Pulmonary Hypertension

Pulmonary hypertension (PH) is a haemodynamic state of raised pressure in the pulmonary arterial circulation that ultimately overloads and fails the right ventricle. For NEET PG it sits at the crossroads of cardiology, respiratory medicine and pharmacology — the WHO five-group classification, the right heart catheterisation (RHC) cut-offs and the targeted drug classes for Group 1 are repeat performers.

Definition and haemodynamic criteria

PH is defined on right heart catheterisation (RHC) — the gold standard — not on echo. The historic threshold of mean pulmonary artery pressure (mPAP) ≥25 mmHg was revised at the 6th World Symposium (Nice, 2018) and retained thereafter:

• mPAP > 20 mmHg at rest (normal is ~14 ± 3 mmHg; the upper limit of normal is ~20).

To then separate pre-capillary (arterial/lung/clot disease) from post-capillary (left heart) PH, two more numbers are needed:

Parameter	Pre-capillary PH	Isolated post-capillary PH
mPAP	> 20 mmHg	> 20 mmHg
PAWP (pulmonary artery wedge pressure)	≤ 15 mmHg	> 15 mmHg
PVR (pulmonary vascular resistance)	> 2 Wood units	≤ 2 Wood units

High-yield: The triad that defines pulmonary arterial hypertension (PAH, Group 1) on RHC is mPAP > 20 mmHg + PAWP ≤ 15 mmHg + PVR > 2 Wood units. A normal/low wedge tells you the left heart is innocent and the lesion is in the precapillary arterioles.

Wood unit = pressure (mmHg) ÷ flow (L/min); 1 Wood unit = 80 dyn·s·cm⁻⁵. PVR is the haemodynamic hallmark distinguishing a "true" vascular disease from passive backward transmission of left-heart pressure.

WHO clinical classification (the five groups)

This is the single most examined fact in the topic. Memorise the group, the prototype disease and the implication for therapy.

Group	Mechanism	Prototype causes	Targeted PAH drugs work?
I — PAH	Pulmonary arteriolar remodelling (pre-capillary)	Idiopathic (IPAH), heritable (BMPR2), drug/toxin (anorexigens — aminorex, fenfluramine; methamphetamine, dasatinib), connective tissue disease (scleroderma), HIV, portal hypertension (portopulmonary), congenital heart disease (Eisenmenger), schistosomiasis	Yes
II — left heart disease	Post-capillary, raised PAWP	HFrEF, HFpEF, mitral/aortic valve disease	No — treat the left heart
III — lung disease / hypoxia	Hypoxic pulmonary vasoconstriction + parenchymal loss	COPD, ILD, OSA, chronic high-altitude exposure	No — treat lung + oxygen
IV — pulmonary artery obstruction	Chronic thromboembolic (CTEPH) + other arterial obstruction	Organised unresolved PE; tumour, arteritis	Surgery first (PEA)
V — multifactorial / unclear	Mixed mechanisms	Sarcoidosis, haematological (myeloproliferative, chronic haemolysis — sickle cell), metabolic (glycogen storage, Gaucher), chronic renal failure on dialysis, fibrosing mediastinitis	Variable

High-yield: Group 2 (left heart disease) is the commonest cause of PH worldwide; Group 3 is next. PAH (Group 1) is rare. Examiners love to test that targeted vasodilator therapy is reserved for Groups 1 (and selected 4) — using it indiscriminately in Group 2 can precipitate pulmonary oedema.

Mnemonic for the five groups — "Arteries, Atrium, Air, Aggregates, Assorted":

1. Arteries → PAH
2. Atrium/left heart → Group 2
3. Air/lungs/hypoxia → Group 3
4. Aggregates/clots (CTEPH) → Group 4
5. Assorted/miscellaneous → Group 5

Etiology and pathophysiology of PAH (Group 1)

The pulmonary vasculature normally is a low-pressure, high-compliance, low-resistance circuit. In PAH a triad of injury converges on the small muscular arterioles:

1. Vasoconstriction — imbalance of vasodilators and vasoconstrictors.
2. Proliferation/remodelling — intimal fibrosis, medial hypertrophy, adventitial thickening.
3. In-situ thrombosis — local microthrombi.

The three signalling axes that are therapeutic targets (learn these — each maps to a drug class):

• Endothelin pathway → endothelin-1 (a potent vasoconstrictor and mitogen) is increased → blocked by endothelin receptor antagonists.
• Nitric oxide pathway → NO/cGMP signalling is decreased → augmented by PDE5 inhibitors (block cGMP breakdown) and soluble guanylate cyclase stimulators.
• Prostacyclin pathway → prostacyclin (PGI₂, a vasodilator/antiproliferative) is decreased → replaced by prostanoids / IP-receptor agonists.

The advanced lesion is the plexiform lesion — a disorganised proliferation of endothelial channels — the histological signature of severe PAH.

High-yield: Idiopathic PAH classically affects young women (F:M ≈ 2–4:1). Heritable PAH is most often due to a mutation in BMPR2 (bone morphogenetic protein receptor type 2, a TGF-β superfamily receptor), autosomal dominant with incomplete penetrance. ALK1/endoglin mutations link PAH with hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu).

As PVR rises, the right ventricle hypertrophies, then dilates and fails (cor pulmonale). RV failure — not the lung itself — is the usual mode of death.

Clinical features

Symptoms are non-specific and insidious, causing diagnostic delay (typically 2 years):

• Exertional dyspnoea — the earliest and commonest symptom.
• Fatigue, exertional chest pain (RV angina), syncope (fixed low cardiac output — an ominous sign).
• Late: peripheral oedema, ascites, hepatic congestion.

Signs of pulmonary hypertension / RV strain:

• Loud P2 (palpable, accentuated pulmonary component of S2) — the classic early sign.
• Left parasternal (RV) heave.
• Right-sided S4 then S3.
• Pansystolic murmur of tricuspid regurgitation (louder on inspiration — Carvallo's sign), large v waves in JVP.
• Early diastolic Graham Steell murmur of pulmonary regurgitation.
• Signs of right heart failure: raised JVP, hepatomegaly, pedal oedema.

Diagnostic approach — investigation of choice

A logical sequence is essential; jumping to RHC without excluding common causes is a classic exam trap.

Stepwise workup:

Suspect PH (dyspnoea + loud P2) → Transthoracic echocardiography (screening test of choice) → exclude Group 2 (left heart) and congenital disease → CXR / PFT / HRCT + ABG (screen Group 3) → V/Q scan (screen Group 4 — CTEPH) → bloods (CTD serology, HIV, LFT) → Right heart catheterisation (confirmatory gold standard) + vasoreactivity test

• Echocardiography — first/screening test. Estimates pulmonary artery systolic pressure from the tricuspid regurgitant jet (modified Bernoulli), shows RV dilatation/dysfunction, septal flattening ("D-shaped" LV in systole), and screens for left heart and shunt disease. It estimates, it does not confirm.
• ECG — RV hypertrophy, right axis deviation, dominant R in V1, RV strain (T inversion V1–V4), P pulmonale.
• Chest X-ray — enlarged central pulmonary arteries with peripheral pruning, RV/RA enlargement.
• V/Q scan — investigation of choice to screen for CTEPH (Group 4); more sensitive than CTPA for chronic thromboembolic disease. A normal V/Q scan effectively excludes CTEPH.
• Pulmonary function tests + DLCO, ABG, overnight oximetry — screen Group 3 / hypoxia.
• Right heart catheterisation — confirmatory gold standard: directly measures mPAP, PAWP, PVR, cardiac output, and allows acute vasoreactivity testing.

High-yield: Echo = best screening (initial) test; RHC = gold-standard confirmatory test; V/Q scan = best test to detect CTEPH. These three "best test" questions recur every year.

Acute vasoreactivity test: performed during RHC using inhaled nitric oxide (or IV epoprostenol/adenosine). A positive response = fall in mPAP ≥ 10 mmHg to reach an absolute mPAP ≤ 40 mmHg, with maintained or increased cardiac output. Only ~10% of IPAH patients respond, and only responders are candidates for high-dose calcium channel blockers.

Management and drug of choice

Treatment depends entirely on the WHO group. Targeted vasodilator drugs are licensed for Group 1 PAH; CTEPH (Group 4) is primarily surgical.

General / supportive measures (all groups, as appropriate)

• Diuretics for RV-failure congestion; oxygen to keep SpO₂ > 90% (especially Group 3).
• Treat the underlying disease (valve surgery, COPD/ILD management, OSA CPAP).
• Anticoagulation — now selective (favoured in IPAH/CTEPH, avoided in scleroderma-PAH).
• Avoid pregnancy (very high maternal mortality), supervised rehabilitation, vaccination.

Vasoreactive responders (the minority)

• High-dose calcium channel blockers — nifedipine, diltiazem, amlodipine. (Verapamil is avoided — negative inotropy.)

Non-responders — the three pathway-targeted drug classes for PAH

Pathway	Class	Examples	Notable adverse effect / caution
Endothelin	Endothelin receptor antagonists (ERA)	bosentan, ambrisentan, macitentan	Hepatotoxic (monitor LFTs — esp. bosentan), teratogenic, anaemia
Nitric oxide	PDE5 inhibitors	sildenafil, tadalafil	Hypotension; contraindicated with nitrates
Nitric oxide	sGC stimulator	riociguat	Do NOT combine with PDE5i (severe hypotension); teratogenic; first-line medical option in inoperable CTEPH
Prostacyclin	Prostanoids / IP agonists	epoprostenol (IV), treprostinil, iloprost (inhaled), selexipag (oral IP agonist)	Jaw pain, flushing, diarrhoea; IV epoprostenol is the drug of choice in the sickest patients

High-yield: IV epoprostenol (prostacyclin) is the agent with proven mortality benefit and is the drug of choice in severe/high-risk Group 1 PAH (WHO functional class IV). Its very short half-life (~3–5 min) mandates continuous infusion via a central line. Riociguat is the standout drug for inoperable or persistent CTEPH.

Modern practice favours upfront combination therapy (e.g., ambrisentan + tadalafil) for intermediate-risk patients. End-stage disease → lung (or heart–lung) transplantation; atrial balloon septostomy is a palliative bridge.

CTEPH (Group 4) — different algorithm

• Pulmonary endarterectomy (PEA) is the potentially curative treatment of choice for operable proximal disease.
• Balloon pulmonary angioplasty + riociguat for inoperable/residual disease.
• Lifelong anticoagulation.

Complications

• Progressive right ventricular failure → cor pulmonale → cardiogenic shock and death.
• Syncope and sudden cardiac death (fixed low output, arrhythmia).
• Supraventricular arrhythmias (atrial flutter/fibrillation) — poorly tolerated.
• Haemoptysis, pulmonary artery dissection/rupture.
• Hepatic congestion → cardiac cirrhosis; refractory ascites and oedema.

Key differentials

Condition	Distinguishing pointer
Left heart failure (Group 2)	PAWP > 15 mmHg, raised LA, history of HTN/IHD/valve disease
COPD / ILD (Group 3)	Abnormal PFTs, HRCT changes, chronic hypoxia; PH usually mild
CTEPH (Group 4)	Mismatched perfusion defects on V/Q scan, history of PE
Eisenmenger syndrome	Reversed shunt, clubbing, differential cyanosis, known CHD
HFpEF mimicking PAH	Older, obese, hypertensive, AF; exercise/fluid-challenge RHC unmasks high wedge

High-yield: Before labelling a patient as Group 1 PAH and starting expensive vasodilators, you MUST exclude left heart disease (wedge pressure) and CTEPH (V/Q scan). Treating an unrecognised Group 2 patient with a pulmonary vasodilator can flood the left atrium and cause flash pulmonary oedema.

Recently asked / exam angle

• Defining haemodynamic criterion of PH → mPAP > 20 mmHg on RHC (updated from ≥25).
• Triad defining PAH → mPAP >20 + PAWP ≤15 + PVR >2 Wood units.
• Commonest cause of PH globally → left heart disease (Group 2).
• Gene in heritable PAH → BMPR2.
• Best screening test → echocardiography; gold standard → right heart catheterisation.
• Best test for CTEPH → V/Q scan (not CTPA).
• Drug with mortality benefit / DOC in severe PAH → IV epoprostenol.
• Definition of positive vasoreactivity → mPAP fall ≥10 to ≤40 mmHg with preserved CO → use CCBs.
• Drug contraindicated combination → riociguat + PDE5 inhibitor; PDE5i + nitrates.
• Curative therapy for CTEPH → pulmonary endarterectomy.
• Histological hallmark of severe PAH → plexiform lesion.
• ECG of PH → P pulmonale, right axis deviation, RV strain, dominant R in V1.

Rapid revision

1. PH = mPAP > 20 mmHg on right heart catheterisation (gold standard).
2. PAWP ≤ 15 + PVR > 2 Wood units distinguishes pre-capillary PAH from post-capillary (Group 2) PH.
3. Five WHO groups: 1 PAH, 2 left heart, 3 lung/hypoxia, 4 CTEPH, 5 miscellaneous.
4. Group 2 is the commonest cause of PH; PAH (Group 1) is rare.
5. Idiopathic PAH → young women; heritable PAH → BMPR2 mutation.
6. Three drug pathways: endothelin (bosentan — hepatotoxic), NO/cGMP (sildenafil; riociguat), prostacyclin (epoprostenol).
7. Echo screens, RHC confirms, V/Q scan finds CTEPH.
8. Loud P2 + parasternal heave are the cardinal clinical signs; exertional dyspnoea is earliest symptom.
9. Positive vasoreactivity (mPAP drop ≥10 to ≤40 mmHg) → high-dose calcium channel blockers.
10. IV epoprostenol = drug of choice in WHO class IV / severe PAH (continuous infusion, t½ ~3 min).
11. Riociguat + PDE5 inhibitor is contraindicated (profound hypotension).
12. Pulmonary endarterectomy is curative for operable CTEPH; lung transplant is last resort for refractory PAH.