5.7 Pulmonary Hypertension & Sleep-Disordered Breathing

1. Pulmonary Hypertension (PH) & Pulmonary Arterial Hypertension (PAH)

Pulmonary hypertension is a hemodynamic and pathophysiological condition defined by an elevation in pulmonary vascular pressures.

Updated Hemodynamic Definitions (2022 ESC/ERS Guidelines)

• Pulmonary Hypertension (All Causes): Mean Pulmonary Artery Pressure (mPAP > 20 mmHg) at rest measured via invasive Right Heart Catheterization (RHC).
• Pre-Capillary Pulmonary Hypertension (Groups 1, 3, 4, 5):
  • mPAP > 20 mmHg
  • Pulmonary Capillary Wedge Pressure (PCWP) <= 15 mmHg (excludes left heart disease)
  • Pulmonary Vascular Resistance (PVR) > 2 Wood Units (WU)
• Post-Capillary Pulmonary Hypertension (Group 2 - Left Heart Disease):
  • mPAP > 20 mmHg and PCWP > 15 mmHg.
  • Isolated Post-Capillary PH (IpcPH): PVR <= 2 WU.
  • Combined Post- and Pre-Capillary PH (CpcPH): PVR > 2 WU.

Clinical Classification (WHO Groups 1–5)

• Group 1: Pulmonary Arterial Hypertension (PAH): Idiopathic, heritable (BMPR2 gene mutation), drug/toxin-induced (methamphetamines, aminorex, fenfluramine), connective tissue disease (Systemic Sclerosis / CREST syndrome >> SLE), HIV infection, portal hypertension (portopulmonary hypertension), congenital systemic-to-pulmonary shunts, schistosomiasis.
• Group 2: PH Due to Left Heart Disease: Heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), mitral/aortic valvular disease. Most common cause of PH overall (~70%).
• Group 3: PH Due to Lung Diseases and/or Hypoxia: COPD, idiopathic pulmonary fibrosis, obstructive sleep apnea, chronic high-altitude exposure.
• Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Persistent thromboembolic occlusion and remodeling of pulmonary arteries following PE. Screening test of choice: V/Q lung scan (shows multiple mismatched segmental perfusion defects; superior sensitivity to CTPA). Treatment of choice: Surgical Pulmonary Thromboendarterectomy (PTE), which can be curative. For inoperable CTEPH: Balloon Pulmonary Angioplasty (BPA) and oral Riociguat.
• Group 5: PH with Unclear/Multifactorial Mechanisms: Hematologic disorders (myeloproliferative neoplasms), systemic disorders (sarcoidosis, histiocytosis X), metabolic disorders (Gaucher disease), chronic renal failure on hemodialysis.

Targeted Pharmacotherapy for WHO Group 1 PAH

Patients with Group 1 PAH should undergo acute vasodilator testing during RHC with inhaled Nitric Oxide. If positive (fall in mPAP >=10 mmHg to <=40 mmHg with preserved cardiac output; ~10%), high-dose oral Calcium Channel Blockers (Diltiazem, Amlodipine) are indicated. Non-responders receive combination therapy targeting specific pathways:

1. Endothelin Receptor Antagonists (ERAs): Block vasoconstriction and vascular smooth muscle proliferation mediated by endothelin-1. Agents: Ambrisentan (selective ETA antagonist), Bosentan (dual ETA/ETB antagonist; requires monthly LFT monitoring due to hepatotoxicity), Macitentan.
2. Nitric Oxide / cGMP Enhancers:
   • Phosphodiesterase-5 (PDE-5) Inhibitors: Sildenafil, Tadalafil (inhibit cGMP degradation, promoting smooth muscle relaxation and vasodilation).
   • Soluble Guanylate Cyclase (sGC) Stimulator: Riociguat (directly stimulates sGC independently of NO). CRITICAL CONTRAINDICATION: Co-administration of Riociguat with PDE-5 inhibitors or nitrates is strictly contraindicated due to severe, potentially fatal systemic hypotension.
3. Prostacyclin Pathway Agonists: Stimulate IP receptors, increasing cAMP to induce potent vasodilation and platelet anti-aggregation. Agents: IV Epoprostenol (continuous infusion; gold-standard therapy for high-risk / NYHA Class IV PAH, proven to improve survival), subcutaneous/inhaled Treprostinil, oral Selexipag (selective non-prostanoid IP receptor agonist).
4. Activin Signaling Inhibitors: Sotatercept (first-in-class activin receptor type IIA-Fc fusion protein). Binds and traps activins and growth differentiation factors, rebalancing pro-proliferative activin signaling with anti-proliferative BMPR2 signaling. Proven in the STELLAR trial to significantly increase 6-minute walk distance, lower PVR, and reduce clinical worsening events.

2. Sleep-Disordered Breathing: OSA vs. OHS

Obstructive Sleep Apnea (OSA)

• Pathophysiology: Repetitive partial (hypopnea) or complete (apnea) collapse of the upper pharyngeal airway during sleep, resulting in paroxysmal arterial oxygen desaturation, surges in sympathetic tone, acute systemic/pulmonary arterial vasoconstriction, and sleep fragmentation.
• Risk Factors: Obesity (BMI > 30 kg/m2), male sex, post-menopausal state, craniofacial disharmony (retrognathia, micrognathia, macroglossia, tonsillar hypertrophy), neck circumference > 17 inches (43 cm) in men, > 16 inches (40 cm) in women.
• Screening: STOP-BANG Questionnaire (Snoring, Tiredness, Observed apnea, high blood Pressure, BMI > 35, Age > 50, Neck circumference, Gender male; score >=3 indicates intermediate-to-high risk).
• Diagnostic Polysomnography (PSG): Quantifies the Apnea-Hypopnea Index (AHI) — total number of apneas (cessation of airflow >=10 seconds with persistent respiratory effort) plus hypopneas (airflow reduction >=30% with >=3% desaturation or arousal) per hour of sleep:
  • Normal: AHI < 5 events/hour
  • Mild OSA: AHI 5 – 14.9 events/hour
  • Moderate OSA: AHI 15 – 29.9 events/hour
  • Severe OSA: AHI >= 30 events/hour
• Treatment:
  • Continuous Positive Airway Pressure (CPAP): First-line gold standard for moderate-to-severe OSA or symptomatic mild OSA.
  • Alternative Therapies: Oral Mandibular Advancement Devices (MAD) for mild-to-moderate OSA in patients intolerant of CPAP; Positional therapy; Hypoglossal Nerve Stimulation (implantable device for moderate-to-severe OSA with BMI < 35 kg/m2 without complete concentric palatal collapse); Weight loss (including GLP-1 receptor agonists / bariatric surgery).

Obesity Hypoventilation Syndrome (OHS / Pickwickian Syndrome)

• Diagnostic Triad:
  1. Obesity (BMI >= 30 kg/m2)
  2. Awake, daytime chronic hypercapnia (arterial PaCO2 >= 45 mmHg) on room air arterial blood gas
  3. Sleep-disordered breathing (OSA present in ~90% of patients; sleep hypoventilation in 10%) Exclusion criterion: Hypercapnia must not be attributable to another underlying condition (severe COPD, neuromuscular weakness, severe kyphoscoliosis).
• Diagnostic Screening Pearl: An elevated serum bicarbonate level (HCO3- >= 27 mEq/L) on a routine basic metabolic panel reflects renal metabolic compensation for chronic nocturnal and daytime respiratory acidosis. In an obese patient, a serum HCO3- >= 27 mEq/L has >92% sensitivity for screening OHS and warrants diagnostic arterial blood gas testing.
• Management: Positive airway pressure therapy (CPAP for concurrent severe OSA; Bilevel PAP / Non-Invasive Ventilation if hypoventilation persists despite CPAP or severe nocturnal desaturations); aggressive weight reduction.