Heritable pulmonary arterial hypertension
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A 30-year-old woman presents with progressive dyspnea on exertion, exertional syncope, and lower-extremity edema. Right heart catheterization confirms pre-capillary pulmonary hypertension (mPAP 45 mmHg, PVR 8 WU, PAWP 10 mmHg). Family history reveals a paternal uncle who died young of "heart failure" and a paternal cousin diagnosed with pulmonary hypertension in her 20s.
AD with markedly reduced penetrance (~14-20% lifetime in carriers overall, but sex-stratified ≈ 14% in males vs. ≈ 42% in females; female:male affected ≈ 2-4:1).
| Gene | Mechanism | Notes |
|---|---|---|
| BMPR2 | LOF / haploinsufficiency of BMP receptor type 2 in pulmonary endothelium | ~70-80% of heritable PAH; ~25% of "idiopathic" PAH |
| ACVRL1 (ALK1) | TGF-β/BMP signaling | Overlap with HHT (HHT-PAH overlap syndrome) |
| ENG | TGF-β co-receptor | Also causes HHT type 1 |
| BMP9 / GDF2 | BMP9 ligand | More recent gene |
| KCNK3 | Two-pore K⁺ channel | Channelopathy mechanism |
| SMAD9 | Downstream of BMPR2 signaling | |
| CAV1 | Caveolin-1 | |
| EIF2AK4 | AR | Pulmonary veno-occlusive disease / pulmonary capillary hemangiomatosis: distinct entity that resembles PAH but has different prognosis and treatment caution |
| TBX4 | Transcription factor | Childhood-onset PAH, often syndromic |
Anticipation has been described in some BMPR2 kindreds (younger age at diagnosis in successive generations); mechanism not fully understood, possibly ascertainment bias plus modifier effects.
- Hemodynamic definition (2022 ESC/ERS guidelines): pre-capillary PH = mPAP ≥20 mmHg, PVR ≥2 WU, PAWP ≤15 mmHg
- Progressive dyspnea on exertion, fatigue, exertional syncope (low cardiac output during exercise)
- Right heart failure: hepatomegaly, ascites, peripheral edema, JVD
- Loud P2, RV heave, tricuspid regurgitation murmur on exam
- ECG: right axis deviation, RV hypertrophy, RA enlargement
- CXR: enlarged central pulmonary arteries with peripheral pruning, RV enlargement
- Echo: estimated PASP, RV dilation/dysfunction, paradoxical septal motion
- Right heart catheterization is required for diagnosis: also rules out left heart disease
- Right heart catheterization is the diagnostic gold standard: confirms pre-capillary PH (mPAP ≥20 mmHg, PVR ≥2 WU, PAWP ≤15 mmHg) and excludes left heart disease; vasoreactivity testing guides calcium-channel-blocker candidacy
- Transthoracic echocardiography is the first-line screening test (estimates PASP, assesses RV size/function) and is used for surveillance of asymptomatic gene carriers
- Workup excludes secondary causes (V/Q scan for chronic thromboembolic PH, PFTs, HRCT, autoimmune serologies) before labeling PAH as heritable/idiopathic
- Gene panel testing (BMPR2 most common) confirms heritable PAH and enables cascade screening; HRCT and EIF2AK4 testing distinguish PVOD, which alters vasodilator safety
- Reduced penetrance is the dominant counseling theme: most carriers will not develop disease, but the ~15-20% who do have severe morbidity/mortality
- Female bias among affected; multifactorial; estrogen metabolism implicated
- Cascade testing at-risk relatives: identifies carriers for surveillance (annual echo + symptom review starting in adolescence)
- Pregnancy is contraindicated in known PAH: historically cited maternal mortality ~30-50% (contemporary specialized-center series report lower, roughly 10–25%, but pregnancy remains contraindicated); preconception counseling for known carriers should address this even before symptoms develop
- PVOD (EIF2AK4) caution: PAH-specific vasodilators can precipitate fatal pulmonary edema in PVOD; distinguishing PAH from PVOD before vasodilator therapy is critical (HRCT findings: septal lines, ground-glass, mediastinal LAD)
- PAH-specific therapy (combination based on risk stratification):
- Endothelin receptor antagonists (bosentan, ambrisentan, macitentan)
- PDE5 inhibitors (sildenafil, tadalafil) or sGC stimulator (riociguat)
- Prostacyclin pathway agents (epoprostenol, treprostinil, selexipag)
- Diuretics for right heart failure
- Anticoagulation in select cases
- Lung (or heart-lung) transplantation for end-stage disease
- Annual screening echo for known asymptomatic gene carriers