Pulmonary Hypertension

Pulmonary Hypertension is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles


Pulmonary hypertension (PH) is the sustained elevation of the mean pulmonary artery pressure (mPAP) to ≥25 mm Hg (at rest).


  • PH is subcategorized into five major groups (Table 10-1)1:
    • Group I—Pulmonary arterial hypertension (PAH)
      Table 10-1: Clinical Classification of Pulmonary Hypertension: Dana Point (2008) Classification System of Pulmonary Hypertension
      1. Pulmonary arterial hypertension (PAH)
        • Idiopathic PAH
        • Heritable:
          • BMPR-II, ACVRL1, ENG, SMAD9, CAV1, KCNK3
          • Unknown
        • Drug and toxin induced
        • Associated with:
          • Connective tissue diseases
          • HIV infection
          • Portal hypertension
          • Congenital heart diseases
          • Schistosomiasis
        • Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
        • Persistent pulmonary hypertension of the newborn
      2. Pulmonary hypertension due to left heart disease
        • Left ventricular systolic dysfunction
        • Left ventricular diastolic dysfunction
        • Valvular disease
        • Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
      3. Pulmonary hypertension due to lung diseases and/or hypoxemia
        • Chronic obstructive lung disease
        • Interstitial lung disease
        • Other pulmonary diseases with mixed obstructive and restrictive pattern
        • Sleep-disordered breathing
        • Alveolar hypoventilation disorders
        • Chronic exposure to high altitude
        • Developmental lung diseases
      4. Chronic thromboembolic pulmonary hypertension (CTEPH)
      5. Pulmonary hypertension with unclear multifactorial mechanisms
        • Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
        • Systemic diseases: sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis, lymphangioleiomyomatosis
        • Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
        • Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on hemodialysis

      ALK1 (ACVR1), activin-like receptor kinase-1; BMPR-II, bone morphogenetic protein receptor II; CAV1, caveolin-1; ENG, endoglin; KCNK3, potassium channel super family K member-3.

      Reprinted from Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-D41; with permission from Elsevier.  [PMID:24355639]

    • Group II—PH due to left heart disease
    • Group III—PH due to lung diseases and/or hypoxemia
    • Group IV—Chronic thromboembolic pulmonary hypertension (CTEPH)
    • Group V—PH with unclear multifactorial mechanisms
  • PAH represents a specific group of disorders with similar pathologies and clinical presentation, with a propensity for right heart failure in the absence of elevated left-sided pressures.


  • PH is most often due to left heart disease (Group II) or parenchymal lung disease (Group III).
  • Idiopathic PAH (IPAH) (Group I) is a rare disorder with an estimated prevalence of 6–9 cases per million compared with an overall PAH prevalence of 15–26 cases per million.2,3 The average age of PAH patients in modern registries is approximately 50 years.2,3,4 IPAH patients tend to be even younger, with a mean age of approximately 35 years.5
  • Despite increased awareness, PAH continues to be diagnosed late in its course, with a reported delay of 27 months from symptom onset and the majority of patients in advanced World Health Organization (WHO) functional class III or IV.2
  • IPAH and PAH associated with systemic sclerosis are the most common subtypes of PAH.4,6
  • Incidence of CTEPH (Group IV) may be as high as 4% among survivors of acute pulmonary embolism.7


  • Complex origins of PAH include infectious/environmental insults or comorbid conditions that “trigger” the condition in individuals susceptible because of a genetic predisposition.
    • Mutations in the bone morphogenetic protein receptor II (BMPR-II) gene are the overwhelming cause of heritable PAH (HPAH).8 Other susceptibility factors are speculated to exist but have not been identified.
    • A total of 70% of familial PAH and 10%–40% of sporadic or anorexigen-associated cases are found to have mutations in BMPR-II.9
  • PAH involves a complex interplay of factors resulting in progressive vascular remodeling with endothelial cell and smooth muscle proliferation, vasoconstriction, and in situ thrombosis at an arteriolar level. Vessel wall changes and luminal narrowing restrict the flow of blood and lead to higher than normal pressure as blood flows through the vessels, which is quantifiable by an elevated pulmonary vascular resistance (PVR).10
    • Elevated PVR results in increased afterload to the right ventricle (RV), which over time increases RV wall tension and work, ultimately impacting RV contractility.
    • Initially, cardiac output diminishes during strenuous exercise. As PH severity worsens, maximal cardiac output is achieved at progressively lower workloads; ultimately, resting cardiac output is reduced.
    • Unlike the left ventricle (LV), the RV has limited ability to hypertrophy and tolerates high afterload poorly, causing “vascular–ventricular uncoupling” and eventual RV failure, the most common cause of death.
    • In very advanced stages, pulmonary artery pressures decline as the failing RV cannot generate enough blood flow to maintain high pressures.
  • Mechanisms of PH in Groups II–V vary and may include high post-capillary pressures, hypoxemia-mediated vasoconstriction and remodeling, parenchymal destruction, thromboembolic narrowing or occlusion of large arteries, compression of proximal vasculature, and hyperdynamic states leading to increased circulatory flow.


Yearly screening transthoracic echocardiogram (TTE) is indicated for high-risk groups including individuals with known BMPR-II mutation, scleroderma spectrum of disease, portal hypertension undergoing liver transplantation evaluation, and congenital systemic-to-pulmonary shunts (e.g., ventricular septal defects, patent ductus arteriosus).

A more formal screening algorithm for early detection of PAH associated with scleroderma is available.11

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