Eisenmenger Syndrome

Definition

Eisenmenger syndrome is the consequence of large, unrepaired intra- or extracardiac left-to-right shunts causing severe pulmonary vascular disease (extremely elevated PVR), resulting in bidirectional or right-to-left shunting, cyanosis, and multiorgan dysfunction. It represents the most severe form of PAH associated with CHD. By definition, all patients with Eisenmenger syndrome are in ACHD physiological Stage D.

Key Concepts

Pathophysiology

• Prolonged left-to-right shunting → pulmonary vascular remodelling → irreversible elevation of PVR → reversal of shunt direction
• Any large unrepaired shunt (VSD, ASD, AVSD, PDA, aortopulmonary window, truncus arteriosus) can cause Eisenmenger syndrome; risk influenced by anatomy, concomitant syndromes (especially Down syndrome), genetics, and environment
• Chronic cyanosis, abnormal cardiac loading, systemic and pulmonary perfusion abnormalities → multiorgan dysfunction, arrhythmias, diastolic and systolic cardiac dysfunction, SCD risk
• Patients with Down syndrome: more comorbidities (OSA, thyroid dysfunction); standard risk tools (6MWT) less accurate in reflecting disease severity
  sources/ACHD-AHA-2025 — very high

Diagnosis

• Invasive haemodynamic assessment mandatory to confirm diagnosis, quantify PAH, perform detailed shunt run, and exclude contributors to bidirectional shunting (COR 1, B-NR)
  • Exclude postcapillary PH, streaming from valvular regurgitation, RV pressure overload from RVOT obstruction
• Joint management by ACHD + PAH subspecialists (COR 1, B-NR)
• After diagnosis confirmed, routine repeat invasive haemodynamics not needed unless clinical worsening or planning MCS/transplantation
  sources/ACHD-AHA-2025 — very high

PAH-Directed Therapy (Major 2025 Upgrade)

Monotherapy — COR 1 (B-R) [upgraded from COR 2a]:

• Initial ERA (bosentan, macitentan, ambrisentan) or PDE5 inhibitor (sildenafil, tadalafil) for symptomatic patients or those with reduced exercise capacity (LVEF >40%)
• Both drug classes recommended equally as initial therapy — all ERAs and all PDE5i are COR 1 (differs from ESC 2022 where bosentan is COR 1 but other ERAs are COR 2a)

Dual combination ERA + PDE5i — COR 1 (B-NR) [upgraded from COR 2a]:

• For patients who remain symptomatic or have worsening exercise capacity on single agent

Inhaled/subcutaneous prostacyclin — COR 2b (C-LD):

• Consider as initial or add-on therapy in high-risk patients (WHO FC 3–4, 6MWT <165 m, TAPSE <16 mm, NT-proBNP >1400 pg/mL) or rapidly progressive disease

Evidence base:

• BREATHE-5 (bosentan, n=54): improved haemodynamics and functional class
• MAESTRO (macitentan, n=226): primary endpoint (6MWT) neutral; benefit in subgroup without Down syndrome with haemodynamic follow-up; macitentan offers dual ET-1 receptor inhibition and excellent pharmacokinetics but risk of new anaemia
• PDE5i: small RCT (n=28) + observational data showing improved 6MWT, functional status, haemodynamics without significant SVR reduction
  sources/ACHD-AHA-2025 — very high

Contraindications and Harms

sources/ACHD-AHA-2025 — very high

Anticoagulation — Selective Use

• Anticoagulation NOT routinely indicated (COR 3: No Benefit)
• Anticoagulation may be considered (COR 2b, C-EO) for patients with high-risk features AND low bleeding risk:
  • Atrial arrhythmia
  • New or enlarging pulmonary arterial thrombosis
  • Prior thromboembolic event
    sources/ACHD-AHA-2025 — very high

Arrhythmia Management

• Atrial arrhythmias → prompt restoration and maintenance of sinus rhythm (COR 1, C-LD) — haemodynamic deterioration risk if AF/AFL persists
• Regular exercise programme + PAH therapy improves exercise capacity (COR 2a, C-LD) — new
  sources/ACHD-AHA-2025 — very high

Supportive Measures and Monitoring

• Iron supplementation for iron deficiency (secondary erythrocytosis depletes iron stores) — annual screening
• Hyperviscosity → rehydration first; phlebotomy only if refractory symptoms with haematocrit >65%
• Avoid: Prolonged high altitude, pregnancy, nephrotoxins, extreme exertion, large fluid volume shifts, hot/humid environments
• High-altitude simulation testing before air travel for risk stratification
• Supplemental O₂ individualised (not to "normalise" saturations)
• Palliative care and advance care planning for refractory cases — survival in ICU setting is poor

Risk Stratification:

• Adverse prognostic factors: Down syndrome, pretricuspid shunt, older age, worse hypoxemia, reduced eGFR, RV dysfunction on echo
• 4-strata PAH risk model applicable if cutoffs adjusted for Eisenmenger population (less applicable in Down syndrome)
  sources/ACHD-AHA-2025 — very high

Transplantation

• Patients with refractory symptoms despite optimal medical management → consider lung transplantation with repair, or heart–lung transplantation
• Optimal timing and eligibility remain controversial

Contradictions / Open Questions

• Riociguat: approved for persistent/recurrent PAH after CHD repair (PATENT 1+2 subgroup analysis); no specific recommendation in Eisenmenger syndrome due to lack of direct data — contrasts with ESC 2022 where it is COR 2a
• Selexipag (oral prostacyclin receptor agonist): no data in Eisenmenger syndrome
• Sotatercept (activin signalling inhibitor): no data in Eisenmenger syndrome; rapidly advancing in idiopathic PAH
• Down syndrome with Eisenmenger: routine risk tools unreliable; disease trajectory poorly characterised; specific management guidance lacking
• Whether combination initial therapy (ERA + PDE5i from the outset) is superior to sequential therapy remains undefined
  sources/ACHD-AHA-2025 — very high

Connections

• Related to entities/Pulmonary-Hypertension — Eisenmenger is a subset of Group 1 PAH (PAH associated with CHD)
• Related to concepts/ACHD-AP-Classification — Eisenmenger = Stage D by definition
• Related to entities/Atrial-Fibrillation — rhythm control critically important in Eisenmenger
• Related to concepts/Right-Heart-Catheterization — essential for diagnosis; quantifies PVR and shunt
• Related to concepts/PAH-Risk-Stratification — 4-strata risk model adapted for Eisenmenger

Sources

• sources/ACHD-AHA-2025