Treatment Guideline Chart
Pulmonary arterial hypertension is a syndrome resulting from restricted flow through the pulmonary arterial circulation resulting in increased pulmonary vascular resistance and ultimately leading to right heart failure.
It is a part of the spectrum of pulmonary hypertension, which is hemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest.
Typical symptoms include progressive dyspnea on exertion, palpitations, fatigue, weakness, angina, syncope and abdominal distention.

Pulmonary%20arterial%20hypertension Diagnosis


  • A series of non-invasive diagnostic tests may be done initially to support the diagnosis of pulmonary hypertension (PH)
  • Complete right heart catheterization should be performed to establish the diagnosis of pulmonary arterial hypertension

Physical Examination

  • Signs of increased pulmonary artery pressure (PAP)
    • Accentuated pulmonary component of the S2 sound audible at the apex
    • Early systolic ejection click from sudden interruption of pulmonary valve opening
    • Mid-systolic ejection murmur
    • Palpable left parasternal lift
    • Pansystolic murmur of tricuspid regurgitation
    • Prominent jugular “a” wave which suggests increased right ventricular filling pressure
    • Right ventricular S4 gallop
    • Diastolic murmur of pulmonary insufficiency and right ventricular S3
    • Lung sounds are usually normal
  • Signs and symptoms of advanced pulmonary hypertension (PH)
    • Jugular venous distention
    • Hepatomegaly
    • Peripheral edema
    • Ascites
    • Cool extremities

Non-Invasive Diagnostic Tests for Pulmonary Hypertension (PH) Detection

Electrocardiogram (ECG)

  • May provide suggestive or supportive evidence demonstrating right ventricular hypertrophy, right axis deviation and right ventricular strain
  • Should be performed in patients with a suspicion of pulmonary arterial hypertension (PAH) to screen for cardiac anatomic problems and arrhythmias
    • Does not serve as an effective screening tool because of its low sensitivity but can assist in determining prognosis

Chest X-ray (CXR)

  • It may also show evidence of underlying lung disease
  • Radiographic signs suggestive of PAH are enlarged main and hilar pulmonary arterial shadows with concomitant attenuation of peripheral pulmonary vascular marking (pruning)
    • Extent of radiographic abnormalities is not representative of severity of pulmonary hypertension (PH)

Transthoracic Doppler-Echocardiography (TTE)

  • Echocardiography is the most useful imaging modality for detecting PH and excluding cardiac disease
  • Can estimate the pulmonary arterial pressure (PAP) and can provide information regarding the cause and consequences of PAH
  • Should be performed in asymptomatic patients to detect elevated PAP
  • Assists in differential diagnosis of possible causes, in PH class identification and PAH evaluation

Pulmonary Function Test and Arterial Blood Gas

  • May be helpful in diagnosis based on evidence of irreversible airflow obstruction with increased residual volume and decreased diffusion capacity for carbon monoxide (40-80% of predicted value) and normal or increased CO2 tension
  • Can identify the presence of underlying airway or parenchymal lung disease

Ventilation/Perfusion Ratio

  • Screening method of choice in patients with pulmonary hypertension (PH) to look for chronic thromboembolic pulmonary hypertension (CTEPH)

High-resolution Computed Tomography (CT) Scan, Contrast-enhanced Computed Tomography and Pulmonary Angiography

  • Provide important details on vascular, cardiac, parenchymal and mediastinal abnormalities, as well as prognostic information
  • Screening method of choice for CTEPH
  • High-resolution CT provides detailed views of the lung parenchyma
  • Facilitates the diagnosis of interstitial lung disease, emphysema and pulmonary veno-occlusive disease (PVOD)

Cardiac Magnetic Resonance Imaging

  • Accurate in the assessment of right ventricle (RV) size, morphology and function
  • Allows non-invasive assessment of blood flow, including stroke volume, cardiac output (CO), pulmonary arterial distensibility and RV mass
  • Provides useful prognostic information in patients with PAH both at baseline and follow-up

Blood Tests and Immunology

  • Routine biochemistry, hematology and thyroid function tests are required in all patients
  • Liver function tests may be abnormal because of high hepatic venous pressure, liver disease and/or endothelin receptor antagonist (ERA) therapy
  • Hepatitis serology should be performed if clinical abnormalities are suspected
  • Thyroid disease is common in PAH and may develop during the course of the disease
  • Serological testing is required to detect underlying connective tissue disease (CTD), hepatitis and human immunodeficiency virus (HIV)
  • Patients with CTEPH should undergo thrombophilia screening, including antiphospholipid antibodies, anticardiolipin antibodies and lupus anticoagulant

Abdominal Ultrasound

  • May be useful for the identification of the clinical entities associated with PAH
  • Portal hypertension can be confirmed or excluded by measuring the gradient between the free and occluded (wedge) hepatic vein pressure at the time of right heart catheterization (RHC)


  • Eg brain natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)
  • May be considered if echocardiography cannot be performed
  • Presence of BNP and NT-proBNP correlates with the presence of PAH
  • Other biomarkers under investigation include atrial natriuretic peptide, endothelin-1, uric acid, troponin T, nitric oxide, asymmetric dimethylarginine, cyclic guanosine monophosphate, D-dimer, and serotonin

Genetic Counseling

  • Patients with sporadic or familial PAH or PVOD/pulmonary capillary hemangiomatosis (PCH) should be advised about the availability of genetic testing and counseling because of the strong possibility having a disease-causing mutation

Invasive Diagnostic Tests for Pulmonary Hypertension (PH) Detection

Right Heart Catheterization (RHC)

  • Remains the gold standard to confirm the diagnosis and evaluate the severity of pulmonary arterial hypertension (PAH)
  • Required to confirm the diagnosis of PAH and chronic thromboembolic pulmonary hypertension (CTEPH), assess the severity of hemodynamic impairment and to undertake vasoreactivity testing of the pulmonary circulation
  • Prior to initiation of therapy, right heart catheterization (RHC) should be ordered in all patients that are still suspected of PAH after noninvasive evaluation
  • Useful in diagnosing occult shunts, congenital heart disease, distal pulmonary artery stenosis
  • Should be performed for confirmation of efficacy of PAH-specific drug therapy and to monitor response to therapy
  • May test vasoreactivity to guide appropriate treatment


  • Group 1 consists of all causes of pulmonary arterial hypertension (PAH) while groups 2 to 5 consist of all causes of non-PAH

    Updated Clinical Classification of Pulmonary Hypertension (PH) from the 6th World Symposium on PH (Nice, 2018)

    Group 1 Pulmonary Arterial Hypertension (PAH)

    1.1 Idiopathic pulmonary arterial hypertension (IPAH)

    1.2 Heritable PAH

    1.2.1 Bone morphogenic receptor (BMPR) type 2
    1.2.2 Other mutations

    1.3 Drug- and toxin-induced PAH

    1.4 PAH associated with:

    1.4.1 Connective tissue diseases
    1.4.2 Human immunodeficiency virus (HIV) infections
    1.4.3 Portal hypertension
    1.4.4 Congenital heart disease (CHD)
    1.4.5 Schistosomiasis

    1.5 PAH long-term responders to Ca channel blockers

     1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement
     1.5 Persistent PH of the newborn syndrome

    Group 2 PH Due to Left Heart Disease

    2.1 PH due to heart failure with preserved left ventricular ejection fraction (LVEF)

    2.2 PH due to heart failure with reduced LVEF

    2.3 Valvular disease

    2.4 Congenital/acquired cardiovascular conditions leading to post-capillary PH

    Group 3 PH Due to Lung Diseases and/or Hypoxia

    3.1 Obstructive lung disease

    3.2 Restrictive lung disease

    3.3 Other pulmonary disease with mixed restrictive and obstructive pattern

    3.4 Hypoxia without lung disease

    3.7 Developmental pulmonary abnormalities

    Group 4 PH due to Pulmonary Artery Obstructions

    4.1 Chronic thromboembolic pulmonary hypertension

    4.2 Other pulmonary artery obstructions

    4.2.1 Sarcoma (high or intermediate grade) or angiosarcoma
    4.2.2 Other malignant tumors (renal carcinoma, uterine carcinoma, testicular germ cell tumors, other tumors)
    4.2.3 Non-malignant tumors (uterine leiomyoma)
    4.2.4 Arteritis without connective tissue disease
    4.2.5 Congenital pulmonary artery stenoses
    4.2.6 Parasites (hydatidosis)

    Group 5 PH with Unclear and/or Multifactorial Mechanisms

    5.1 Hematological disorders: Chronic hemolytic anemia, myeloproliferative disorders, splenectomy

    5.2 Systemic and metabolic disorders: Pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogen storage disease, neurofibromatosis, sarcoidosis

    5.3 Others: Chronic renal failure with or without hemodialysis, fibrosing mediastinitis

    5.4 Complex CHD


Diagnostic Tests for PH Clinical Classification

  • Two or more pathologies may co-exist and any one may be contributory to or be the predominant cause of PH; thus, an abnormality in 1 test does not preclude abnormality in another

The following will help clarify etiology of PH:

Ventilation and Perfusion (V/Q) Lung Scan

  • May be able to differentiate between chronic thromboembolic pulmonary hypertension (CTEPH) from IPAH
  • Screening method of choice for CTEPH because of its high sensitivity and specificity
  • A normal or low probability scan effectively excludes a diagnosis of CTEPH

High Resolution Computed Tomography (HRCT) scan of the Lung

  • Assists in the diagnosis of interstitial lung disease and emphysema
  • Pulmonary veno-occlusive disease may be seen along with lymphadenopathy and pleural shadows and effusions
  • Pulmonary capillary hemangiomatosis may also become apparent

Pulmonary Angiography

  • Important in managing patients with CTEPH
  • Confirms the diagnosis and helps assess operability

Diagnostic Tests to Determine Associated Causes of PAH

  • Complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), thyroid function
  • Thrombophilia screen including antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies)
  • Autoimmune screen consists of antinuclear antibodies (ANA), anti-centromere antibody, anti-SCL-70 and RNP
    • Patients with elevated ANA may need further serological assessment and rheumatology consultation
  • HIV test
  • Liver function tests (LFT), hepatitis serology
  • Abdominal ultrasound (to detect liver cirrhosis and/or portal hypertension)
  • Exercise capacity with the 6-minute walk test
  • Assess hemodynamics with right heart catheterization if it has not been done already
  • Clinical and hemodynamic assessments are important in the prognosis and consequent management


  • Clinical and hemodynamic assessments are important in determining prognosis and consequent management
  • Functional Classification of Patients with Pulmonary Hypertension (PH) [From New York Heart Association (NYHA)/World Health Organization (WHO)]
    Class I
    • Patients with PH but without limitation of physical activity
    • Ordinary physical activity does not cause increased dyspnea or fatigue, chest pain or pre-syncope
    Class II
    • Patients with PH resulting in slight limitation of physical activity. These patients are comfortable at rest
    • Ordinary physical activity causes increased dyspnea or fatigue, chest pain or pre-syncope
    Class III
    • Patients with PH resulting in marked limitation of physical activity. These patients are comfortable at rest
    • Less than ordinary physical activity causes increased dyspnea or fatigue, chest pain or pre-syncope
    Class IV
    • Patients with PH resulting in inability to perform any physical activity without symptoms
    • - These patients may have signs of right heart failure at rest
    • Dyspnea and/or fatigue may be present at rest and discomfort is increased by almost any physical activity

Tests for Assessment of PH Severity

The following tests are indicated to establish baseline severity as well as for follow-up of therapy

  • 6-Minute Walk Test (6MWT)
    • Objective assessment of exercise capacity
    • Influenced by several factors, including sex, age, height, weight, comorbidities, need for oxygen (O2), learning curve and motivation
    • Distance walked, exertional dyspnea (Borg scale), and finger oxygen saturation are measured
    • Walking distances <332 meters or <250 meters and oxygen desaturation >10% indicate poor prognosis
  • Cardiopulmonary Exercise Testing (CPET)
    • Also an objective assessment of exercise capacity but less acceptable and less frequently used than 6MWT
    • Gas exchange and ventilation are continuously recorded while on incremental exercise
    • O2 uptake at anaerobic threshold and at peak exercise, peak work rate, peak heart rate, O2 pulse, ventilator efficiency are reduced according to PH severity
    • Peak VO2 is the most widely used for therapeutic decision making
  • Biochemical Markers
    • Noninvasive tool for assessment and monitoring of right ventricle (RV) dysfunction in patients with PH
    • Serum uric acid - marker of impaired oxidative metabolism of ischemic peripheral tissue; high values relate to poor survival in
    • Idiopathic pulmonary arterial hypertension (IPAH)
    • Brain natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP) - directly proportionate to RV dysfunction which is the major cause of death in PAH
  • Cardiac Magnetic Resonance Imaging (MRI)
    • Provides accurate and reproducible assessment of RV size and function
    • Stroke volume ≤25 mL/m2, RV end-diastolic volume ≥84 mL/m2, left ventricle (LV) end-diastolic volume ≤40 mL/m2, and pulmonary artery stiffness as measured by change <16% in relative cross-sectional area all correspond to poor prognosis
  • Echocardiography
    • Generates indices that have good prognostic value - pericardial effusion, indexed right atrium area, LV eccentricity index and RV Doppler index
  • Right Heart Catheterization (RHC)
    • Mean right atrial pressure (mRAP), cardiac index (CI), and mean pulmonary artery pressure (mPAP) are predictive of survival and may be used together with pulmonary artery (PA) oxygen saturation, pulmonary vascular resistance (PVR), and a marked vasoreactivity response for prognostication

Definition of Patient Status

  • Assessment of patient risk depends on the following factors:
(estimated 1-year mortality)
 Low Risk
Intermediate Risk
 High Risk
Clinical signs of right ventricular failure None None  Present 
Progression of symptoms None Slow Rapid
Syncope Absent Occasional Repeated
6-Minute Walk Test >440 m 165-440 m <165 m
Cardiopulmonary Exercise Testing (CPET) Peak oxygen consumption >15 mL/min/kg (>65% predicted)
Ventilatory eqiuvalents for carbon dioxide slope <36
Peak oxygen consumption 11-15 mL/min/kg (35-65% predicted)
Ventilatory eqiuvalents for carbon dioxide slope 36-44.9
Peak oxygen consumption <11 mL/min/kg (<35% predicted)
Ventilatory eqiuvalents for carbon dioxide slope ≥45
NT-proBNP plasma levels BNP <50 ng/L
NT-proBNP <300 ng/L 
BNP 50-300 ng/L
NT-proBNP 300-1400 ng/L 
BNP >300 ng/L
NT-proBNP >1400 ng/L 
Imaging Right atrium area <18 cm2
No pericardial effusion
Right atrium area 18-26 cm2
No or minimal pericardial effusion
Right atrium area >26 cm2
With pericardial effusion
Hemodynamics Right atrial pressure (RAP) <8 mmHg
Cardiac index (CI) ≥2.5 L/min/m2
Mixed venous oxygen saturation >65%
RAP 8-14 mmHg
CI 2-2.4 L/min/m2
Mixed venous oxygen saturation 60-65%
RAP >14 mmHg
CI <2 L/min/m2
Mixed venous oxygen saturation <60%

Adapted from: 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.

  • Stable and satisfactory
    • Such patients on oral therapy are evaluated every 3-6 months with FC assessment and 6MWT done every clinic visit, echocardiogram done every 12 months, RHC done on clinical deterioration
  • Stable and not satisfactory
    • Patient, although stable, has not fulfilled all the characteristics of the stable and satisfactory patient status
    • Complete reassessment and consideration for additional or different treatment is recommended
    • Complete re-evaluation done on clinical deterioration and every 3-4 months after initiation or changes in therapy until patient becomes stable and satisfactory
  • Unstable and deteriorating
    •  Such patients on intravenous (IV) Epoprostenol and/or combination therapy are evaluated every 1-3 months with FC assessment and 6MWT done every clinic visit, echocardiogram done every 6-1 months, RHC done on clinical deterioration and every 6-12 months

Acute Vasoreactivity Test

  • Should be performed in all patients with pulmonary arterial hypertension (PAH) even though patients with idiopathic PAH (IPAH) and PAH associated with anorexigen use tend to have a greater incidence of positive response
  • Patients with IPAH who respond acutely to vasodilators have an improved survival with long-term use of calcium (Ca) antagonists

Acute Vasoreactivity Test

  • Positive result may be considered as a decrease in mean pulmonary arterial pressure (mPAP) of at least 10 mmHg to ≤40 mmHg with an increase or unchanged cardiac output during acute challenge with inhaled nitric oxide (NO), intravenous (IV) Epoprostenol or IV Adenosine
  • Patients with a positive result, including PAH associated with scleroderma or congenital heart disease (without right heart failure) should be considered for trial therapy with Ca antagonist
  • Adequate response should be confirmed after 3-4 months of treatment
  • Not indicated in patients with overt right heart failure, hemodynamic instability, WHO FC IV and significantly elevated left heart filling pressures
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