Pulmonary Hypertension

General Principles


Pulmonary hypertension (PH) is defined by sustained elevation of the mean pulmonary artery pressure (mPAP) to >20 mm Hg (at rest).1


  • PH is subcategorized into five major groups (Table 10-1):
    • Group I—Pulmonary arterial hypertension (PAH)
    • Group II—PH due to left heart disease
    • Group III—PH due to lung diseases and/or hypoxia
    • Group IV—PH due to pulmonary artery obstructions
    • Group V—PH with unclear multifactorial mechanisms
  • PAH is a specific group of disorders with similar pathologies and clinical presentation, and a high propensity for right heart failure in the absence of elevated left-sided pressures.
    • Hemodynamic definition = mPAP > 20 mm Hg, pulmonary artery wedge pressure (PAWP)15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Wood units1
Table 10-1: Clinical Classification of Pulmonary Hypertension: Dana Point (2008) Classification System of Pulmonary Hypertension
Group I: Pulmonary arterial hypertension (PAH)
Idiopathic (IPAH)
Heritable (HPAH)
Drugs and toxin-induced: methamphetamines, fenfluramine, dasatinib
Associated (APAH)
  • Connective tissue diseases
  • HIV infection
  • Portal hypertension
  • Congenital heart disease (systemic-to-pulmonary shunt)
  • Schistosomiasis
PAH long-term responders to calcium channel blockers
PAH with overt features of venous/capillaries (PVOD/PCH) involvement
Group II: Pulmonary hypertension (PH) due to left heart disease
PH due to heart failure with preserved LVEF
PH due to heart failure with reduced LVEF
Valvular disease
Group III: PH due to lung disease and/or hypoxia
Obstructive lung disease
Restrictive lung disease
Other pulmonary diseases with mixed restrictive and obstructive pattern
Hypoxia without lung disease
Developmental lung disorders
Group IV: PH due to pulmonary artery obstructions
Chronic thromboembolic PH
Other pulmonary artery obstructions
Group V: PH with unclear and/or multifactorial mechanisms
Hematologic disorders: myeloproliferative disorders, hemoglobinopathies
Systemic and metabolic disorders: sarcoidosis, PLCH, LAM, neurofibromatosis, glycogen storage disease, Gaucher disease
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
Complex congenital heart disease

LAM, lymphangioleiomyomatosis; LVEF, left ventricular ejection fraction; PCH, pulmonary capillary hemangiomatosis; PLCH, pulmonary Langerhans cell histiocytosis; PVOD, pulmonary veno-occlusive disease.


  • PH is most often due to left heart disease (Group II) or parenchymal lung disease (Group III).
  • Prevalence of idiopathic PAH (IPAH) (Group I) is 6–9 cases per million compared with overall PAH prevalence of 15–26 cases per million.2,3
    • Average age of PAH patients is ∼50 years.2,3,4 IPAH patients tend to be even younger, with a mean age of ∼35 years.5
  • IPAH and PAH associated with connective tissue diseases (CTD) are the most common subtypes.4,6
  • Incidence of chronic thromboembolic pulmonary hypertension (CTEPH) (Group IV) may be as high as 4% among survivors of acute pulmonary embolism.7


  • PAH is suspected to develop in susceptible individuals who develop a comorbid condition (e.g., systemic sclerosis or portal hypertension), contract an infection (e.g., HIV), or get exposed to a culpable drug/toxin (e.g., fenfluramine, methamphetamines, or dasatinib).
    • Mutations in bone morphogenetic protein receptor II (BMPR-II) gene account for ∼
70% of heritable PAH (HPAH).8
    • Mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) gene cause PAH with significant venous/capillary involvement (formerly known as pulmonary veno-occlusive disease).9
    • Other susceptibility factors are speculated to exist but have not been identified.
    • Comprehensive gene panels are commercially available.
  • 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 PVR.10
    • Elevated PVR results in increased afterload for the right ventricle (RV), which increases RV wall tension and work, leading to reduced RV contractility, decreasing cardiac output and progressive exercise intolerance.
    • The RV has limited ability to hypertrophy and tolerates high afterload poorly, causing “vascular–ventricular uncoupling” and eventual RV failure and death.
  • Mechanisms of PH in Groups II–V vary and include high postcapillary pressures, hypoxemia-mediated vasoconstriction, vascular remodeling, parenchymal destruction, thromboembolic narrowing or occlusion of large arteries, compression of proximal vasculature, and hyperdynamic states leading to increased circulatory flow.
  • Combined pre- and postcapillary PH describes situations when multiple conditions lead to elevated pressures in the left-sided heart chambers (postcapillary) and simultaneous abnormalities in the pulmonary arterial side (precapillary).
    • Hemodynamic definition = mean PAP > 20 mm Hg, PAWP > 15 mm Hg, and PVR ≥ 3 Wood units1


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

  • More formal screening algorithm for early detection of PAH in scleroderma is available.11

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