Reductions on haemoglobin levels and impaired spermatogenesis have also been observed.

2. Sitaxentan: A selective orally active endothelin-A receptor antagonist, has been assessed in RCTs (STRIDE 1 and 2) on patients with IPAH and PAH associated with CTDs or CHD and demonstrated improvements in exercise capacity and hemodynamics [14] . The incidence of abnormal liver function tests was 3-5% for the approved dose of 100 mg once daily. Monthly checking of liver function tests is required. Warfarin dose reductions required when co-administrated with sitaxentan.

3. Ambrisentan: A non-sulfonamide, propanoic acid- class, ERA that is selective for the endothelin-A receptor. Demonstrated efficacy on symptoms, exercise capacity, haemodynamics, and time to clinical worsening of patients with IPAH and PAH associated with CTD and HIV infection. The approved dose is 5 mg once daily which can be increased to 10 mg when tolerated. The incidence of abnormal liver function tests was 0.8 to 3%.

VII.3d. Phosphodiesterase type-5 inhibitors

1. Sildenafil:
Is an orally phosphodiesterase type-5 inhibitor. A favourable effects found in IPAH, PAH associated with CTD, CHD, and CTEPH [15] . In clinical practice, up-titration beyond 20 mg (40-80mg) t.i.d. is needed quite frequently.

2. Tadalafil: Is a once-daily, selective phosphodiesterase type-5 inhibitor. An RCT (PHIRST) on PAH patients treated with tadalafil 5, 10, 20, or 40mg once daily has shown favourable results on exercise capacity, symptoms, haemodynamics, and time to clinical worsening at the largest dose [16] . The side effect profile was similar to that of sildenafil.

VII.4. Combination therapy

Combination therapy has become the standard of care in many PAH centers, although long-term safety and efficacy have not yet been amply explored. Numerous case series have suggested that various drug combinations appear to be safe and effective. Combination therapy of established PAH drugs is recommended for patients not responding adequately to monotherapy, but combination therapy should be instituted by expert centers only.

VII.5. Balloon atrial septostomy (BAS)

The creation of an interatrial right-to-left shunt can decompress the right heart chambers, and increase LV preload and CO. In addition, this improves systemic O 2 transport despite arterial O 2 desaturation and decreases sympathetic hyperactivity. While it is regarded as a palliative or bridging procedure, the recommended technique is graded balloon dilation atrial septostomy.

VII.6. Transplantation

The advent of disease-specific therapy for severe PAH has reduced patient referral for lung transplant programs. The long-term outcomes of medically treated patients remain uncertain and transplantation should remain an important option for those who fail on such therapy. Studies indicate that up to 25% of patients with IPAH may fail to improve on disease-specific therapy. The overall 5-year survival following transplantation for PAH is 45-50%, with evidence of continued good quality of life.

   VIII.Drugs and toxins Top

Association between anorexigens and PAH was initially observed in the 1960s when an epidemic of IPAH was noted in Europe following the introduction of aminorex fumarate. However, related compounds, such as fenfluramine and dexfenfluramine, were subsequently developed in the 1980s. Exposure to these agents for as little as 3 months also has been associated with an increased incidence of IPAH [17] . Studies have also linked to a list of substances with the development of PAH. [Table 3]

   IX. Pediatric pulmonary arterial hypertension Top

All forms of PH included in the clinical classification [Table 2] have been described in children, but the majority of patients present with PH associated with CHD or idiopathic / heritable forms.

   X.Pulmonary arterial hypertension associated with congenital cardiac shunts Top

The prevalence of PAH in adult CHD was 5-10% as suggested in a recent study [18] . Of all patients with CHD, those with Eisenmenger's syndrome are the most severely compromised in terms of exercise intolerance. Nevertheless they had better survival compared with IPAH. Patients with CHD (in particular those without shunts) may also develop PH due to left heart disease or to concomitant lung diseases.

   XI.Collagen vascular disease Top

PAH associated with CTD is the second most prevalent type of PAH after IPAH. Treatment appears more complex than that of patients with IPAH. Immunosuppressive therapy combining glucocorticosteroids and cyclophosphamide may result in clinical improvement in patients with systemic lupus erythematosus or mixed CTD [19] . The risk-to-benefit ratio of oral anticoagulation is not well understood. Treatment of patients with CTD and PAH should follow the same treatment algorithm as in IPAH [Figure 2].

   XII. Pulmonary arterial hypertension associated with portal hypertension Top

Portopulmonary hypertension is not uncommon and represents about 10% of the PAH population. It is believed that 1 -2% of patients with liver disease and portal hypertension develop PAH. Patients also have a significantly higher CO and lower systemic vascular resistance and PVR, compared with patients with IPAH.

   XIII. Pulmonary arterial hypertension associated with human immunodeficiency virus infection Top

The initial prevalence was found to be 0.1- 0.5%. The pathogenesis remains unclear. It shares a similar clinical presentation with IPAH and asymptomatic patients need not be screened for PAH. Treatment of HIV-related PAH is less well established and appears to be non-responders to vasoreactivity tests. Anticoagulation is not routinely recommended because of an increased risk of bleeding, anticipated compliance issues, and drug interactions. Several uncontrolled studies suggest that prostanoids may improve exercise tolerance, haemodynamics and symptoms in HIV-related PAH and it is generally considered an exclusion criterion for lung transplantation.

   XIV. Pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis (Group 1') Top

Both are uncommon conditions, but are increasingly recognized causes of PAH. Familial occurrence has been reported, and a bone morphogenetic protein receptor-2 mutation has been found in a patient with this disease.

The diagnosis of PVOD can be established with a high probability by the combination of clinical suspicion, physical examination, bronchoscopy, and radiological findings. Digital clubbing and bibasal crackles on lung auscultation are unusual in other forms of PAH. High-resolution CT scanning is the investigation of choice. This non-invasive approach may avoid lung biopsy which is a gold standard for confirming the diagnosis. Hemodynamic presentation of PVOD is similar to IPAH. Importantly, PWP is almost invariably normal because the pathological changes occur in small venulae and do not affect the larger pulmonary veins.

There is no established medical therapy for PVOD. Most importantly, vasodilators and especially prostanoids must be used with great caution because of the high risk of pulmonary oedema. Atrial septostomy may be considered but is usually limited by hypoxaemia. The only curative therapy for PVOD and pulmonary capillary haemangiomatosis is lung transplantation.

Pulmonary capillary hemangiomatosis may be difficult to differentiate from PVOD, and the diagnostic and therapeutic aspects are very similar. Often, only pathological examination is able to distinguish the two conditions.

   XV. Pulmonary hypertension due to left heart disease (group 2) Top

PH carries a poor prognosis for patients with chronic heart failure. The mortality rate was 57% in patients with moderate PH compared with 17% in patients without PH20. The diagnostic approach is similar to that for PAH. Although increased left-sided filling pressures can be estimated by Doppler echocardiography, invasive measurements of PWP or LV end-diastolic pressure may be necessary to confirm the diagnosis. PWP and LV end-diastolic pressure can be 'pseudo-normal', especially when patients have been treated with diuretics. In some patients, it may be difficult to distinguish PAH from PH associated with LV dysfunction especially in patients with borderline values of PWP (15-18mmHg).

Currently, there is no specific therapy for PH due to left heart disease. A number of drugs (including diuretics, nitrates, hydralazine, ACE inhibitors, B-adrenoceptor blockers, nesiritide, and inotropic agents) or interventions (LV assist device implantation, valvular surgery, resynchronization therapy, and heart transplantation) may lower PAP more or less rapidly through a drop in left- sided filling pressures. Therefore, management of PH due to left heart disease should be aimed at the optimal treatment of the underlying disease. No heart failure drugs are contraindicated because of PH. The use of PAH specific drugs is not recommended until robust data from long-term studies are available, in particular in 'out of proportion' PH associated with left heart disease.

   XVI. Pulmonary hypertension due to lung diseases and/or hypoxia (group 3) Top

In COPD, the presence of PH is associated with shorter survival and frequent episodes of exacerbation. PH is a poor prognostic factor in interstitial lung diseases and PAP is the most important predictor of mortality [5] .

Clinical symptoms and physical signs of PH may be difficult to identify in patients with respiratory disorders. In addition, in COPD, peripheral oedema may not be a sign of RV failure, because it may result from the effects of hypoxaemia and hypercapnia on the renin - angiotensin- aldosterone system. Furthermore, concomitant left heart disease, which is commonly associated with chronic respiratory diseases, may also contribute to raise PAP. A definite diagnosis of PH relies on measurements obtained at RHC.

Currently there is no specific therapy for PH associated with COPD or interstitial lung diseases. Long-term O2 administration has been shown partially to reduce the progression of PH in COPD. Nevertheless, with this treatment PAP rarely returns to normal values and the structural abnormalities of pulmonary vessels remain unaltered. Treatment with conventional vasodilators is not recommended because they may impair gas exchange due to the inhibition of hypoxic pulmonary vasoconstriction and their lack of efficacy after long-term use. Patients with 'out of proportion' PH due to lung diseases (characterized by dyspnea insufficiently explained by lung mechanical disturbances and mean PAP ≥ 40-45mmHg at rest) should be referred to expert centres.

   XVII. Chronic thromboembolic pulmonary hypertension (group 4 CTEPH) Top

CTEPH is one of the most prevalent forms of PH. While acute pulmonary embolism may be clinically silent, there is accumulating evidence that CTEPH may also develop in the absence of previous pulmonary embolism. Certain conditions are associated with an increased risk of CTEPH, including previous splenectomy, the presence of a ventriculo-atrial shunt for the treatment of hydrocephalus, myeloproliferative disorders, and chronic inflammatory bowel diseases.

Any patient with unexplained PH should be evaluated for the presence of CTEPH. Survivors of acute pulmonary embolism should be followed clinically after the acute episode and by echocardiography if showing signs of PH or RV dysfunction. A ventilation/perfusion lung scan is recommended to exclude CTEPH. A multirow CT angiography is indicated when the ventilation/perfusion lung scan is indeterminate or reveals perfusions defects. Even in the era of modern multirow CT scanners, there is not yet enough evidence to suggest that a normal CT angiography excludes the presence of operable CTEPH. Once ventilation/perfusion scanning and/or CT angiogram show signs compatible with CTEPH, the patient should be referred to a center with expertise in the medical and surgical management of these patients.

Patients should receive life-long anticoagulation with a target INR between 2.0 and 3.0. pulmonary endarterectomy (PEA) is the treatment of choice for patients with CTEPH as it is a potentially curative option. Specific PAH drug therapy may play a role in selected CTEPH patients. For the present time, no medical therapy has been approved in Europe or the USA for CTEPH. Bilateral lung transplantation is an option for advanced cases that are not suited for PEA.

   Conclusion Top

As the understanding of PAH continues to evolve, so too, do the therapeutic options available for this devastating disease. Developing an evidence-based approach to treating PAH will remain a constant challenge, mainly due to the rarity of PAH and thus the small number of patients enrolled in trials.

Currently, the evidence indicates that manipulation of the Nitric Oxide, endothelin, and prostacyclin pathways is a viable therapeutic approach; Combination therapy remains another murky area. Is combination therapy truly superior to monotherapy? Which agents are best used in combination? How does combination therapy affect the side effect profiles of these drugs? Cost is also a concern, since all of the currently available drugs are expensive when used as monotherapy alone. These issues all underline the need for additional well-designed and robust trials before widespread adoption of combination therapy for PAH is considered.[20]

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17.Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drug and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med.1996;335:609-616.  Back to cited text no. 17      
18.Engelfriet PM, Duffels MGJ, Moller T, Boersma E, Tijssen JGP, Thaulow E, Gatzoulis MA, Mulder BJM. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007;93:682-687.   Back to cited text no. 18      
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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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  In this article
    II. Classificati...
    IV.Pathology of ...
    V. Pulmonary art...
    VI. Diagnostic a...
    VII. Therapy
    VIII.Drugs and t...
    IX. Pediatric pu...
    X.Pulmonary arte...
    XI.Collagen vasc...
    XII. Pulmonary a...
    XIII. Pulmonary ...
    XIV. Pulmonary v...
    XV. Pulmonary hy...
    XVI. Pulmonary h...
    XVII. Chronic th...
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