How pulmonary hypertension is tested on Step 1

Vignettes describe exertional dyspnea, a loud P2, and signs of right heart failure in a young woman, a patient with COPD or sleep apnea, or a patient with prior PE, and ask about the mechanism, genetics, or drug.

workspace_premium Pulmonary vessels respond oppositely

Hypoxia dilates systemic arterioles but constricts pulmonary arterioles, diverting blood to better-ventilated lung. Chronic, widespread hypoxia turns this useful reflex into pulmonary hypertension.

Classification

The WHO groups organize causes by mechanism and guide treatment.

Pulmonary hypertensionGroup 1:PAHBMPR2, drugs,CTD, HIVGroup 2:Left heartHFrEF, HFpEF,mitral diseaseGroup 3:LungCOPD, ILD,sleep apneaGroup 4:CTEPHChronicthromboembolismGroup 5:OtherSarcoid, sicklecell,myeloproliferative
WHO groups. Group 4 (CTEPH) is the one group potentially cured by surgery (pulmonary thromboendarterectomy).
GroupMechanismTreatment focus
1 — PAHArteriolar remodeling (precapillary)PAH-specific vasodilators
2 — Left heart disease↑ Left atrial pressure transmitted backward (postcapillary)Treat heart failure or valve disease
3 — Lung disease/hypoxiaHypoxic vasoconstriction, capillary lossOxygen, treat lung disease, CPAP
4 — CTEPHOrganized clots obstruct arteriesAnticoagulation, thromboendarterectomy, riociguat
5 — MultifactorialMixedTreat underlying disease

Pulmonary capillary wedge pressure separates precapillary (≤ 15 mm Hg) from postcapillary (> 15 mm Hg) disease.

Pathogenesis of PAH

An imbalance favors vasoconstriction and proliferation: too much endothelin and thromboxane, too little nitric oxide and prostacyclin.

BMPR2lossOrendothelialinjuryImbalance↑ Endothelin,↓ NO and PGI₂RemodelingMedialhypertrophy,plexiformlesions↑ PApressureHigh RVafterloadRVfailureCorpulmonale,death
PAH pathogenesis. Plexiform lesions are tufts of capillary-like channels in severely remodeled arteries.
Drug targetDrugsMechanism
Endothelin pathwayBosentan, ambrisentan, macitentanEndothelin receptor antagonists (hepatotoxic, teratogenic)
Nitric oxide–cGMP pathwaySildenafil, tadalafil; riociguatPDE-5 inhibitors prolong cGMP; riociguat stimulates guanylate cyclase
Prostacyclin pathwayEpoprostenol, treprostinil; selexipagProstacyclin analogs or IP-receptor agonist → vasodilation, ↓ platelet aggregation
Vasoreactive subsetHigh-dose calcium channel blockersOnly if vasoreactivity testing is positive

Never combine PDE-5 inhibitors with nitrates or riociguat — severe hypotension.

Clinical features and cor pulmonale

Symptoms come from low cardiac output and right-sided congestion.

Pulmonary hypertensionExertional dyspnea, fatigueExertional syncope or chest painLoud P2Right ventricular heaveTricuspid regurgitation murmurRight heart failure (corpulmonale)Elevated JVPHepatomegaly, ascitesPeripheral edemaRV S3 or S4Right axis deviation, RVH on ECGvs
Signs. Cor pulmonale specifically means RV failure caused by lung disease or pulmonary vascular disease, not by left heart failure.

Clinical application

Young women with unexplained dyspnea and a loud P2 are the classic PAH presentation.

functions Worked example — the familial dyspnea

A 29-year-old woman has 1 year of exertional dyspnea and two episodes of syncope while running. Exam shows a loud P2 and a right ventricular heave. Her mother died of a similar illness. Right heart catheterization shows mean PA pressure 46 mm Hg with PCWP 9 mm Hg. Which gene is likely mutated, and what is the pathway?

  1. Elevated PA pressure with normal wedge pressure means precapillary (group 1) disease.
  2. Family history suggests heritable PAH.
  3. BMPR2 loss-of-function mutations remove an antiproliferative signal in pulmonary vascular smooth muscle.
  4. Smooth-muscle and endothelial proliferation narrow the arterioles, raising RV afterload.

Answer. BMPR2 (autosomal dominant, incomplete penetrance). Treat with PAH-specific therapy targeting endothelin, nitric oxide, and prostacyclin pathways; screen relatives.