Pulmonary hypertension (PH) is an observation, not a single diagnosis or disease. It encompasses a diverse group of conditions that lead to elevated pulmonary vascular pressure. Pulmonary Arterial Hypertension (PAH) is a syndrome resulting from restricted flow through the pulmonary arterial circulation, which leads to pathological increases in pulmonary vascular resistance and ultimately to right heart failure.

Pulmonary hypertension is defined clinically as an increase in the pulmonary vascular pressure that is caused by conditions that are associated with an increase in the pulmonary arterial pressure or both the arterial and venous pressure. Hemodynamically, Pulmonary hypertension is defined as an increase in the mean pulmonary arterial pressure (PAP) to > 25 mmHg at rest or > 30 mm Hg during exercise. Pulmonary Arterial Hypertension (PAH) also requires a pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg and a pulmonary vascular resistance (PVR) ≥240 dynes/s/cm 3 .

Previously considered a rare disease, the most recent evidence from a French registry suggests that the prevalence of PAH is about 15 per million. PAH usually affects women in their 30s and 40s but can also affect others. Due to the non-specific nature of the symptoms, PAH is most frequently diagnosed when patients have reached an advanced stage of disease (WHO Functional Class III and IV), suggesting that the true prevalence may be higher than documented in the literature.

PAH has long been distinguished by a very poor prognosis and a paucity of effective medical therapies. However, the last decade has witnessed significant advances in understanding the pathogenesis of this disorder, and this understanding has translated into the development of a variety of new, more effective medical therapies.

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Pulmonary hypertension was previously described as either primary or secondary pulmonary hypertension, depending on the presence or absence of identifiable causes of increased pulmonary pressure. Updated clinical classification of pulmonary hypertension (PH) was presented at t he 2008 4th World Symposium on pulmonary hypertension held in Dana Point, California ( Table 1 ).

Table 1. Updated Clinical Classification of Pulmonary Hypertension (PH) (Dana Point , 2008)

1. Pulmonary Arterial Hypertension (PAH)
2. Pulmonary hypertension owing to left heart disease
3. Pulmonary hypertension owing to lung diseases and/or hypoxia
4. Chronic thromboembolic pulmonary hypertension
5. Pulmonary hypertension with unclear multifactorial mechanisms

PAH may occur as a primary disease or as a complication of various systemic, cardiac, or pulmonary conditions (Table 2).

Table 2. Updated Clinical Classification of Pulmonary Arterial Hypertension (PAH) (Dana Point , 2008)  

• Idiopathic (IPAH)
• Heritable
  • BMPR2
  • ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia)
  • Unknown
• Drug- and toxin-induced
• Associated with
  • Connective tissue disease
  • HIV infection
  • Portal hypertension
  • Congenital heart diseases
  • Schistosomiasis
  • Chronic haemolytic anemia
• Persistant pulmonary hypertension of the newborn

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Normal Physiology
The normal pulmonary circulation is a high-capacitance, low-resistance system. The pulmonary vasculature is able to accommodate a greater than 6-fold increase in cardiac output with relatively small increases in pulmonary-artery pressure, by recruiting closed vessels and distending open vessels. Even though the blood flow to the lungs is greater than the flow to any other organ, normal mean pulmonary-artery pressure remains less than one sixth of mean systemic arterial pressure. Associated with this low transmural pressure, the pulmonary arteries are larger in caliber and have thinner vessel walls than their systemic counterparts, and they possess little resting vascular tone.

In accordance with this low-pressure circuit, the right ventricle is normally accustomed to a relatively low after-load, even with stress. It is a thin muscle, with limited contractile reserve and limited capacity.

Pathophysiology
The pathology of PAH involves both, the pulmonary arterial vessel level as well as consequences of PAH on the myocardium of the right heart.

The increase in pulmonary vascular resistance is related to a number of progressive changes in the pulmonary arterioles, including:

• Vasoconstriction
• Obstructive remodeling of the pulmonary vessel wall through proliferation in the various layers of the blood vessel wall (smooth muscle cell and endothelial cell proliferation)
• Inflammation
• In-situ thrombosis.

As a consequence of unrelieved pulmonary hypertension, regardless of the cause, there is progressive systolic-pressure overload of the right ventricle, which then becomes hypertrophied and dilated, which ultimately leads to right-heart failure (cor pulmonale).

Pathogenesis
The pathogenesis of PAH is complicated and multifactorial. The initiating event leading to the progressive increase in pulmonary vascular resistance remains unknown. Several important contributing mechanisms have been acknowledged. The most recent thinking is that a combination of molecular and pathologic mechanisms plus an underlying genetic predisposition and risk factors lead to PAH.

PH was long held to be a manifestation of pulmonary vasoconstriction and proliferation of vascular smooth muscle cells; however, a growing body of evidence implicates dysfunction of the pulmonary vascular endothelium in the pathogenesis of this disorder. Alterations in the production of a variety of endothelial-derived vasoactive mediators appear to be crucial to the development of pulmonary hypertension. Impaired production of vasodilators (nitric oxide, prostaglandins) along with an overexpression of vasoconstrictors (endothelin-1 and thromboxane A2) culminates in the development of endothelial cell proliferation and vasoconstriction (Figure 1) .

Fig 1. Pathogenesis of pulmonary arterial hypertension

The main histological features include medial hypertrophy, intimal thickening, adventitial thickening, plexiform lesions and in-situ thrombosis ( Figure 2 ). The plexifom lesion represents a focal proliferation of endothelial and smooth muscle cells and is pathognomonic of PAH.

Figure 2: Pulmonary arterial hypertension: histopathological features

Haemodynamic changes in the progression of PAH
Hemodynamically, PAH is the combination of an elevated pulmonary-artery pressure and a decreased cardiac output with a normal wedge pressure. Haemodynamic measurements have been predictors of survival in numerous studies, including both observational and clinical trials. Survival is less consistently linked with mean pulmonary artery pressures (mPAP), and both increasing and decreasing values have been associated with worsened outcomes. This reflects the natural history of right-heart failure in PAH: mPAP increases progressively as the vascular derangements worsen only to fall later as the right heart progressively fails and is no longer able to generate an increased pressure (Figure 3) .

Figure 3: Haemodynamic changes in the progress of PAH. Pulmonary vascular resistance (PVR) rises progressively as the vascular derangements progress, eventually leading to the development of right heart dysfunction. Pulmonary artery pressures (PAP) initially rise as the right ventricle remains capable of generating the increased pressures required to maintain a given degree of cardiac output (CO). However, with more advanced disease, CO decreases and the PAP falls, because of the inability of the failing right ventricle to generate increased pressures.

The first and most critical step in making the diagnosis of PAH is to have a heightened awareness to consider it as a diagnosis. Because it shares many symptoms of other disorders, a high index of suspicion is necessary for an accurate and timely diagnosis of PAH. The diagnosis should be considered in any patient with unexplained dyspnea on exertion, fatigue, or exercise limitation, those with clinical signs consistent with right-heart dysfunction (e.g. peripheral edema, ascites), patients with symptoms and who have a process known to be associated with PAH and/or a family history of pulmonary hypertension.

The principal symptoms of PH are non-specific and the clinical signs subtle until patients present with advanced disease. As a consequence the diagnosis is most readily made where a systematic approach is taken to investigation and high risk patients are targeted with screening programmes. Consequently, it may be useful to adopt a four stage approach shown in Table 3 .

Table 3. Four Stage Approach For PAH Diagnosis  

1. Clinical suspicion of pulmonary hypertension
2. Detection of pulmonary hypertension

• ECG (electrocardiogram)
• Chest radiograph
• Echocardiography

3. Identify other causes of pulmonary hypertension

• Pulmonary function tests (PFTs) and arterial blood gas samples
• Ventilation and perfusion lung scan
• Abdominal ultrasound scan
• High resolution computed tomography (HRCT)

4. PAH evaluation

• Blood tests and immunology
• 6 minute walk test (6-MWT)
• Pulmonary angiography
• Right heart catheterisation and vasoreactivity testing

1. Clinical suspicion of pulmonary hypertension
There is usually a substantial delay between the presence of initial symptoms and the diagnosis of PAH, because the symptoms of PAH are initially insidious and nonspecific. In general, the mean interval from the onset of symptoms to diagnosis is 2 years.

The symptoms are caused by the high resistance to blood flow through the lungs resulting in increased stress on the heart.

Dyspnea, especially on exertion, is the most common and universal symptom, which is present in the majority of patients on presentation. It worsens as the disease progresses.

Common early symptoms include:

• Dyspnoea, particularly on physical activity
• Fatigue
• Dizziness
• Syncope,
• Peripheral oedema
• Chest pain, particularly during physical activity.

The symptoms may not be obvious at first and are often attributed to more common conditions such as asthma, general fatigue, or lack of physical fitness. Over time, however, they can become more severe and begin to limit normal activities. As the disease progresses, some patients may experience constant dyspnoea and fatigue so that even simple tasks such as getting dressed and walking short distances become difficult.

Symptoms of related conditions: Other symptoms may provide insight into the etiology of pulmonary arterial hypertension. For example, a complaint of snoring or apnea by the patient or the patient's partner should prompt an evaluation for obstructive sleep apnea. While Raynaud's phenomenon occurs in approximately 2% of patients with idiopathic PAH, it is much more common in the setting of PAH secondary to underlying collagen-vascular disease.

Clues to the diagnosis may also be found in the medical history. A family history of pulmonary hypertension is critical in light of the known genetic predisposition to the pulmonary hypertension. Exposure to toxic agents (eg, appetite suppressants, chemotherapeutic agents, or illicit drugs) as well as exposure to human immunodeficiency virus (HIV) are important clues. A history of pulmonary embolism and deep venous thrombosis suggests the diagnosis of chronic thromboembolic pulmonary hypertension. Symptoms of liver and thyroid disease should also be elicited.

Signs
Physical signs of pulmonary arterial hypertension become more pronounced with the progression of right ventricular dysfunction. The presence of an accentuated pulmonary component of the second heart sound is very common, occurring in 90% of patients with IPAH. Other signs include:

• A right-sided gallop,
• A palpable right ventricular lift,
• A mid-systolic ejection murmur across the pulmonary valve,
• Increased jugular venous pressure,
• Tricuspid regurgitation,
• Hepatomegaly
• Ascites, and
• Peripheral edema.

Other physical signs may be useful in elucidating the cause of pulmonary hypertension. Cyanosis may also point to the presence of right-to-left shunting, severely decreased cardiac output or an impairment in intrapulmonary gas transfer. Clubbing should raise the possibility of undiagnosed congenital heart disease or pulmonary veno-occlusive disease. Rales are consistent with pulmonary congestion and left-sided heart disease, while decreased breath sounds and wheezing are suggestive of fibrosis and ulmonary parenchymal disease, respectively.

2. Detection of pulmonary hypertension
Electrocardiogram
The ECG may provide suggestive or supportive evidence of PH by demonstrating RV hypertrophy and strain, and right atrial dilatation. Right ventricular (RV) hypertrophy on ECG is present in 87% and right axis deviation in 79% of patients with IPAH. The absence of these findings does not exclude the presence of PH nor does it exclude severe haemodynamic abnormalities. The ECG has insufficient sensitivity (55%) and specificity (70%) to be a screening tool for detecting significant PH. Ventricular arrhythmias are rare. Supraventricular arrhythmias may be present in advanced stages, in particular atrial flutter, but also atrial fibrillation, which almost invariably leads to further clinical deterioration.

Chest Radiograph
In 90% of patients with IPAH the chest radiograph is abnormal at the time of diagnosis . Findings include central pulmonary arterial dilatation, which contrasts with ‘‘pruning'' (loss) of the peripheral blood vessels. Right atrium and RV enlargement may be seen in more advanced cases. The chest radiograph allows associated moderate-to-severe lung diseases or pulmonary venous hypertension due to left heart disease to be reasonably excluded. Overall, the degree of PH in any given patient does not correlate with the extent of radiographic abnormalities.

Echocardiography
Transthoracic echocardiography provides several variables which correlate with right heart haemodynamics including PAP, and should always be performed in the case of suspected PH. The estimation of PAP is based on the peak velocity of the jet of tricuspid regurgitation. Estimation of PAP based on Doppler transthoracic echocardiography measurements is not suitable for screening for mild, asymptomatic PH. An alternative approach to echocardiographic diagnosis of PH is based on comparison of tricuspid regurgitation velocity with values reported in a healthy population.

Other echocardiographic variables that might raise or reinforce suspicion of PH independently of tricuspid regurgitation velocity should always be considered. They include an increased velocity of pulmonary valve regurgitation and a short acceleration time of RV ejection into the PA. Increased dimensions of right heart chambers, abnormal shape and function of the interventricular septum, increased RV wall thickness and dilated main PA are also suggestive of PH, but tend to occur later in the course of the disease. Their sensitivity is questionable.

 Echocardiography can be helpful in detecting the cause of suspected or confirmed PH.

3. Identify other causes of pulmonary hypertension
Pulmonary function tests (PFTs) and arterial blood gas samples
Pulmonary function tests and arterial blood gases identify the contribution of underlying airway or parenchymal lung disease. Patients with PAH usually have decreased lung diffusion capacity for carbon monoxide (typically in the range of 40–80% predicted) and mild to moderate reduction of lung volumes. Peripheral airway obstruction can also be detected.

Arterial oxygen tension is normal or only slightly lower than normal at rest and arterial carbon dioxide tension is decreased because of alveolar hyperventilation. COPD as a cause of hypoxic PH is diagnosed on the evidence of irreversible airflow obstruction together with increased residual volumes and reduced diffusion capacity for carbon monoxide and normal or increased carbon dioxide tension. A decrease in lung volume together with a decrease in diffusion capacity for carbon monoxide may indicate a diagnosis of interstitial lung disease. The severity of emphysema and of interstitial lung disease can be diagnosed using high-resolution computed tomography (CT).

Ventilation and perfusion lung scan
The ventilation/perfusion lung scan should be performed in patients with PH to look for potentially treatable CTEPH. A normal- or low-probability ventilation/ perfusion scan effectively excludes CTEPH with a sensitivity of 90–100%.

Abdominal ultrasound scan
Liver cirrhosis and/or portal hypertension can be reliably excluded by the use of abdominal ultrasound.

High resolution computed tomography (HRCT)
Chest computed tomography is an important diagnostic tool, because it provides excellent visualization of the pulmonary vasculature, pulmonary parenchyma, and mediastinal structures. A mean-pulmonary-artery diameter > 29 mm is suggestive of (but not diagnostic for) pulmonary hypertension. In the setting of CTEPH, thrombus may be seen within the pulmonary arteries.

4. PAH evaluation
Blood tests and immunology
Routine biochemistry, haematology and thyroid function tests are required in all patients, as well as a number of other essential blood tests. Serological testing is important to detect underlying CTD, HIV and hepatitis. Up to 40% of patients with IPAH have elevated anti-nuclear antibodies, usually in low titre (1:80).

HIV testing is mandatory. Up to 2% of individuals with liver disease manifest PAH and therefore liver function tests and hepatitis serology should be examined if clinical abnormalities are noted. Thyroid disease is commonly seen in PAH and should always be considered, especially if abrupt changes in the clinical course occur.

6 minute walk test (6-MWT)
The 6 min walk test is used in the initial workup of a patient with PAH to assess exercise performance and predict prognosis. The 6-MWT is technically simple, inexpensive, reproducible and well standardised. In addition to distance walked in 6 minutes, dyspnoea on exertion and finger O2 saturation are recorded. Walking distances <332 m and O 2 desaturation >10% indicate impaired prognosis in PAH. Following serial 6-min walk tests at follow up visits is valuable in monitoring the patient's progress and evaluating response to therapy.

Pulmonary angiography
Pulmonary angiography is required for evaluation of CTEPH to identify patients who may benefit from pulmonary endarterectomy (PEA).

Right heart catheterisation and vasoreactivity testing
Right heart catheterisation is required to confirm the diagnosis of PAH, to assess the severity of the haemodynamic impairment and to test the vasoreactivity of the pulmonary circulation.

The World Health Organization has classified PAH patients based on reported exercise tolerance ( Table 4 ). This scheme offers important prognostic information and is used in most research and therapeutic algorithms.

Table 4. Functional classification of pulmonary hypertension modified after the New York Heart Association functional classification according to the World Health Organization

Class	Description
I	Patients with pulmonary hypertension in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or presyncope.
II	Patients with pulmonary hypertension who have mild limitation of physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope.
III	Patients with pulmonary hypertension who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope.
IV	Patients with pulmonary hypertension who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity.

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In the past few years, treatment of PAH has undergone an extraordinary evolution . Advances in understanding of the disease has led to introduction of treatments which have helped to improve prognosis for patients with this disease. Medical therapy for pulmonary arterial hypertension begins with therapy directed toward any underlying cause of pulmonary hypertension.

The approach to treating PAH can be divided into:

1. General measures

   a) Physical activity
   b) Family planning
   c) Immunisations
   d) Psychosocial support

2. Supportive therapy

   a) Oxygen therapy
   b) Anticoagulation
   c) Diuretics
   d) Digoxin

3. Disease-targeted therapies

   a) Calcium-channel blockers (CCBs)
   b) Phosphodiesterase inhibitors
   c) Endothelin-1 receptor antagonists
   d) Prostanoids: Synthetic prostacyclin and prostacyclin analogues

4. Combination Therapy
5. Invasive therapies

1. General measures
Patients with PAH require advice about general activities of daily living and need to adapt to the uncertainty associated with a serious chronic life-threatening disease.

a) Physical activity: Patients should be encouraged to be as active as their symptoms allow. Mild breathlessness is acceptable but patients should be advised to stop exercising if they become moderately or severely breathlessness, or develop exertional dizziness or chest pain.

 b) Family planning: Pregnancy is associated with 30–50% mortality in patients with PAH. Patients should be given proper contraceptive advice. It should be remembered that the endothelin receptor antagonist (ERA) bosentan may reduce the efficacy of oral contraceptive agents. The patient who becomes pregnant should be informed of the high risk of pregnancy, and termination of pregnancy discussed.

 c) Immunisations: Patients with PAH are susceptible to developing pneumonia, which is the cause of death in 7% of cases. Patients should be vaccinated against influenza and pneumococcal pneumonia.

 d) Psychosocial support: Many PAH patients develop anxiety and depression leading to impairment in quality of life. Timely referral to a psychiatrist or psychologist should be made when appropriate.

2. Supportive therapy

a) Oxygen therapy: Although oxygen administration has been demonstrated to reduce PVR in both hypoxic and non-hypoxic patients with PAH there are no randomised data available to suggest that long term oxygen therapy (LTOT) is beneficial. All patients should have nocturnal oxygen saturation monitoring at initial assessment and thereafter when clinically indicated. Oxygen should be administered to maintain daytime and nocturnal PaO 2 >8 kPa. Ambulatory oxygen can be considered in those with correctable exercise desaturation for symptomatic benefit.

b) Anticoagulation: Anticoagulation is effective in both decreasing the likelihood of thromboembolic complications because of decreased activity and in reducing in situ intrarterial microvascular thrombosis, which are found pathologically in patients with PAH .

c) Diuretics: Decompensated right heart failure leads to fluid retention, raised central venous pressure, hepatic congestion, ascites and peripheral oedema. Fluid-overloaded patients should be treated with diuretics.

d) Digoxin: Digoxin has been shown to improve cardiac output acutely in IPAH although its efficacy is unknown when administered chronically. It may be given to slow ventricular rate in patients with PAH who develop atrial tachyarrhythmias.

3. Disease - targeted therapies
The number of specific treatment options has increased substantially, paralleling to an increased understanding of the pathologic and molecular mechanisms of the disease. Recent developments have concerned three pathobiological pathways: prostacyclin pathway, endothelin pathway, and nitric oxide pathway.

These therapies differ in their mechanisms, indications, routes of delivery, and adverse-effect profiles. In appropriately selected patients, these specific therapies substantially modify the course of PAH, improving symptoms and hemodynamics.

a) Calcium-channel blockers (CCBs): Only in a minority of patients (approx 12%) with IPAH a clinically significant reduction of pulmonary artery pressure associated with long-term clinical benefits can be achieved by the use of traditional vasodilators such as CCBs (e.g.Nifedipine & Diltiazem).

 b) Phosphodiesterase Inhibitors: Nitric oxide is a potent vasodilator whose action is dependent upon augmentation of cyclic guanosine monophosphate (cGMP). cGMP is rapidly degraded by phosphodiesterases, including phosphodiesterase 5, which is widely distributed in the lungs. Sildenafil is a potent inhibitor of phosphodiesterase 5, and as such, it augments the pulmonary vascular response to endogenous nitric oxide.

Sildenafil: Sildenafil has been approved by FDA as an oral therapy for PAH. It is the first drug approved in India for PAH.

The Sildenafil use in pulmonary arterial hypertension (SUPER – 1) trial evaluated the use of sildenafil for the treatment of PAH ((idiopathic, associated with connective-tissue disease, or occurring after surgical repair of congenital systemic-to-pulmonary shunts that had been performed at least five years previously) in a randomized, placebo-controlled manner. It is the largest trial to date evaluating the use of sildenafil.

6-minute walk distance improved between 45 and 50m, and significant improvements in mean pulmonary artery pressure (mPAP), PVR and CO occurred. 35% of sildenafil-treated patients also exhibited improvements in NYHA class.

Based upon the results of the 12-week double-blind trial, the US FDA approved sildenafil for use in PAH in 2005 at the dosage of 20mg every 8 hours.

Sildenafil shows great promise as a single agent treatment in the management of PAH. It has also demonstrated efficacy in PH due to known etiologies including lung fibrosis, chronic heart failure and sickle cell anemia. It is a good treatment option for patients who have failed or are unable to tolerate other therapies, or those who are in early stage of the disease.

Although sildenafil has been approved only for use in PAH it has been used successfully to treat patients with other forms of PH such as in hypoxia- induced PH, PH due to lung fibrosis & COPD, chronic thromboembolic pulmonary hypertension patients (CTEPH).

Sildenafil has an acceptable side-effect profile. Commonly encountered adverse events are headache, flushing and myalgia.

Sidenafil was shown to potentiate the hypotensive effects of nitrates. Administration of sildenafil to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated.

Tadalafil: Tadalafil is a once-daily dispensed, selective phosphodiesterase type-5 inhibitor, used for the treatment of erectile dysfunction. It has recently been approved for PAH. PAH patients treated with tadalafil once daily have shown favourable results on exercise capacity, symptoms, haemodynamics and time to clinical worsening at the largest dose. Side-effect profile is similar to that of sildenafil.

b) Endothelin Receptor Antagonists: Endothelin-1 is a vasoconstrictor and promoter of smooth muscle cell proliferation that may contribute to the development of PAH. Attmpting to treat PAH by endothelin receptor blockade is a promosing approach. Among the approved endothelin receptor antagonists, bosentan is available in India while sitaxsentan and ambrisentan are not.

Bosentan: Bosentan is an orally active dual endothelin receptor antagonist (ERA). It works by blocking the binding of endothelin (ET).  ET is produced and secreted by the endothelium, a monolayer of cells covering the inner surface of blood vessels.  Bosentan blocks both ETA and ETB receptors preventing the deleterious effects of endothelin.

Since its introduction in the USA (2001), Europe (2002) and other countries worldwide, bosentan has become a recommended treatment for pulmonary arterial hypertension (PAH) as reflected in current guidelines for PAH.

Through dual endothelin receptor blockade, bosentan has been shown to significantly improve exercise capacity, dyspnea scores, decrease the rate of clinical worsening and improve WHO functional; class as well as hemodynamic measures.

Close follow-up over time, of both efficacy and safety of bosentan is encouraged.

Increases in hepatic aminotransferases occur in ~10% of the subjects but were found to be dose dependent and reversible after dose reduction or discontinuation. For these reasons, liver function test should be performed monthly in patients receiving bosentan. Reductions on haemoglobin levels and impaired spermatogenesis have also been observed. Hematocrit should be checked every 3 months. Hormonal methods of birth control may be less effective with concurrent administration of bosentan, therefore, barrier techniques of contraception are recommended. This is particularly important because bosentan is potentially teratogenic. It is contraindicated during pregnancy.

c) Prostanoids ( Synthetic prostacyclin and prostacyclin analogues): These drugs act mainly by relaxing vascular smooth muscle cells (acute) and inhibition of platelet aggregation however, the precise mechanism of action of prostacyclin administration in PAH is unknown and is likely to be multifactorial. Though these drugs have contributed tremendously to the management of PAH their usage has been is limited due their drawbacks like the route of administration, frequent dosing schedules and short half-lives. These drugs are currently not available in India .

4. Combination Therapy
Combination therapy is an attractive option to address the multiple pathophysiological mechanisms that are present in PAH. The most commonly applied combination therapy approach involves the addition of a second drug where patients deteriorate (or fail to sufficiently improve) despite optimal dose of an initial therapy). Various combinations have been tested in clinical trials.

5. Invasive therapies
Despite advances in medical treatment for PAH, many patients experience progressive functional decline, largely related to worsening right heart failure. It is in these patients that invasive therapies are considered.

Balloon Atrial Septostomy: This procedure is performed in severely ill patients as a palliative bridge to lung transplantation.

Lung Transplantation: This is indicated inpatients with advanced NYHA class III and class IV symptoms that are refractory to available medical treatments.

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Treatment algorithm recommended in the ESC/ERS guidelines Dec. 2009 is shown in Figure 4.

Figure 4: Evidence-based treatment algorithm for pulmonary arterial hypertension patients
APAH: associated pulmonary arterial hypertension; BAS: balloon atrial septostomy; CCB: calcium channel blocker; ERA: endothelin receptor antagonist; IPAH: idiopathic pulmonary arterial hypertension; PAH: pulmonary arterial hypertension; PDE-5 I: phosphodiesterase type-5 inhibitor; s.c. : subcutaneously; WHO-FC: World Health Organization functional class. #: to maintain arterial blood O2 pressure .8 kPa (60 mmHg); ": under regulatory review in the European Union; +: IIa-C for WHO-FC II.

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Target values and treatment goals should be adjusted to the individual patient. For example, a 6-MWT >400 m is usually considered acceptable in PAH patients. Suggested follow-up strategies for patients with PAH are shown in table 5.

Table 5: Suggested assessments and timing for the follow-up of patients with pulmonary arterial hypertension

WHO-FC: World Health Organization functional class; 3: assessment is suggested; 6-MWT: 6-min walking test; BNP: brain natriuretic peptide; NT-proBNP: N-terminal proBNP; RHC: right heart catheterisation. #: intervals should to be adjusted to individual patients needs; ": usually one of the two exercise tests is performed; +: is recommended; 1: should be performed.

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PAH was earlier believed to be untreatable and invariably fatal. Earlier diagnoses, advanced understanding of the pathogenetic and molecular pathways, and a rapidly growing armamentarium of drugs have all assisted in changing the course of this challenging disease. Studies from India , Japan and Mexico have suggested median survival in the range of 2-3 years. Predictors of poor prognosis include: advanced functional class, poor exercise capacity as measured by 6-minute walk (6MW) test or cardiopulmonary exercise test, high right atrial (RA) pressure, significant right ventricular (RV) dysfunction, evidence of RV failure, low cardiac index, elevated brain natriuretic peptide (BNP), and underlying diagnosis of scleroderma spectrum of diseases. Important prognostic variables are summarized in Table 6.

Table 6. PAH*: Determinants of Prognosis
Determinants of Risk	Lower Risk (Good Prognosis)	Higher Risk (Poor Prognosis)
Clinical evidence of RV failure	No	Yes
Progression of symptoms	Gradual	Rapid
WHO class†	II, III	IV
6MW distance‡	Longer (greater than 400 m)	Shorter (less than 300 m)
CPET	Peak VO 2 greater than 10.4 mL/kg/min	Peak VO 2 less than 10.4 mL/kg/min
Echocardiography	Minimal RV dysfunction	Pericardial effusion, significant RV enlargement/dysfunction, right atrial enlargement
Hemodynamics	RAP less than 10 mm Hg, CI greater than 2.5 L/min/m 2	RAP greater than 20 mm Hg, CI less than 2.0 L/min/m 2
BNP	Minimally elevated	Significantly elevated

*Most data available pertains to IPAH. Little data is available for other forms of PAH. One should not rely on any single factor to make risk predictions.

†WHO class is the functional classification for PAH and is a modification of the New York Heart Association functional class.

‡6MW distance is also influenced by age, gender, and height.

§As there is currently limited data regarding the influence of BNP on prognosis, and many factors including renal function, weight, age, and gender may influence BNP,absolute numbers are not given for this variable.

6MW indicates 6-minute walk; BNP, brain natriuretic peptide. CI, cardiac index; CPET, cardiopulmonary exercise testing; peak VO2, average peak oxygen uptake during exercise; RAP, right atrial pressure; RV, right ventricle; and WHO, World Health Organization.

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Pulmonary arterial hypertension (PAH) comprises a group of clinical and pathophysiological entities with similar features but a variety of underlying causes. It is a rare, but devastating and life-threatening chronic condition. The exact cause of PAH is as yet unknown.

PAH usually affects women in their 30s and 40s but can also affect others. The patient experiences breathlessness, is easily tired, feels tightness of chest and is always fatigued. Other common conditions like asthma present similar symptoms. As a result, PAH is often misdiagnosed and the right treatment is delayed.  Other causes are the collagen vascular diseases such as scleroderma, or systemic lupus erythematosus. Congenital heart diseases, chronic pulmonary thromboembolism, HIV infection, liver disease and diet drugs like fenfluramine and dexfenfluramine are also causes of pulmonary hypertension.

Newer, successful therapies have changed the outlook of the disease. These include prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors. Sildenafil, a phosphodiesterase inhibitor, was the first drug to be approved in India for the treatment of PAH. It can be used either as a single agent or in combination with other agents. Bosentan, an orally active dual endothelin receptor antagonist (ERA), widely used for the treatment of PAH, is now available in India .

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