> Table of Contents > Pulmonary Arterial Hypertension
Pulmonary Arterial Hypertension
Urooj Najm, MBBS
Najm Hasan Siddiqui, MD
image BASICS
  • Pulmonary arterial hypertension (PAH) is a category of pulmonary hypertension (PH) characterized by abnormalities in the small pulmonary arteries (precapillary PH) that produce increased pulmonary arterial pressure (PAP) and vascular resistance, eventually resulting in right-sided heart failure. PAH is a progressive disorder associated with increased mortality.
    • Previously, PH was classified as primary PH (without cause: now idiopathic pulmonary arterial hypertension [IPAH]) or secondary PH (with cause or associated condition); now it is clear that some types of secondary PH closely match primary PH (IPAH) in their histology, natural history, and response to treatment. Therefore, WHO classifies PH into five groups based on mechanism, with PAH as group 1 in this classification.
  • PAH is diagnosed by right-heart catheterization and defined by:
    • Mean PAP ≥25 mm Hg at rest
    • Pulmonary capillary wedge pressure ≤15 mm Hg (to exclude PH owing to left heart disease; i.e., group 2 PH)
    • Mild or absent chronic lung disease or other causes of hypoxemia (excludes PH owing to lung disease or hypoxemia; i.e., group 3 PH)
    • Absent venous thromboembolic disease (excludes chronic thromboembolic PH; i.e., group 4 PH)
    • Absent systemic disorder (like sarcoidosis), hematologic disorders (like myeloproliferative disease), and metabolic disorders (like glycogen storage disease). Purpose is to exclude group 5 PH.
  • PAH is divided into following main categories:
    • Idiopathic: sporadic, with no family history or risk factors
    • Heritable: IPAH with mutations or familial cases with or without mutations
    • Drug- or toxin-induced: mostly associated with anorectics (e.g., fenfluramine), rapeseed oil, L-tryptophan, and illicit drugs such as methamphetamine and cocaine
    • Associated: connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), HIV infection, portal hypertension, congenital heart disease, schistosomiasis, chronic hemolytic anemia (e.g., sickle cell disease)
    • Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) and persistent pulmonary hypertension of the newborn (PPHN) are classified as separate categories due to more differences than similarities with PAH.
      • PVOD and/or PCH: rare cause of PH characterized by extensive diffuse occlusion of the pulmonary veins (unlike PAH which involves the small muscular pulmonary arterioles)
    • PPHN
  • System(s) affected: pulmonary, cardiovascular
  • Age: can occur at any age; mean age, 37 years
  • Sex (IPAH): female > male (˜4:1)
  • Overall PAH: 5 to 52 cases/million
  • IPAH: low, ˜2 to 6 per million
  • Drug-induced PAH: 1/25,000 with >3 months of anorectic use
  • HIV-associated: 0.5/100
  • Portal hypertension-associated: 1 to 6/100
  • Scleroderma-associated: 6-60%
  • PAH: ˜15 to 50 cases per million
  • IPAH: ˜6 cases per million
  • Pulmonary: Inflammation, vasoconstriction, endothelial dysfunction, and remodeling of pulmonary arteries produced by increased cell proliferation and reduced rates of apoptosis lead to obstruction.
  • Cardiovascular: right ventricular hypertrophy (RVH), eventually leading to right-sided heart failure
  • IPAH: by definition, unknown. True IPAH is mostly sporadic or sometimes familial in nature.
  • Pulmonary arteriolar hyperactivity and vasoconstriction, occult thromboembolism, or autoimmune (high frequency of antinuclear antibodies)
  • 75% of heritable pulmonary arterial hypertension (HPAH) cases and 25% of IPAH cases have mutations in BMPR2 (autosomal dominant).
  • Mutations in ALK1 and endoglin (autosomal dominant) also are associated with PAH.
  • Female sex
  • Previous anorectic drug use
  • Recent acute pulmonary embolism
  • Commonly associated conditions
  • First-degree relatives of patient with familial PAH
See associated PAH, earlier discussed.
Symptoms of PAH are nonspecific, which can lead to missed or delayed diagnosis of this serious disease.
  • Pulmonary component of S2 (at apex in >90% of patients)
  • Right ventricular (RV) lift
  • Early systolic click of pulmonary valve
  • Pansystolic murmur of tricuspid regurgitation
  • Diastolic murmur of pulmonic insufficiency (Graham-Steell murmur)
  • RV S3 or S4
  • Edema as jugular vein distention, ascites, hepatomegaly, or peripheral edema
Other causes of dyspnea:
  • Pulmonary parenchymal disease such as chronic obstructive pulmonary disease
  • Pulmonary vascular disease such as pulmonary thromboembolism
  • Cardiac disease such as cardiomyopathy
  • Other disorders of respiratory function such as sleep apnea
  • ECG: RVH and right axis deviation
  • Pulmonary function testing and/or arterial blood gas: arterial hypoxemia, reduced diffusion capacity, hypocapnia
  • Ventilation-perfusion ratio (V/Q) scan: must rule out proximal pulmonary artery emboli and chronic thromboembolic PH (CTEPH)
  • Exercise test: reduced maximal O2 consumption, high-minute ventilation, low anaerobic threshold, increased PO2 alveolar-arterial gradient; correlation to severity of disease with 6-minute walk test
  • Antinuclear antibody positive (up to 40% of patients)
  • LFTs to evaluate for portopulmonary HTN, a complication of chronic liver disease
  • HIV test, thyroid function tests, sickle cell disease screening
  • Elevated brain natriuretic peptide (BNP) and N-terminal-proBNP may be useful for early detection of PAH in young, otherwise healthy patients with mild symptoms. It can also be used to assess disease severity and prognosis.
  • Chest radiograph
    • Prominent central pulmonary arteries with peripheral hypovascularity of pulmonary arterial branches
    • RV enlargement is a late finding.
  • Echo Doppler
    • Should be performed with suspicion of PAH; recent studies show some inaccuracy compared with right-sided heart catheterization
    • Most commonly used screening tool
      • Estimates mean PAP and assesses cardiac structure and function, excludes congenital anomalies
      • Echo suggests, but does not diagnose, PAH. Invasive hemodynamic evaluation confirms PAH diagnosis.
  • Right atrial and ventricular enlargement; tricuspid regurgitation
  • Important to rule out underlying cardiac disease such as atrial septal defect with secondary PH or mitral stenosis
  • Cardiac magnetic resonance is not commonly used.
Diagnostic Procedures/Other
  • Pulmonary angiography
    • Should be done if V/Q scan suggests CTEPH
    • Use caution; can lead to hemodynamic collapse; use low osmolar agents, subselective angiograms.
  • Right-sided cardiac catheterization (gold standard for diagnosis of PAH)
    • Essential first step to confirm diagnosis and determine severity and prognosis by measuring pulmonary arterial pressures and hemodynamics
    • Rule out underlying cardiac disease (e.g., left-sided heart disease) and response to vasodilator therapy.
  • Lung biopsy: not recommended unless primary pulmonary parenchymal disease exists
  • 6-Minute walk test: classifies severity of PAH and estimates prognosis
Test Interpretation
  • Distal arterioles show medial hypertrophy, proliferative/fibrotic intima, complex lesions, and thrombosis.
  • Pulmonary veins usually are not affected.
  • Treat underlying diseases/conditions that may cause PAH to relieve symptoms and improve quality of life and survival.
  • PAH-specific treatment has been studied mostly in IPAH.

Oxygen supplementation to O2 >90% is indicated for rest, exercise, or nocturnal hypoxemia.
  • Acute vasodilator test (performed during cardiac catheterization) for all IPAH patients who are potential candidates for long-term oral calcium channel blocker (CCB) therapy
    • Screens for pulmonary vasoreactivity/responsiveness using inhaled nitrous oxide; IV epoprostenol or IV adenosine: Positive response may be a prognostic indicator.
    • Contraindicated in right-sided heart failure or hemodynamic instability
  • Chronic vasodilator therapy
    • If IPAH with positive response to acute vasodilator test (a fall in mean PAP of ≥10 mm Hg and to a value <40 mm Hg, with unchanged/increased cardiac output), use CCBs (1)[C]
      • ˜13% will initially respond. Long-term clinical response to CCB therapy is small (˜7%) (1)[C].
      • CCBs include nifedipine (long-acting), diltiazem, amlodipine.
      • Avoid verapamil due to its significant negative inotropic effect.
      • CCBs are contraindicated in patients with a cardiac index of <2 L/min/m2 or a right atrial pressure >15 mm Hg.
    • PAH with negative response to acute vasodilator test or worsening on therapy; specific vasodilator choice based on risk stratification (1)[C].
      • Higher risk (NYHA class III-IV): prostacyclins: improve exercise capacity, cardiopulmonary hemodynamics: epoprostenol (IV) (only drug with demonstrated survival benefit and treatment of choice for most ill; i.e., NYHA functional class IV patients) (1)[B]; treprostinil (IV, SC, or inhaled); iloprost (inhaled); inhaled products associated with bronchospasm
      • FDA recently approved treprostinil extended-release tablets for PAH to improve exercise capacity.
      • Lower risk (NYHA class I-III)
        • Endothelin receptor antagonists: Improve exercise capacity; reducing mortality has been noted (2)[A]: bosentan (PO); ambrisentan (PO). Pregnancy Category X; monitor LFTs monthly.
        • Phosphodiesterase-5 inhibitors: suggested improvement in exercise capacity, cardiopulmonary hemodynamics, and symptoms (1)[C]: sildenafil (PO); tadalafil (PO)
        • Guanylate cyclase stimulant: stimulators of the nitric oxide receptor, improves exercise capacity (3)[B]: riociguat (PO)
        • It is unclear whether any of the above separate classes of drugs significantly reduces mortality; however, pooling all the vasodilators in a recent systematic review shows 39% reduction in mortality (4)[A]; another recent meta-analysis shows that only prostanoid class has survival benefit, particularly IV prostacyclins (1)[B].
        • If one agent fails, vasodilator combination therapy (CT) using two vasodilators (e.g., epoprostenol plus sildenafil) is currently being studied. A recent meta-analysis found CT did not improve outcomes compared with monotherapy (MT). Only 6-minute walk distance was improved when using CT versus MT (5)[A].
  • Anticoagulation
    • Improved survival originally suggested in patients with IPAH only. Newer studies show some evidence for favorable effects of anticoagulation on survival in IPAH, HPAH, or PAH associated with anorexigens (1)[B].
    • Warfarin with international normalized ratio of 1.5 to 2.5
      • Contraindications: Avoid in patients with syncope or significant hemoptysis; consider drug interactions.
  • Diuretics indicated in patients with RV volume overload (e.g., peripheral edema or ascites) (1)[B]
  • Digoxin has little long-term data in PAH: used in RV failure and/or atrial dysrhythmias, increases cardiac output and preserves RV contractility
Refer to a pulmonologist and/or a cardiologist for further evaluation/treatment if PAH is suspected.
  • Patients with documented large-vessel thromboembolic disease should be considered for pulmonary thrombectomy.
  • Balloon atrial septostomy for severe PAH with right-sided heart failure despite optimized medical therapy to relieve symptoms prior to lung transplant or as a treatment on its own
  • Heart-lung or lung transplantation
Admission Criteria/Initial Stabilization
  • Medical therapy is primarily palliative.
  • Hospitalization with invasive monitoring is needed to screen vasodilator responsiveness and initiate vasodilator therapy.
  • National registry has been established by the National Heart, Lung, and Blood Institute.
  • Pneumococcal and influenza vaccines
  • Exercise: walking or low-level aerobic activity, as tolerated, once stable; respiratory training
Patient Monitoring
Frequently evaluate disease progression and therapeutic efficacy. Objective tests to measure treatment response include 6-minute walk test and cardiopulmonary exercise test.
Fluid and salt restrictions, especially with RV failure
Discuss disease, prognosis, lifestyle changes, and all therapeutic options (including transplant).
  • Median survival is 2 to 3 years from diagnosis; 5-year survival rate is 34% for National Institutes of Health registry; newer studies show 5-year survival near 70% with new treatment.
  • Mode of death: right-sided heart failure (most common), pneumonia, sudden death, cardiac death
  • Poor prognostic factors
    • Rapid symptom progression
    • Clinical evidence of RV failure
    • WHO functional PAH class 4 (or NYHA functional class III or IV)
    • 6-Minute walk distance <300 m
    • Peak VO2 during cardiopulmonary exercise testing <10.4 mL/kg/min
    • Echocardiography with pericardial effusion, significant RV enlargement/dysfunction, right atrial enlargement
    • Mean right atrial pressure >20 mm Hg
    • Cardiac index <2 L/min/m2
    • Elevated mean PAP
    • Significantly elevated BNP and NT-proBNP; other markers also show promise in predicting survival: RDW, GDF-15, interleukin-6, creatinine
    • Scleroderma spectrum of diseases
1. Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131(6):1917-1928.
2. Liu C, Chen J, Gao Y, et al. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev. 2009;(3):CD004434.
3. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340.
4. Macchia A, Marchioli R, Tognoni G, et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am Heart J. 2010;159(2):245-257.
5. Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. Am J Cardiol. 2011;108(8):1177-1182.
See Also
Cor Pulmonale; Pulmonary Embolism
  • I27.0 Primary pulmonary hypertension
  • I27.2 Other secondary pulmonary hypertension
Clinical Pearls
  • PAH involves abnormalities in the small pulmonary arteries (precapillary PH) that produce increased PAP and vascular resistance, eventually resulting in right-sided heart failure.
  • In patients with PAH, a V/Q scan should be performed to rule out CTEPH; a normal scan effectively excludes a diagnosis of CTEPH.
  • CCBs are the first-line agents to manage IPAH.