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.


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

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 & right ventricular S3
    • Lung sounds are usually normal
  • Signs & 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 & right ventricular strain
  • Should be performed in patients with a suspicion of pulmonary arterial hypertension (PAH) to screen for cardiac anatomic problems & 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 & 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 & excluding cardiac disease
  • Can estimate the pulmonary arterial pressure (PAP) & can provide information regarding the cause & consequences of PAH
  • Should be performed in asymptomatic patients to detect elevated PAP
  • Assists in differential diagnosis of possible causes, in PH class identification & PAH evaluation

Pulmonary Function Test & Arterial Blood Gas

  • May be helpful in diagnosis based on evidence of irreversible airflow obstruction with increased residual volume & decreased diffusion capacity for carbon monoxide (40-80% of predicted value) & 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 & pulmonary angiography

  • Provide important details on vascular, cardiac, parenchymal & 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 & pulmonary veno-occlusive disease (PVOD)

Cardiac Magnetic Resonance Imaging

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

Blood tests & immunology

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

Genetic Counseling

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


  • Eg brain natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)
  • May be considered if echocardiography cannot be performed
  • Presence of BNP & 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, & serotonin

Invasive Diagnostic Tests for Pulmonary Hypertension (PH) Detection

Right Heart Catheterization (RHC)

  • Remains the gold standard to confirm the diagnosis & evaluate the severity of pulmonary arterial hypertension (PAH)
  • Required to confirm the diagnosis of PAH & chronic thromboembolic pulmonary hypertension (CTEPH), assess the severity of hemodynamic impairment & 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 & 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

    Revised Clinical Classification of Pulmonary Hypertension (PH) From 4th World Symposium on PH (Dana Point, 2008)

    Group 1’ Pulmonary arterial hypertension (PAH)

    1.1 Idiopathic pulmonary arterial hypertension (IPAH)

    1.2 Heritable

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

    1.3 Drugs & toxins induced

    1.4 Associated with pulmonary arterial hypertension (APAH)

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

    Group 1’’ Persistent pulmonary hypertension of the newborn

    Group 2 PH due to left heart disease

    2.1 Left ventricular systolic dysfunction

    2.2 Left ventricular diastolic dysfunction

    2.3 Valvular disease

    2.4 Congenital/acquired left heart inflow/outflow tract obstruction & congenital cardiomyopathies

    2.5 Congenital/acquired pulmonary veins stenosis

    Group 3 PH due to lung diseases &/or hypoxia

    3.1 Chronic obstructive pulmonary disease (COPD)

    3.2 Interstitial lung disease

    3.3 Other pulmonary diseases with mixed restrictive & obstructive pattern

    3.4 Sleep-disordered breathing

    3.5 Alveolar hypoventilation disorders

    3.6 Chronic exposure to high altitude

    3.7 Developmental abnormalities

    Group 4 Chronic thromboembolic pulmonary hypertension (CTEPH)

    4.1 Chronic thromboembolic pulmonary hypertension

    4.2 Other pulmonary artery obstructions

    4.2.1 Angiosarcoma
    4.2.2 Other intravascular tumors
    4.2.3 Arteritis
    4.2.4 Congenital pulmonary arteries stenoses
    4.2.5 Parasites (hydatidosis)

    Group 5 PH with unclear &/or multifactorial mechanisms

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

    5.2 Systemic disorders: Sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis

    5.3 Metabolic disorders: Glycogen storage disease, Gaucher’s disease, thyroid disorders

    5.4 Others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure (with or without dialysis), segmental pulmonary hypertension


Diagnostic Tests for PH Clinical Classification

  • Two or more pathologies may co-exist & 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 & Perfusion (V/Q) Lung Scan

  • May be able to differentiate between chronic thromboembolic pulmonary hypertension (CTEPH) from idiopathic primary pulmonary arterial hypertension (IPAH)
  • Screening method of choice for CTEPH because of its high sensitivity & 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 & emphysema
  • Pulmonary veno-occlusive disease may be seen along with lymphadenopathy & pleural shadows & effusions
  • Pulmonary capillary hemangiomatosis may also become apparent

Pulmonary Angiography

  • Important in managing patients with CTEPH
  • Confirms the diagnosis & 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 & RNP
    • Patients with elevated ANA may need further serological assessment & rheumatology consultation
  • HIV test
  • Liver function tests (LFT), hepatitis serology
  • Abdominal ultrasound (to detect liver cirrhosis &/or portal hypertension)
  • Exercise capacity with the 6-min walk test
  • Assess hemodynamics with right heart catheterization if it has not been done already
  • Clinical & hemodynamic assessments are important in the prognosis & consequent management


  • Clinical & hemodynamic assessments are important in determining prognosis & 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 &/or fatigue may be present at rest & 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-Min Walking Test (6MWT)
    • Objective assessment of exercise capacity
    • Influenced by several factors, including sex, age, height, weight, comorbidities, need for oxygen (O2), learning curve & motivation
    • Distance walked, exertional dyspnea (Borg scale), & finger oxygen saturation are measured
    • Walking distances <332 meters or <250 meters & oxygen desaturation >10% indicate poor prognosis
  • Cardiopulmonary Exercise Testing (CPET)
    • Also an objective assessment of exercise capacity but less acceptable & less frequently used than 6MWT
    • Gas exchange & ventilation are continuously recorded while on incremental exercise
    • O2 uptake at anaerobic threshold & 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 & 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 & reproducible assessment of RV size & function
    • Stroke volume ≤25 mL/m2, RV end-diastolic volume ≥84 mL/m2, left ventricle (LV) end-diastolic volume ≤40 mL/m2, & 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 & RV Doppler index
  • Right Heart Catheterization (RHC)
    • Mean right atrial pressure (mRAP), cardiac index (CI), & mean pulmonary artery pressure (mPAP) are predictive of survival & may be used together with pulmonary artery (PA) oxygen saturation, pulmonary vascular resistance (PVR), & a marked vasoreactivity response for prognostication

Definition of patient status

  • Stable & satisfactory
    • Patient has the following characteristics:
      • No clinical signs of RV failure
      • Stable WHO-Functional Class (FC) I or II without syncope
      • 6MWT >500 meters
      • Peak O2 consumption >15 mL/kg/min on cardiopulmonary exercise testing
      • Normal or near-normal BNP/NT-proBNP plasma levels
      • No pericardial effusion & tricuspid annular plane systolic excursion (TAPSE) >2 cm on Doppler echocardiography
      • Right atrial pressure (RAP) <8 mmHg & cardiac index (CI) ≥2.5 L/min/m2 on RHC
      • Such patients on oral therapy are evaluated every 3-6 months with FC assessment & 6MWT done every clinic visit, echocardiogram done every 12 months, RHC done on clinical deterioration
  • Stable & not satisfactory
    • Patient, although stable, has not fulfilled all the characteristics of the stable & satisfactory patient status
    • Complete reassessment & consideration for additional or different treatment is recommended
    • Complete re-evaluation done on clinical deterioration & every 3-4 months after initiation or changes in therapy until patient becomes stable & satisfactory
  • Unstable & deteriorating
  • Patient has the following characteristics:
    • Progression of RV failure signs & symptoms
    • Worsening WHO-FC
    • 6MWT <300 m
    • Peak O2 consumption <12 mL/kg/min on cardiopulmonary exercise testing
    • Rising BNP/NT-proBNP plasma levels
    • Evidence of pericardial effusion & tricuspid annular plane systolic excursion (TAPSE) <1.5 cm on Doppler echocardiography
    • Right atrial pressure (RAP) >15 mmHg & rising or a CI ≤2.0 L/min/m2 & falling on RHC
    • Such patients on intravenous (IV) Epoprostenol &/or combination therapy are evaluated every 1-3 months with FC assessment & 6MWT done every clinic visit, echocardiogram done every 6-1 months, RHC done on clinical deterioration & 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) & 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
  • This test is not indicated in patients with overt right heart failure, hemodynamic instability, & significantly elevated left heart filling pressures
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