Pulmonary Hypertension

Definition

• Murray & Nadel's Textbook of Respiratory Medicine

WHO Classification (6th WSPH)

• Murray & Nadel's Textbook of Respiratory Medicine

Pathobiology (Group 1 PAH)

• Intimal hyperplasia
• Medial hypertrophy
• Adventitial proliferation and metalloprotease activation
• In situ thrombosis
• Plexiform lesions (pathognomonic)
• Inflammation

• Goldman-Cecil Medicine

Clinical Features

• Dyspnea on exertion (most common presenting complaint)
• Fatigue
• Exercise intolerance
• Syncope or pre-syncope (indicates severely reduced cardiac output)
• Chest pain (RV ischemia)
• Peripheral edema, ascites (right heart failure)

• Loud P2 (pulmonic component of S2)
• Right-sided S3 or S4
• Tricuspid regurgitation murmur (systolic, increases with inspiration)
• Elevated JVP, hepatomegaly, ascites, peripheral edema
• Left parasternal heave (RV hypertrophy)
• Central cyanosis

Diagnosis

Step 1: Initial Workup

• NT-proBNP / BNP - elevated in PH; normal does not exclude
• ECG - right axis deviation, RV hypertrophy, right atrial enlargement, anterior ST/T changes (RV strain)
• Chest X-ray - enlarged proximal PAs with peripheral pruning; increased retrosternal space loss on lateral (RV enlargement)

Step 2: Echocardiography (screening cornerstone)

• Estimates RV systolic pressure via tricuspid regurgitation jet velocity (modified Bernoulli equation)
• Identifies: RA and RV enlargement, flattened interventricular septum ("D-sign"), underfilled LV
• Evaluates left-sided causes of PH (systolic/diastolic dysfunction, valvular disease, CHD)
• Note: Echo is prone to error especially in parenchymal lung disease

Step 3: Exclude CTEPH

• V/Q scan is the study of choice - shows mismatched perfusion defects
• CT pulmonary angiogram - good for acute PE but can miss chronic disease
• Pulmonary angiography if V/Q or CTPA shows abnormality

Step 4: Further workup

• Pulmonary function tests - mild restrictive/obstructive pattern, reduced DLCO in PAH; identifies significant lung disease (Group 3)
• Polysomnography - excludes sleep apnea (Group 3)
• Serology: ANA, anti-Scl-70, anti-centromere (CTD screening); HIV; liver function tests; hepatitis screen
• 6-minute walk test (6MWT) - functional capacity, baseline, prognosis
• CT chest - lung parenchyma, mediastinum

Step 5: Right Heart Catheterization (mandatory for definitive diagnosis)

• Only tool providing definitive hemodynamic diagnosis
• Measures: mPAP, PCWP, PVR, cardiac output
• Acute vasodilator testing (with inhaled nitric oxide, adenosine, or IV epoprostenol) in Group 1 PAH:
  • Positive response: mPAP falls ≥10 mmHg to <40 mmHg with stable/increased CO
  • ~7% of idiopathic PAH are responders - these may benefit from calcium channel blockers
• Goldman-Cecil Medicine; Murray & Nadel's Textbook of Respiratory Medicine

Drug and Toxin Causes of PAH (Group 1)

• Murray & Nadel's Textbook of Respiratory Medicine

Treatment

General Measures (All PH Groups)

• Refer to a specialized PH center
• Supplemental O2 if SpO2 < 90% (goal >90% at rest and >90% with exercise)
• Low-level graded aerobic exercise; specialized pulmonary rehabilitation
• Avoid high altitude and strenuous activity
• Sodium restriction (<2400 mg/day); fluid restriction if RV failure present
• Vaccinations: influenza, pneumococcal, COVID-19
• Pregnancy avoidance - hemodynamic changes are potentially life-threatening; mortality historically 30-50%
• Diuretics (furosemide ± spironolactone) for RV volume overload - monitor electrolytes/renal function
• Anticoagulation: NOT routinely recommended unless other indications exist

Group 1 PAH: Targeted Therapies

1. Calcium Channel Blockers (CCBs)

• Reserved for acute vasoreactor responders only (~7% of idiopathic PAH)
• Agents: long-acting nifedipine (90-180 mg/day), diltiazem (360-720 mg/day), amlodipine (10-20 mg/day)
• Avoid verapamil (negative inotropic effects)
• Must closely monitor for safety and efficacy; if not achieving FC I-II, add targeted therapy

2. Endothelin Receptor Antagonists (ERAs)

• Block ET-A and/or ET-B receptors, reducing vasoconstriction and smooth muscle proliferation
• Bosentan (dual ERA): 62.5 mg BID → up to 125 mg BID; requires monthly LFTs (hepatotoxic); increases OCP metabolism
• Ambrisentan (selective ET-A): lower liver toxicity rate
• Macitentan: once-daily; longest duration of action
• Class precaution: All ERAs are teratogenic - require monthly pregnancy testing + 2 reliable contraception methods

3. PDE-5 Inhibitors

• Inhibit cGMP-specific phosphodiesterase type 5, enhancing NO-cGMP signaling → vasodilation + antiproliferation
• Sildenafil (Revatio): 20 mg TID (pivotal SUPER-1 trial)
• Tadalafil: once-daily dosing
• Generally well tolerated; avoid in combination with nitrates

4. Soluble Guanylate Cyclase (sGC) Stimulators

• Riociguat: stimulates sGC directly and sensitizes it to endogenous NO, ↑ cGMP
• Also approved for CTEPH (group 4)

5. Prostacyclin Pathway Agents

• Replaces deficient prostacyclin, promoting vasodilation + antiproliferation via cAMP
• Epoprostenol (IV): most potent; first-line for FC IV and highest-risk patients; very short half-life (requires continuous IV infusion)
• Treprostinil: SC, IV, inhaled, or oral; longer stability
• Iloprost: inhaled prostacyclin
• Selexipag: oral selective IP receptor agonist

6. Targeting the BMP Pathway (Novel)

• Sotatercept: a fusion protein (activin receptor type IIA - Fc fusion) that corrects TGF-β/BMP pathway imbalance
• Dose: 0.3 mg/kg SC every 3 weeks, escalated to 0.7 mg/kg
• Reduces PVR, improves 6MWT, lowers NT-proBNP

Treatment Algorithm

• Non-vasoreactors without comorbidities: Initial dual combination therapy (ERA + PDE5i) is standard of care
• Non-vasoreactors with cardiopulmonary comorbidities: Initial oral monotherapy (PDE5i preferred)
• High-risk (FC III/IV): Triple therapy including IV/SC prostacyclin analogue
• Vasoreactors: CCB trial; escalate if no improvement to FC I/II

Invasive Therapies

• Pulmonary endarterectomy (PEA): Potentially curative surgical treatment for operable CTEPH (Group 4)
• Balloon pulmonary angioplasty (BPA): For inoperable CTEPH
• Atrial septostomy: Creates R-to-L interatrial shunt to decompress RV; reserved for refractory cases at specialized centers (significant morbidity/mortality)
• Bilateral lung or heart-lung transplantation: For patients with FC III/IV refractory to optimized therapy including prostanoids; referral at time of diagnosis in selected patients

Group 2 (PH due to LHD)

• No approved PAH-specific therapy
• Focus on treating underlying heart failure (reduce pulmonary venous pressure)
• PAH-targeted drugs are NOT indicated and may be harmful

Group 3 (PH due to Lung Disease)

• Treat underlying lung disease; supplemental oxygen
• PAH therapies generally reserved for patients with pre-capillary component (PVR ≥3 WU)

Group 4 (CTEPH)

• Anticoagulation (lifelong)
• Surgical PEA is first-line for accessible disease
• Riociguat for inoperable or persistent/recurrent CTEPH
• BPA for non-surgical candidates

Prognosis and Risk Stratification

• WHO Functional Class III or IV
• Low 6MWT distance (<165 m = very high risk)
• Elevated NT-proBNP/BNP
• RV dysfunction on imaging (TAPSE <1.8 cm, pericardial effusion)
• Low cardiac index, high PVR
• Syncope

Recent Evidence (2024-2025)

• STELLAR trial (FC II/III PAH): Sotatercept added to background therapy improved 6MWT, PVR, and time to clinical worsening vs. placebo.
• ZENITH trial (PMID: 40167274) - NEJM, 2025: Among high-risk PAH patients (FC III/IV, REVEAL Lite 2 score ≥9) on maximum background therapy, sotatercept reduced the composite of death, lung transplantation, or hospitalization by 76% (HR 0.24, 95% CI 0.13-0.43; P<0.001). The trial was stopped early for efficacy. Death occurred in 8.1% vs. 15.1% (sotatercept vs. placebo).
• PHOENIX trial (PMID: 41025556) - NEJM, 2025: Sotatercept within the first year after PAH diagnosis showed significant benefit.
• Macitentan + tadalafil initial combination (PMID: 38966990) - Eur J Heart Fail, 2024: Initial combination therapy effective even with cardiac comorbidities.