A 33-year-old woman is evaluated for slowly worsening breathlessness over several months. Investigations confirm idiopathic pulmonary arterial hypertension. She is commenced on an endothelin-receptor blocking medication. What is the primary therapeutic goal of this drug?

A. Improve airflow into the lungs
B. Prevent development of pulmonary scarring
C. Lower pulmonary arterial resistance to reduce pressure overload on the right ventricle
D. Reduce pulmonary venous congestion
E. Increase oxygen content of blood returning to the left heart

Table of Contents

Correct Answer: C — Lower pulmonary arterial resistance to reduce pressure overload on the right ventricle

Detailed Explanation

Pulmonary arterial hypertension (PAH) is defined by a mean pulmonary artery pressure ≥20 mmHg at rest measured via right-heart catheterisation. In idiopathic PAH, the pulmonary arteries become narrowed, thickened, and stiff, largely due to endothelial dysfunction. One major contributor is endothelin-1, a potent vasoconstrictor and promoter of vascular smooth muscle proliferation.

Endothelin receptor antagonists (ERAs) such as bosentan (dual ETA/ETB blocker) and ambrisentan (selective ETA blocker) directly oppose endothelin’s effects. Their purpose is to reduce pulmonary vascular resistance, which subsequently lowers right ventricular (RV) systolic pressure, easing RV workload. This improves exercise capacity, delays clinical deterioration, and may improve survival.

Right-ventricular failure is the leading cause of death in PAH, therefore reducing RV afterload is the central therapeutic aim. ERAs do not significantly improve oxygenation, airflow, or prevent fibrosis. They also do not target pulmonary venous pathology (Group 2 pulmonary hypertension).

Who gets PAH?

More common in women (3:1)
Typical onset: 20–40 years
Risks: anorexigens, connective-tissue diseases (especially systemic sclerosis), HIV, methamphetamine, heritable mutations (BMPR2)

Key symptoms

Progressive exertional dyspnoea
Exertional syncope (poor RV output)
Chest pain
Peripheral oedema
Cyanosis in advanced disease

Key signs

Loud P2, narrow splitting of S2
RV heave
Raised JVP with prominent a-waves
Tricuspid regurgitation

Management pathway

Treat reversible factors (oxygen, anticoagulation if idiopathic PAH).
Right-heart catheterisation → mandatory for diagnosis + vasoreactivity testing.
If vasoreactive → high-dose CCB (rare responders).
If non-vasoreactive (most patients) →
- ERAs (bosentan, ambrisentan)
- PDE-5 inhibitors (sildenafil)
- Prostacyclin analogues (epoprostenol, iloprost, treprostinil)
Advanced disease → consider lung or heart–lung transplantation.

Cheat Sheet for Exam

Definition

PAH = mean pulmonary artery pressure ≥20 mmHg at rest on RHC.

Pathophysiology

↑ Endothelin → vasoconstriction + smooth-muscle proliferation.
↑ Pulmonary vascular resistance → RV hypertrophy → RV failure.

Endothelin Receptor Antagonists

Bosentan (ETA + ETB)
Ambrisentan (ETA)
Main goal: ↓ pulmonary vascular resistance → ↓ RV systolic pressure.

Clinical features

Progressive dyspnoea
Syncope
Chest pain
Loud P2
RV heave
Raised JVP
TR murmur

Management overview

Vasoreactivity testing
CCB if vasoreactive
Otherwise: ERA, PDE5 inhibitor, prostacyclin analogue
Transplant for refractory disease

Flashcards

Flashcard 1
Q: What defines pulmonary arterial hypertension?
A: Mean pulmonary artery pressure ≥20 mmHg at rest on right-heart catheterisation.

Flashcard 2
Q: What is the primary action of endothelin receptor antagonists?
A: Reduce pulmonary vascular resistance.

Flashcard 3
Q: Why does reducing PVR improve survival?
A: Decreases RV afterload and prevents RV failure.

Flashcard 4
Q: Name two endothelin receptor antagonists.
A: Bosentan, ambrisentan.

Flashcard 5
Q: What is a hallmark early sign of PAH?
A: Loud P2.

Flashcard 6
Q: Most common cause of death in PAH?
A: Right ventricular failure.

Flashcard 7
Q: Which test is mandatory to diagnose PAH?
A: Right-heart catheterisation.

Flashcard 8
Q: What drug group is used if vasoreactivity testing is positive?
A: Calcium channel blockers.

Flashcard 9
Q: Who commonly develops idiopathic PAH?
A: Young to middle-aged women.

Flashcard 10
Q: What symptom suggests poor RV output in PAH?
A: Exertional syncope.

Flashcard 11
Q: What murmur may be heard due to RV dilatation?
A: Tricuspid regurgitation.

Flashcard 12
Q: What pathway is overactive in PAH and targeted by ERAs?
A: Endothelin-1 pathway.

Flashcard 13
Q: What is the hemodynamic consequence of increased PVR?
A: Elevated RV systolic pressure.

Flashcard 14
Q: Name a prostacyclin analogue used in PAH.
A: Epoprostenol / iloprost / treprostinil.

Flashcard 15
Q: Name a PDE-5 inhibitor used in PAH.
A: Sildenafil.

Flashcard 16
Q: What are prominent ‘a’ waves in JVP a sign of?
A: Increased resistance to RA emptying due to high RVEDP.

Flashcard 17
Q: What imaging might show signs of PAH?
A: Echo showing RV hypertrophy/dilation.

Flashcard 18
Q: Is PAH associated with COPD?
A: No—COPD causes Group 3 pulmonary hypertension, not PAH.

Flashcard 19
Q: What condition increases PAH risk in rheumatology?
A: Systemic sclerosis.

Flashcard 20
Q: When is transplant considered?
A: Progressive PAH despite maximal therapy.

MCQs

MCQ 1
Which mechanism best explains the benefit of endothelin receptor antagonists in PAH?
A. Increased systemic vascular resistance
B. Blockade of pulmonary venous hypertension
C. Reduced pulmonary arterial vasoconstriction
D. Improved oxygen diffusion
E. Increased cardiac preload
Answer: C

MCQ 2
A loud P2 on auscultation in a young woman suggests:
A. Aortic stenosis
B. Raised pulmonary arterial pressure
C. Mitral stenosis
D. Atrial septal defect only
E. Left ventricular failure
Answer: B

MCQ 3
A patient responds to vasoreactivity testing. Which medication class is first-line?
A. PDE-5 inhibitors
B. High-dose calcium channel blockers
C. Endothelin receptor antagonists
D. Beta-blockers
E. Steroids
Answer: B

MCQ 4
Which is the most common terminal event in untreated PAH?
A. Pulmonary embolism
B. Sudden arrhythmia
C. Left-ventricular failure
D. Right-ventricular failure
E. Hypoxic respiratory arrest
Answer: D

MCQ 5
Systemic sclerosis increases risk of which type of pulmonary hypertension?
A. Group 1 – PAH
B. Group 2 – Left heart disease
C. Group 3 – Hypoxic lung disease
D. Group 4 – CTEPH
E. Group 5 – Miscellaneous
Answer: A

Summary

Pulmonary arterial hypertension (PAH) is characterised by a mean pulmonary artery pressure ≥20 mmHg due to progressive narrowing and stiffening of the pulmonary arterioles. Endothelin-1, a potent vasoconstrictor, plays a key role in disease progression, leading to high pulmonary vascular resistance and increased afterload on the right ventricle. Endothelin receptor antagonists work by blocking endothelin receptors, reducing pulmonary vascular resistance and thereby lowering right-ventricular systolic pressure. This slows the progression toward right-ventricular failure, the major cause of death in PAH. The condition typically affects young or middle-aged women and presents with progressive exertional dyspnoea, exertional syncope, chest discomfort, and sometimes cyanosis or peripheral oedema. Clinical signs include a loud P2, RV heave, raised JVP with prominent a-waves, and tricuspid regurgitation. Diagnosis requires right-heart catheterisation and assessment of vasoreactivity. Only a small subset of patients respond to vasodilator testing and are treated with high-dose calcium channel blockers. The majority require specific PAH therapies such as ERAs, PDE-5 inhibitors, or prostacyclin analogues. Early treatment is crucial to preserve RV function. In advanced or treatment-refractory disease, lung or heart–lung transplantation may be considered.