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
- Proliferative vasculopathy
- Involving small muscular arteries
- Hyperplasia/hypertrophy of all three layers of vascular wall (intima, media, adventitia)
- Fibrosis
- Thrombi
- SiMFis lesion (singular millimetric
fibrovascular lesions): collagen-rich conglomerate of vessels with a prominent muscular component, likely anastomosis between systemic and pulmonary vessels, especially hereditary form with BMPR2 mutation.
Diagnosis
- Confirmation of pulmonary hypertension
- Right heart catherization
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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