Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension

Updated: 10/12/2022

© Jun Wang, MD, PhD

 

Definition

  • Formerly called primary pulmonary hypertension
  • Resting mPAP ≥ 20 mm Hg, pulmonary capillary wedge pressure (PCWP) < 15 mm Hg, and PVR above 3 Wood units
  • Absence of more prevalent causes of pulmonary hypertension such as left heart disease (group 2), chronic lung disease (group 3), or venous thromboembolism (group 4)

General features

  • Precapillary pulmonary hypertension
  • Heterogenous in pathogenesis
  • More common in women
  • More common in white population
  • Schistosomiasis likely the most common cause worldwide
  • Most cases in the US are idiopathic 
  • Prognosis depends on etiology, severity and treatment

Subclassification

  • Idiopathic PAH
  • Heritable PAH: BMPR2, ALK2 etc
  • Drug- and toxin-induced PAH
  •  PAH associated with:

o   Connective tissue disease

o   HIV infection

o   Portal hypertension

o   Congenital heart disease

o   Schistosomiasis

  • PAH long-term responders to calcium channel blockers
  • PAH with overt features of venous/capillaries (PVOD/PCH) involvement
  • Persistent PH of the newborn syndrome

Heritable PAH

  • Two forms
    • Familial PAH (≥2 family members affected) 
    • Simplex PAH (single occurrence) with positive identification of mutation in one of the associated genes
  • Associated wtih BMPR2, ALK2 etc
  • Diagnosis needs confirmation of PAH and associated mutations

Pathogenesis

  •  Heterogenous etiology

o   Host: genetics, hormones, age

o   Environment: hypoxia, drugs

o   Stimulus: shear stress, virus

  • Endothelial dysfunction

o   Sustained vasoconstriction

§  Reduced NO or PGI2

§  Elevated ET-1, 5-HT, etc

o   Hyperproliferation

§  Elevated growth factors: FGF2, PDGF, EGF

§  Reduced pro-apoptotic factors: Bcl2, Bcl-XL

o   Hyper-coagulation

§  Elevated vWF, P-selectin, thrombomodulin, thromboxane A2

  • Vascular smooth muscle hyperplasia

o   Hyper-proliferation

§  Elevated growth factors: FGF2, PDGF, EGF

§  Elevated anti-apoptotic factors

§  Suppressed BMPRII pathway

§  Elevated migration activities

o   Hyper-polarisation

§  Elevated: TRPC1, Ca2+-sensing receptor

§  Suppressed: TASK1, KV1.5

o   Abnormal cellular energetics

§  Mitochondrial abnormalities

§  Glycolytic shift

  • Abnormal immune and inflammatory reactions

o   Sustained inflammation

o   Abnormal immune activities

Clinical presentations

  • Presentation of pulmonary hypertension
  • PAPm≥20 mm Hg
  • PAWP ≤ 15 mm Hg
  • Pulmonary vascular resistance (PVR) > 3 mm Hg

Key morphological features

Diagnosis

o   PAPm≥25 mm Hg

o   PAWP ≤ 15 mm Hg

o   PVR > 3 mm Hg

  • Identify underlying disorders

o   Connective tissue disease

o   Drug/toxin

o   Congenital heart disease

o   Portopulmonary

o   Schistosomiasis

o   HIV

o   Genetic testing: BMPR2

Genetic abnormalities

  • BMPR2, ALK2 etc

Treatment

  • Supportive therapy: Oxygen, diuretics, digoxin, etc
  • Vasodilatory therapy

o   Endothelin receptor antagonists: Block activation of endothelin system

o   Phosphodiesterase-5 (PDE-5) inhibitors and guanylate cyclase stimulators: Activation of nitric oxide pathway

o   Prostacyclin analogues and prostacyclin receptor agonists: Activation of prostacyclin pathway

  • Balloon atrial septostomy
  • Lung transplant

 

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