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PULMONARY HYPERTENSION

Comprehensive Postgraduate Notes (MD/DM/DNB Internal Medicine)

Primary Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Supplemented: 2022 ESC/ERS Guidelines (Humbert M et al., Eur Heart J 2022)

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SECTION 1: DEFINITION

1.1 Historical Definition

• Pre-2018 (historical): Pulmonary hypertension was defined as mean pulmonary artery pressure (mPAP) ≥ 25 mmHg at rest, measured by right heart catheterization (RHC). This threshold was arbitrary and chosen to avoid overdiagnosis in mild disease.
• The 25 mmHg cutoff was used in clinical guidelines from 2009 and 2015 ESC/ERS editions.

1.2 Current Hemodynamic Definition (2018 WSPH / 2022 ESC-ERS)

PH = mPAP > 20 mmHg at rest, measured by right heart catheterization (RHC)

1.3 Normal Pulmonary Circulation Values

1.4 Complete Hemodynamic Definitions (2022 ESC/ERS + 2018 WSPH)

EXAM PEARL: Previous definition ≥25 mmHg changed to >20 mmHg. This "gray zone" of mPAP 21-24 mmHg with PVR 2-3 WU is clinically relevant but has NO approved therapies as of 2022.

Harrison vs ESC Note: Harrison's 22E uses PVR >2.0 WU for precapillary PH. Some sources (Murray & Nadel, older WSPH) use ≥3 WU. The 2022 ESC/ERS guidelines adopted >2 WU to align with the lower mPAP threshold.

1.5 Key Changes from Previous Guidelines

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SECTION 2: EPIDEMIOLOGY

2.1 Global Prevalence and Incidence

• PH is not rare - may be as common as multiple sclerosis and more than twice as common as IPF (Murray & Nadel)
• Overall PH prevalence: 99.8 to 127.3 per 100,000 population (Canadian universal health care data, 2002-2012)
• PAH specifically (Group 1): estimated prevalence 15-50 per million persons - the rarest form
• Group 2 (Left heart disease) is the most common form of PH in community-based studies
• ~20% of PH cases are PAH; majority are Group 2 (LHD) or Group 3 (lung disease)

2.2 Age and Sex Distribution

• PH affects individuals of all ages and races
• Women more commonly affected than men - especially in PAH
• IPAH: female predominance with female:male ratio ~2-4:1
• CTD-associated PAH: predominantly female (reflects CTD demographics)
• CTEPH (Group 4): more equal sex distribution
• Age at diagnosis of IPAH: median ~50 years (registry data); older patients more often have Group 2 PH
• Trend: increasing age at diagnosis as HFpEF and sleep apnea-related PH become more prevalent

2.3 Major Etiologies

India-specific: Mitral stenosis from rheumatic heart disease remains a common cause of Group 2 PH. Sickle cell disease-associated PH occurs in 6-10% of patients. Schistosomiasis is a globally significant cause.

2.4 Prognosis and Survival

• Without treatment: median survival in IPAH historically ~2.8 years from diagnosis
• With modern combination therapy: 1-year survival ~82%, 3-year ~67%, 5-year ~58% (Harrison's 22E)
• CTD-PAH (especially SSc): prognosis worse than IPAH; SSc-PAH accounts for 30% of SSc deaths
• CTEPH: best prognosis if amenable to pulmonary endarterectomy (PEA), which can be curative

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SECTION 3: ETIOLOGY - WHO CLINICAL CLASSIFICATION

3.1 WHO/WSPH Group Classification (6th WSPH 2018 / 2022 ESC-ERS)

GROUP 1 - PULMONARY ARTERIAL HYPERTENSION (PAH)
1.1 Idiopathic PAH (IPAH)
   1.1.1 Non-responders at vasoreactivity testing
   1.1.2 Acute responders at vasoreactivity testing (long-term CCB responders)
1.2 Heritable PAH
   - BMPR2 mutations (most common)
   - ALK1, ENG (endoglin), SMAD9, CAV1, KCNK3
   - EIF2AK4 (PVOD/PCH associated)
   - TBX4 (pediatric PAH)
1.3 Drug/toxin-induced PAH
   - Definite: aminorex, fenfluramine, dexfenfluramine, toxic rapeseed oil,
     dasatinib, benfluorex
   - Likely: amphetamines, interferon alpha/beta, alkylating agents
   - Possible: cocaine, phenylpropanolamine, SSRIs (neonatal PH)
1.4 Associated PAH (APAH)
   1.4.1 Connective tissue diseases (SSc, SLE, MCTD, RA, Sjogren's)
   1.4.2 HIV infection
   1.4.3 Portal hypertension / portopulmonary hypertension
   1.4.4 Congenital heart disease (ASD, VSD, PDA, AVSD - Eisenmenger)
   1.4.5 Schistosomiasis
1.5 PAH with long-term response to calcium channel blockers (NEW in 6th WSPH)
1.6 PAH with overt venous/capillary involvement (PVOD/PCH)
1.7 Persistent pulmonary hypertension of the newborn (PPHN)

GROUP 2 - PH DUE TO LEFT HEART DISEASE
2.1 Heart failure with preserved EF (HFpEF) [most common cause of Group 2]
2.2 Heart failure with reduced EF (HFrEF)
2.3 Valvular heart disease (mitral stenosis, mitral regurgitation, aortic stenosis)
2.4 Congenital/acquired cardiovascular conditions causing post-capillary PH
   - Congenital pulmonary veins stenosis
   - Cor triatriatum

GROUP 3 - PH DUE TO LUNG DISEASES AND/OR HYPOXIA
3.1 Obstructive lung disease (COPD)
3.2 Restrictive lung disease (ILD, including UIP/IPF)
3.3 Mixed obstructive-restrictive pattern
3.4 Sleep-disordered breathing (OSA, OHS)
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung disorders

GROUP 4 - PH DUE TO PULMONARY ARTERY OBSTRUCTIONS
4.1 Chronic thromboembolic PH (CTEPH) [most common in Group 4]
4.2 Other pulmonary artery obstructions:
   - Angiosarcoma, other intravascular tumors
   - Arteritis without connective tissue disease
   - Congenital pulmonary artery stenosis
   - Parasites (hydatid cyst)

GROUP 5 - PH WITH UNCLEAR AND/OR MULTIFACTORIAL MECHANISMS
5.1 Hematological disorders:
   - Chronic hemolytic anemia (sickle cell disease, thalassemia, hereditary spherocytosis)
   - Myeloproliferative neoplasms
   - Splenectomy
5.2 Systemic disorders:
   - Sarcoidosis (granulomatous vasculitis + lymph node compression)
   - Pulmonary histiocytosis (Langerhans cell)
   - Lymphangioleiomyomatosis (LAM)
   - Neurofibromatosis type 1
5.3 Metabolic disorders:
   - Glycogen storage diseases
   - Gaucher disease
   - Thyroid disorders (hypo/hyperthyroidism)
5.4 Complex congenital heart disease (post-surgical, segmental PH)
5.5 Others:
   - Fibrosing mediastinitis
   - Tumour emboli
   - Chronic renal failure with dialysis

3.2 Genetic Mutations in Heritable PAH

EXAM PEARL: BMPR2 mutations show incomplete penetrance - only 15-20% of carriers develop clinical PAH. Female sex increases penetrance. EIF2AK4 is the signature mutation for PVOD (pulmonary veno-occlusive disease) and PCH (pulmonary capillary hemangiomatosis).

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SECTION 4: PULMONARY CIRCULATION PHYSIOLOGY

4.1 Anatomy

• The pulmonary circulation receives the entire cardiac output from the right ventricle
• Pulmonary arteries: thin-walled, highly compliant, low-pressure system
• Pulmonary arteries branch in parallel with airways down to the level of terminal bronchioles
• Pulmonary arterioles (diameter 70-500 µm) are the primary site of vascular resistance
• Pulmonary capillary bed: enormous surface area (~70 m²); single-cell thickness for gas exchange
• Pulmonary veins drain into left atrium; four main veins (two from each lung)

4.2 Pulmonary Vascular Resistance

• mPAP = mean pulmonary artery pressure (mmHg)
• PAWP = pulmonary artery wedge pressure (mmHg) [reflects LVEDP]
• CO = cardiac output (L/min)

• Hypoxia (hypoxic pulmonary vasoconstriction - main defense against V/Q mismatch)
• Thromboembolism
• Vascular remodeling (smooth muscle hypertrophy, intimal proliferation)
• Acidosis, hypercapnia
• Inflammatory mediators

• Oxygen, NO, prostacyclin
• Sildenafil, bosentan
• Lung recruitment (positive pressure breathing can paradoxically increase PVR at high volumes)

4.3 Right Ventricular - Pulmonary Artery Coupling

• RV-PA coupling = ratio of RV contractility (Ees) to arterial elastance (Ea)
• Normal Ees/Ea ratio ≥ 1.5-2.0 (RV is an efficient pump at normal afterload)
• In PAH: progressive ↑ PVR → ↑ RV afterload → RV compensates by hypertrophy (adapted state)
• When Ees/Ea falls <0.8, the RV is uncoupled from the PA - maladaptive remodeling
• Uncoupling manifests as RV dilatation, decreased RV EF, systemic venous congestion
• TAPSE/sPAP ratio (echocardiographic surrogate of RV-PA coupling): >0.32 mm/mmHg = favorable; <0.19 mm/mmHg = high risk (2022 ESC/ERS risk stratification)

4.4 Pulmonary Vascular Compliance

• Reflects the capacitance (elastic recoil) of the pulmonary vasculature
• Reduced PVC is an early marker of pulmonary vascular disease
• Inversely related to PVR: as PVR rises, PVC falls
• Low PVC increases RV pulsatile load (additional to resistive load)
• PVC × PVR product is ~remarkably constant (~0.5 mL/mmHg × WU) across disease states

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SECTION 5: PATHOPHYSIOLOGY

5.1 Overview - Three Core Molecular Pathways Targeted by Therapy

NORMAL ENDOTHELIUM
       |
   INJURY/TRIGGER
  (genetic, immune, hypoxic, toxic)
       |
ENDOTHELIAL DYSFUNCTION
       |
  Three Imbalanced Pathways:
  
  [1] ↓ NO production/↑ PDE5    [2] ↓ Prostacyclin/↑ TXA2    [3] ↑ Endothelin-1
         (vasoconstriction)          (vasoconstriction +            (vasoconstriction +
                                      thrombosis)                    proliferation)
                                              |
                             PULMONARY VASCULAR REMODELING
                             (SMC proliferation, intimal fibrosis,
                              adventitial thickening, neomuscularization)
                                              |
                           PROGRESSIVE ↑ PVR → ↑ mPAP
                                              |
                              RV PRESSURE OVERLOAD
                                    /         \
                          ADAPTIVE (early)   MALADAPTIVE (late)
                         (RV hypertrophy)   (RV dilatation, failure)

5.2 Nitric Oxide (NO) Pathway

• Endothelial NO synthase (eNOS) produces NO from L-arginine
• NO activates soluble guanylate cyclase (sGC) → ↑ cGMP → smooth muscle relaxation + anti-proliferative
• In PAH:
  • ↓ eNOS expression/activity
  • ↑ PDE5 activity (breaks down cGMP)
  • ↑ Asymmetric dimethylarginine (ADMA) - endogenous NOS inhibitor
  • Net result: ↓ cGMP → vasoconstriction + SMC proliferation

• PDE-5 inhibitors (sildenafil, tadalafil): ↑ cGMP by blocking its degradation
• sGC stimulators (riociguat): directly stimulate sGC, even in low/absent NO states

5.3 Prostacyclin Pathway

• Prostacyclin (PGI₂) produced by endothelial cells from arachidonic acid via cyclooxygenase
• Activates adenylate cyclase → ↑ cAMP → smooth muscle relaxation + vasodilation
• Also: anti-aggregatory (↓ platelet aggregation), anti-proliferative
• Thromboxane A₂ (TXA₂) is the opposing vasoconstrictor + pro-aggregatory
• In PAH:
  • ↓ prostacyclin synthase expression (↓ PGI₂)
  • ↑ TXA₂ production
  • Net: vasoconstriction + platelet activation + in situ thrombosis

• Prostacyclin analogues: epoprostenol (IV), treprostinil (IV/SC/inhaled/oral), iloprost (inhaled), beraprost (oral, Asia)
• IP receptor agonists: selexipag (oral, selective IP receptor)

5.4 Endothelin Pathway

• Endothelin-1 (ET-1): most potent endogenous vasoconstrictor produced by endothelial cells
• Acts via two receptors:
  • ET-A receptors (smooth muscle): mediate vasoconstriction + proliferation
  • ET-B receptors (endothelium): mediate vasodilation (via NO/PGI₂), clearance of ET-1
• In PAH:
  • ↑ ET-1 production by dysfunctional endothelium
  • ↑ ET-A:ET-B ratio on smooth muscle
  • Net: vasoconstriction + SMC proliferation + fibrosis

• Dual ERA (ET-A + ET-B blockade): bosentan, macitentan
• Selective ET-A antagonist: ambrisentan (theoretically preserves ET-B mediated vasodilation)

5.5 Vascular Remodeling

1. Intimal proliferation: myofibroblast/smooth muscle-like cell migration + fibrous intimal hyperplasia → narrowed lumen
2. Medial hypertrophy: smooth muscle cell (SMC) hypertrophy + hyperplasia → increased media thickness
3. Adventitial thickening: fibroblast proliferation + excess collagen deposition
4. Neomuscularization of normally non-muscular arterioles
5. Plexiform lesions (pathognomonic of PAH and CTEPH): disordered, angioproliferative lesions forming distal to obstructed arterioles

5.6 Plexiform Lesions

• Pathognomonic of advanced PAH (Group 1) and CTEPH
• Located at bifurcations of pulmonary arterioles
• Composed of: channels lined by disorganized endothelial cells, smooth muscle cells, myofibroblasts, and inflammatory cells
• Mechanism: endothelial cells become monoclonal and apoptosis-resistant ("pseudo-neoplastic" phenotype)
• BMPR2 dysfunction leads to unchecked cell proliferation
• Endothelial-Mesenchymal Transition (End-MT) contributes to fibrotic and plexigenic remodeling

Harrison's 22E: "Plexigenic and fibrotic remodeling of pulmonary arterioles impairs pulmonary arterial compliance and results in a progressive increase in total PVR."

5.7 In Situ Thrombosis

• Due to: ↓ prostacyclin, ↓ thrombomodulin, ↓ fibrinolysis, activated platelets, and vascular stasis
• Microthrombi in small pulmonary arterioles (distinct from macrovascular thromboemboli in CTEPH)
• Contributes to progressive vascular occlusion
• Historically justified anticoagulation in IPAH (now debated - see treatment section)

5.8 Inflammation

• Inflammatory cells (T cells, B cells, macrophages, mast cells) infiltrate pulmonary vascular adventitia
• Elevated IL-1, IL-6, TNF-α, CXCL12 in PAH
• Regulatory T-cell dysfunction: loss of immune tolerance allowing autoimmune vascular injury
• Relevant in CTD-PAH, HIV-PAH
• JAK2 overactivation in PAH - ruxolitinib (JAK2 inhibitor) is an emerging therapeutic

5.9 Right Ventricular Adaptation and Failure

• Concentric RV hypertrophy (↑ wall thickness, preserved cavity size)
• ↑ RV systolic pressure matches ↑ pulmonary load
• Normal/near-normal CO
• RV-PA coupling maintained (Ees/Ea ≥ 1.5)
• Metabolic shift: fatty acid oxidation to glycolysis (Warburg-like)

• RV dilatation (cavity enlargement, wall thinning - "volume overload pattern")
• ↑ RV wall stress → subendocardial ischemia (RV O₂ supply-demand mismatch)
• Septal flattening → D-shaped LV → ↓ LV preload → ↓ CO
• Tricuspid regurgitation (functional, due to annular dilatation)
• Elevated RAP → systemic venous hypertension, hepatic congestion, ascites, edema
• RV-PA uncoupling: TAPSE/sPAP < 0.19 mm/mmHg

↑ PVR → ↑ RV Afterload
           ↓
    RV Pressure Overload
           ↓
   RV Hypertrophy (adaptive)
           ↓
   RV Dilatation (maladaptive)
           ↓
Septal shift left → ↓ LV filling
           ↓
     ↓ Cardiac Output
           ↓
 Systemic hypoperfusion + venous congestion
           ↓
Multi-organ dysfunction (liver, kidneys)
           ↓
          DEATH

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SECTION 6: HEMODYNAMIC CLASSIFICATION

6.1 Complete Hemodynamic Classification Table

• DPG ≥7 mmHg suggests pre-capillary component in a post-capillary background
• Less affected by volume status compared to TPG (transpulmonary gradient)

• TPG >12 mmHg = raised; but affected by high flow states

EXAM PEARL: In a patient with heart failure, diuresis before RHC may artificially lower PAWP, making isolated post-capillary PH appear as pre-capillary PH ("Group 2 masquerading as Group 1"). Always assess clinical context and volume status.

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SECTION 7: WHO CLINICAL CLASSIFICATION - DETAILED

7.1 Group 1 - Pulmonary Arterial Hypertension

• mPAP >20 mmHg, PAWP ≤15 mmHg, PVR >2 WU (pre-capillary)
• Normal or reduced CO (in advanced disease)

• Medial hypertrophy, intimal proliferation, adventitial fibrosis
• Plexiform lesions (most advanced)
• Thrombotic lesions in small arterioles

• RHC: pre-capillary hemodynamics
• Echo: elevated RVSP, RV enlargement, D-shaped septum
• PFTs: mild restrictive pattern, low DLCO (especially PVOD/PCH)
• HRCT: normal parenchyma in IPAH; ground glass + septal lines in PVOD/PCH
• ANA, anti-Scl-70, anti-dsDNA (CTD screen)
• HIV, LFTs (portal hypertension screen)

7.2 Group 2 - PH Due to Left Heart Disease

• mPAP >20 mmHg, PAWP >15 mmHg (post-capillary)
• ↑ LVEDP

• Venous congestion, medial hypertrophy of small pulmonary veins
• In CpcPH: additional arteriolar remodeling

• Echo: LV systolic/diastolic dysfunction, valvular disease, LA enlargement
• Coronary angiography (if ischemic cardiomyopathy suspected)
• RHC: confirms elevated PAWP; rules out PAH

7.3 Group 3 - PH Due to Lung Disease/Hypoxia

• Usually mild PH (mPAP 25-35 mmHg); if mPAP >35 mmHg in COPD/ILD, suspect concomitant PAH or CTEPH

• PFTs: obstructive (COPD) or restrictive (ILD) pattern
• HRCT: emphysema, bronchiectasis, interstitial fibrosis
• ABG: hypoxemia, hypercapnia
• V/Q scan: patchy matched defects (vs. segmental mismatch in CTEPH)

7.4 Group 4 - CTEPH

• Pre-capillary PH
• Significant increase in PVR (often severe: >5-10 WU)
• May have severely impaired CO

• Organized intraluminal thrombus (not fresh clot - chronic, fibrotic)
• Intimal webs, pouches, bands in pulmonary arteries
• Microvascular disease in patent vessels (small vessel remodeling - secondary PH component)

• V/Q scan: BEST screening test - segmental perfusion defects without matched ventilation defects
• CT pulmonary angiography (CTPA): webs, pouches, mural thrombus, mosaic perfusion
• Digital subtraction angiography (DSA): gold standard for surgical planning
• RHC: pre-capillary hemodynamics with high PVR

7.5 Group 5 - Miscellaneous/Multifactorial

• Sarcoidosis: multiple mechanisms (granulomatous vasculitis, lymphadenopathy compression, hypoxia, LV dysfunction)
• Sickle cell disease: hemolysis (↓ NO via free Hb scavenging), thromboembolism, hypoxia; 6-10% prevalence in SCD
• Myeloproliferative disorders: ↑ viscosity, ↑ thrombotic risk
• Thyroid disease: both hypo and hyperthyroidism can cause PH

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SECTION 8: CLINICAL FEATURES

8.1 Symptoms (in order of progression)

• Raynaud's phenomenon, skin thickening, sicca symptoms → CTD-PAH
• Chronic cough, sputum → COPD/ILD-related PH (Group 3)
• History of DVT/PE → CTEPH (Group 4)
• Cirrhosis → portopulmonary PH

8.2 Physical Examination

• Loud P2 (pulmonic component of S2): most consistent sign of PH; heard best at left upper sternal border
• Right ventricular heave (left parasternal heave): sustained, palpable
• Murmur of tricuspid regurgitation: holosystolic at LLSB; ↑ with inspiration (Carvallo's sign)
• Pulmonic regurgitation murmur (Graham Steell murmur): early diastolic at LUSB
• Right-sided S3/S4: gallop rhythm

• Elevated JVP with prominent a and v waves
• Hepatomegaly (pulsatile if TR present)
• Ascites (in advanced disease)
• Peripheral edema (dependent, bilateral)
• Cyanosis: due to ↓ CO, right-to-left shunting through PFO
• Clubbing: suggests congenital heart disease (Eisenmenger) or pulmonary venocclusive disease

• Telangiectasias, sclerodactyly → SSc-PAH
• Oral ulcers, malar rash → SLE-PAH
• Spider angiomas, splenomegaly → portopulmonary PH
• Kyphoscoliosis → Group 3 PH

8.3 WHO Functional Classification

EXAM PEARL: WHO FC is a key prognostic variable AND determines initial therapy intensity. FC III-IV at presentation → initiate triple combination therapy including parenterals (per 2022 ESC/ERS).

8.4 Red Flag Features (Rapid Referral Triggers per 2022 ESC/ERS)

• Rapid progression of symptoms
• Severely reduced exercise capacity (6MWD <165 m)
• Pre-syncope or syncope on mild exertion
• Signs of right heart failure (edema, ascites)
• mPAP >50 mmHg on echo estimate
• CT evidence of RV dilation + septal bowing

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SECTION 9: DIAGNOSTIC APPROACH

9.1 Stepwise Diagnostic Algorithm (2022 ESC/ERS Three-Step Approach)

STEP 1: SUSPICION (Primary Care / General Physician)
Clinical evaluation:
- Unexplained exertional dyspnea
- Known associated condition (CTD, CHD, portal HTN, HIV, PE history)
- Risk factors for PAH or CTEPH

Initial tests:
- ECG, O₂ saturation (pulse oximetry)
- CXR
- Basic blood work (CBC, LFTs, TFTs, ANA)

↓

STEP 2: DETECTION (Echocardiography + Further Testing)
Echocardiogram - KEY SCREENING TOOL:
- TRV > 2.8 m/s → LOW probability PH
- TRV 2.9-3.4 m/s + other signs → INTERMEDIATE probability
- TRV > 3.4 m/s OR TRV 2.9-3.4 + other signs → HIGH probability

Supporting tests:
- PFTs + DLCO
- ABG
- HRCT chest
- V/Q scan
- Sleep study if suspected OSA

↓

STEP 3: CONFIRMATION (PH Center - Specialist)
Right Heart Catheterization (RHC) - GOLD STANDARD
- Confirms hemodynamic diagnosis
- Rules in/out precapillary vs postcapillary PH
- Vasoreactivity testing if indicated

Additional:
- CTPA (CTEPH)
- Pulmonary angiography (surgical planning)
- Cardiac MRI
- Genetic testing (BMPR2 etc.)
- Connective tissue disease work-up
- HIV, hepatitis serology
- BNP/NT-proBNP (baseline + monitoring)

9.2 ECG Findings

ECG has poor sensitivity for early PH but suggests severity in established disease. Normal ECG does not exclude PH.

9.3 Chest X-Ray Findings

9.4 Echocardiography

• A (right ventricle): RVOT AcT <105 ms, mid-systolic notching
• B (pulmonary artery): Estimated PA systolic pressure >35 mmHg, PAWP >15 mmHg (IVRT-based)
• C (right heart): RA area >18 cm², RA/LA ratio >1, RV/LV ratio >1.0, IVC dilation >21 mm (no inspiratory collapse)
• Pericardial effusion (reflects severe PH + right heart failure)

• TAPSE (tricuspid annular plane systolic excursion): <18 mm = RV dysfunction
• S' wave (TDI at TV annulus): <9.5 cm/s = RV dysfunction
• FAC (fractional area change): <35% = RV systolic dysfunction
• TAPSE/sPAP ratio <0.19 mm/mmHg = high risk (RV-PA uncoupling)

9.5 Pulmonary Function Tests

• Spirometry: usually normal in IPAH; obstructive in COPD, restrictive in ILD
• DLCO (diffusing capacity): most important PFT in PAH
  • Mild reduction (60-80% predicted) common in IPAH
  • Severely reduced DLCO (<40-50%) → suspect CTD-PAH, PVOD/PCH, or ILD
  • Low DLCO in SSc even without ILD → suggests PAH
• Lung volumes: mild restrictive pattern can occur in PAH without parenchymal disease
• Serial PFTs (every 3-6 months) indicated in high-risk SSc patients for ILD monitoring

9.6 HRCT Chest

PVOD/PCH on HRCT: bilateral ground glass + septal lines + mediastinal lymphadenopathy + pleural effusions. These patients develop severe pulmonary edema with vasodilators - must not be given prostanoids/ERAs aggressively.

9.7 CT Pulmonary Angiography (CTPA)

• Webs, bands, pouches, complete occlusions
• Mosaic perfusion pattern
• Bronchial artery collaterals
• Sensitivity ~70%, specificity ~90% for CTEPH
• Digital subtraction angiography (DSA) = gold standard for surgical planning

9.8 V/Q Scan

KEY: V/Q scan is PREFERRED over CTPA for CTEPH screening (higher sensitivity for segmental perfusion defects). 2022 ESC/ERS: V/Q scan should be done in ALL patients with unexplained PH to exclude CTEPH.

9.9 Cardiac MRI

• Gold standard for RV volumes and function
• Can detect pericardial effusion, myocardial fibrosis (LGE)
• Not widely available; used in specialist centers
• MRI-derived RVEF, RVESVI, SVI are key prognostic markers (2022 ESC/ERS risk stratification):
  • RVEF >54% → low risk
  • RVEF 37-54% → intermediate risk
  • RVEF <37% → high risk

9.10 Right Heart Catheterization (RHC)

• Right atrial pressure (RAP)
• Right ventricular pressure (RVP - systolic and diastolic)
• Pulmonary artery pressure (PAP - systolic, diastolic, mean)
• Pulmonary artery wedge pressure (PAWP) - reflects LVEDP
• Cardiac output (CO) by thermodilution or Fick method
• Pulmonary vascular resistance (PVR = [mPAP-PAWP]/CO)
• Mixed venous O₂ saturation (SvO₂)
• Cardiac index (CI)
• Stroke volume index (SVI)

9.11 Vasoreactivity Testing

• Inhaled nitric oxide (NO) 10-20 ppm - preferred
• Inhaled epoprostenol (iloprost)
• IV adenosine (5% NaOH NOT used anymore)
• NOT oral/IV CCBs for testing - too unpredictable

• ↓ mPAP by ≥10 mmHg
• Absolute mPAP ≤40 mmHg
• Without decrease in cardiac output

• Only <5% of IPAH patients are vasoreactive
• Vasoreactive patients → long-term CCBs (nifedipine, diltiazem, amlodipine) → excellent prognosis
• Diltiazem preferred if heart rate is high; nifedipine or amlodipine if heart rate normal/low
• If CCBs fail after 3-6 months → re-evaluate, consider PAH-specific therapy

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SECTION 10: BIOMARKERS AND BLOOD INVESTIGATIONS

10.1 Key Blood Tests

10.2 Biomarkers

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SECTION 11: RISK STRATIFICATION

11.1 ESC/ERS 2022 Risk Model

• Low risk: majority of variables in low-risk column
• Intermediate-low (IL): 3 low + 1 high = IL, or ≥3 low + others intermediate
• Intermediate-high (IH): 2+ high-risk variables, majority intermediate/high
• High risk: majority high-risk, especially CI <2.0, RAP >14, FC IV

2022 ESC/ERS Update: Introduced Intermediate-Low (IL) and Intermediate-High (IH) sub-categories for better treatment stratification at follow-up.

11.2 REVEAL Registry Score (U.S.-Based Validation Tool)

• ≤6: Low risk (estimated 1-year survival >95%)
• 7: Average risk (~91%)
• 8: Moderately high (~77%)
• ≥9: High risk (<65%)

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SECTION 12: TREATMENT - GENERAL MEASURES AND SUPPORTIVE THERAPY

12.1 General Measures

• Exercise rehabilitation is recommended (supervised exercise training in stable patients)
• Avoid strenuous exercise to exhaustion (risk of syncope/sudden death)
• Cardiac rehabilitation - Class I recommendation in 2022 ESC/ERS

• Avoid high-altitude areas (>1500-2000 m) without supplemental O₂
• In-flight supplemental O₂ during air travel if resting SpO₂ <92% or during exertion

• Pneumococcal and influenza vaccinations recommended
• COVID-19 vaccination (no data suggesting increased PH risk from vaccines)

12.2 Oxygen

• Indication: Maintain SpO₂ >92% at rest (>95% optimal)
• Group 3 (COPD, ILD): long-term O₂ therapy (LTOT) per standard criteria (PaO₂ <55 mmHg)
• Group 1 PAH: O₂ indicated for hypoxemia to prevent secondary vasoconstriction
• Nocturnal O₂: especially important in sleep-disordered breathing-related PH

12.3 Diuretics

• Indication: Volume overload, RV failure (peripheral edema, ascites, hepatic congestion)
• Agents: Loop diuretics (furosemide, torasemide); aldosterone antagonists (spironolactone)
• Avoid over-diuresis - reduces RV preload → ↓ CO (RV is preload-dependent)
• Monitor electrolytes (hypokalemia, hyponatremia)

12.4 Digoxin

• Limited role in PAH
• May be used for rate control in atrial fibrillation/flutter (common arrhythmias in advanced PH)
• Historical use: modest improvement in RV contractility and CO (short-term data only)
• No survival benefit demonstrated

12.5 Anticoagulation

2022 ESC/ERS Update: Anticoagulation in IPAH downgraded - now "may be considered" (Class IIb) rather than recommended. DOACs not validated in PAH.

12.6 Iron Supplementation

• Iron deficiency (with or without anemia) is common in PAH (seen in ~40%)
• Iron deficiency independently worsens exercise capacity and prognosis
• IV iron supplementation improves 6MWD and quality of life in iron-deficient PAH patients
• Oral iron often poorly absorbed - IV preferred

12.7 Pregnancy

• Pregnancy is CONTRAINDICATED in PAH - maternal mortality ~30-50% historically
• Risk from: 30-50% increase in CO during pregnancy, systemic vasodilation, delivery-related hemodynamic shifts, postpartum RV failure
• 2022 ESC/ERS: Pregnancy is strongly discouraged (Class III - Harm)
• Effective contraception essential: progesterone-only pill, IUD, or sterilization
• Avoid: estrogen-containing OCP (↑ VTE risk, pulmonary vasoconstriction)
• If pregnancy occurs: multidisciplinary care at expert center; IV epoprostenol + mode of delivery discussion

---

SECTION 13: PAH-SPECIFIC PHARMACOTHERAPY

13.1 Overview of Approved Drug Classes

THREE THERAPEUTIC PATHWAYS:

1. ENDOTHELIN PATHWAY          2. NO-cGMP PATHWAY           3. PROSTACYCLIN PATHWAY
   (↓ vasoconstriction,            (↑ vasodilation)              (↑ vasodilation,
    ↓ proliferation)                                              ↓ platelet aggregation)
         ↓                                ↓                              ↓
ENDOTHELIN RECEPTOR         PDE-5 INHIBITORS         PROSTACYCLIN ANALOGUES
ANTAGONISTS (ERAs):         + sGC STIMULATORS        + IP RECEPTOR AGONISTS
Bosentan, Ambrisentan,                                
Macitentan               Sildenafil, Tadalafil       Epoprostenol (IV)
                         + Riociguat                 Treprostinil (IV/SC/inh/oral)
                                                     Iloprost (inhaled)
                                                     Beraprost (oral, Asia)
                                                     Selexipag (oral IP agonist)

13.2 Endothelin Receptor Antagonists (ERAs)

• Peripheral edema (ET-B blockade → fluid retention)
• Hepatotoxicity (monitor LFTs monthly - especially bosentan)
• Teratogenicity (Category X - mandatory contraception)
• Drug interactions: CYP3A4 inducers/inhibitors (especially bosentan - induces CYP3A4 reducing cyclosporine, warfarin, statin levels)
• Anemia (macitentan - dose-dependent)

13.3 PDE-5 Inhibitors

13.4 Soluble Guanylate Cyclase (sGC) Stimulator

1. PAH (Group 1) - PATENT-1: ↑ 6MWD +30 m
2. CTEPH (inoperable or persistent post-PEA) - CHEST-1: ↑ 6MWD +46 m
3. NOT approved for Group 2 (left heart disease) - DILATE-1/LEPHT showed harm (↓ BP, no benefit)

13.5 Prostacyclin Analogues

EXAM PEARL: Epoprostenol (IV continuous) is the ONLY PAH drug with proven mortality benefit in an RCT (Barst RJ, 1996 NEJM). It remains the treatment of choice for WHO FC IV patients and acutely decompensated PAH.

• Jaw pain (on eating), flushing, headache, nausea, diarrhea, skin flushing
• Leg pain (treprostinil SC)
• Risk of line sepsis and pump failure with IV routes (potentially fatal)

13.6 IP Receptor Agonist (Prostacyclin Receptor Agonist)

• Oral administration
• Selective IP receptor (avoids EP3-mediated side effects)
• Longer half-life than prostanoids

13.7 Calcium Channel Blockers (CCBs)

13.8 Treatment Algorithm (2022 ESC/ERS - Initial Therapy)

NEWLY DIAGNOSED PAH
         |
    VASOREACTIVITY TEST?
    (IPAH/Heritable only)
         |                              |
    POSITIVE (<5%)                 NEGATIVE (>95%)
         |                              |
  Long-term CCB              Assess WHO FC + Comorbidities
         |                              |
  Re-assess at 3-6 months      LOW/INT RISK          HIGH RISK
  If inadequate → switch        (FC I-III)            (FC IV)
         |
  INITIAL COMBINATION THERAPY           TRIPLE COMBINATION
  (Oral dual combination):              including IV Prostanoid:
  ERA + PDE5i                           ERA + PDE5i + Epoprostenol IV
  (e.g., Macitentan + Tadalafil)        (or Treprostinil IV/SC)
         |
  FOLLOW-UP REASSESSMENT AT 3-6 MONTHS
  Risk stratification (3-strata model)
         |
  ACHIEVED LOW RISK?     NOT ACHIEVED LOW RISK?
         |                         |
    Continue                SEQUENTIAL COMBINATION
                            Add third drug
                            (e.g., add Selexipag to ERA+PDE5i)
                                   |
                            STILL NOT AT LOW RISK?
                                   |
                           LUNG TRANSPLANTATION
                           (refer early; bridge with IV prostanoid)

2022 ESC/ERS Key Change: Initial ORAL COMBINATION THERAPY (Era + PDE5i or sGC) is now preferred over monotherapy for most treatment-naive patients. This is a significant upgrade from previous "sequential add-on" approach.

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SECTION 14: MANAGEMENT BY WHO GROUP

14.1 Group 1 PAH - Treatment Priorities

1. Establish diagnosis via RHC at PH center
2. Vasoreactivity testing (IPAH/heritable only)
3. Risk stratification (low/intermediate/high)
4. Initial combination oral therapy (ERA + PDE5i) for most patients
5. High-risk/FC IV: IV epoprostenol as first-line or add-on
6. Reassess at 3-6 months; escalate if not at low risk
7. Lung transplantation listing for non-responders (bilateral lung or heart-lung)

• Screen annually with echo in all SSc patients
• Anti-centromere antibody positivity → higher PAH risk
• Respond less well to therapy than IPAH
• SSc-PAH accounts for 30% of SSc deaths (Harrison's 22E)

• PVR must be <5 WU and mPAP <50 mmHg before liver transplantation (transplantation contraindicated with severe PH)
• Treat with ERA, PDE5i; IV prostanoids as bridge to transplantation
• Avoid β-blockers (used for portal hypertension) - worsen RV function

• PAH-specific therapy (bosentan - BREATHE-5 trial: improved 6MWD and hemodynamics)
• Lung transplantation + cardiac repair OR heart-lung transplantation
• Avoid pulmonary vasodilators that reduce systemic resistance without reducing PVR (risk of worsening right-to-left shunt)

14.2 Group 2 PH (Left Heart Disease) - Treatment Priorities

1. Optimize treatment of underlying LHD (diuretics, ACEi/ARB, β-blockers, valve surgery)
2. NO PAH-specific therapy for isolated post-capillary PH
3. CpcPH with high PVR: PAH drugs may be considered in specialized centers only (riociguat contraindicated per LEPHT)
4. Mitral valve repair/replacement for mitral stenosis → may resolve PH
5. Left heart assist devices (LVAD) for end-stage HFrEF may lower PAP

CRITICAL EXAM POINT: PAH-specific drugs are NOT indicated for Group 2 PH. Sildenafil and riociguat showed harm (increased hospitalizations, no benefit) in HFpEF-related PH trials.

14.3 Group 3 PH (Lung Disease/Hypoxia) - Treatment Priorities

1. Optimize management of underlying lung disease (bronchodilators, ICS for COPD; antifibrotics for IPF)
2. Long-term oxygen therapy (PaO₂ <55 mmHg or SaO₂ <88%)
3. Inhaled treprostinil (TYVASO): INCREASE trial (2021) showed benefit in ILD-PAH (IPF + PH): ↑ 6MWD +21 m at 16 weeks, ↓ clinical worsening
4. No routine PAH therapy for mild-moderate Group 3 PH
5. Severe "out-of-proportion" Group 3 PH (mPAP >35-40 mmHg despite advanced lung disease): refer to specialized center; consider PAH therapy
6. Lung transplantation for advanced disease

Harrison's Caution: Systemic vasodilators in Group 3 PH can worsen V/Q mismatch by increasing blood flow to poorly ventilated areas → worsening hypoxemia.

14.4 Group 4 - CTEPH - Treatment Priorities

CTEPH CONFIRMED (RHC + CTPA + V/Q Scan)
              |
    MULTIDISCIPLINARY EXPERT TEAM ASSESSMENT
    (technical operability + patient fitness)
              |
     OPERABLE          INOPERABLE or      RESIDUAL PH AFTER PEA
         |             PATIENT REFUSES           |
    PULMONARY               |              REASSESS AT 6 MONTHS
  ENDARTERECTOMY     BALLOON PULMONARY           |
   (PEA) - CURATIVE   ANGIOPLASTY (BPA)    If persistent PH:
         |             + Riociguat         Riociguat (CHESS-1+)
     ANTICOAGULANT      (CHEST-1 trial)    or BPA
   (LIFELONG: LMWH
    or VKA or DOAC)

• Surgical removal of organized thrombus from main, lobar, and segmental pulmonary arteries
• Done via median sternotomy + cardiopulmonary bypass + deep hypothermic circulatory arrest
• Can be curative - normalizes PVR in 70-80% of cases
• Operative mortality: ~4-5% at expert centers
• Prognosis: 5-year survival >80% post-PEA

• Catheter-based intervention for inoperable or distal CTEPH
• Multiple sessions required (typically 4-6 sessions)
• Complications: reperfusion pulmonary edema, vessel injury, hemoptysis
• Riociguat + BPA combination increasingly used

• Approved for inoperable CTEPH or persistent/recurrent PH after PEA
• Improved 6MWD +46 m vs. placebo; improved PVR, WHO FC
• Class I recommendation for inoperable CTEPH (2022 ESC/ERS)

14.5 Group 5 - Miscellaneous

• Treat underlying condition (e.g., steroids for sarcoidosis, hydroxycarbamide for sickle cell)
• PAH-specific therapy may be considered on case-by-case basis
• No prospective RCT data for most Group 5 conditions
• Refer to expert PH center for individualized management

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SECTION 15: SPECIAL SITUATIONS

15.1 Pregnancy and Contraception

• Multidisciplinary team (cardiologist, obstetrician, anesthesiologist, intensivist)
• IV epoprostenol as primary therapy during pregnancy
• Elective cesarean section preferred (around 28-34 weeks depending on status)
• Highest risk: peripartum and early postpartum period (acute RV failure)

15.2 Connective Tissue Disease-Associated PAH

• Screen ALL SSc patients annually: Echo + DLCO
• DETECT algorithm: for limited SSc patients with DLCO <60% predicted → echo + RHC
• Respond less well to PAH therapy compared to IPAH
• Macitentan + tadalafil combination → SERAPHIN + PHIRST data applicable

• Immunosuppression (cyclophosphamide + glucocorticoids) may reduce PAP → treat inflammatory component
• PAH-specific therapy needed if vascular disease established
• Better prognosis than SSc-PAH

• Anti-U1-RNP antibodies
• Intermediate prognosis between IPAH and SSc-PAH

15.3 Portopulmonary Hypertension

• Definition: PAH in setting of portal hypertension (hepatic or non-hepatic)
• Prevalence: ~5-10% of patients with portal hypertension
• Mechanism: ↑ portal venous flow → ↑ pulmonary venous return → endothelial shear stress + humoral mediators (estrogens, gut-derived toxins)
• Liver transplantation CONTRAINDICATED if mPAP >50 mmHg or PVR >5 WU
• Treatment: ERA, PDE5i as first-line; IV prostanoids as bridge to transplant
• Avoid β-blockers (used for portal hypertension) - worsen RV function in significant PH

15.4 HIV-Associated PAH

• Prevalence: ~0.5% of HIV patients (higher than general population)
• Mechanism: HIV envelope protein gp120 → endothelial apoptosis; inflammatory cytokines
• Independent of CD4 count or viral load
• Treatment: HAART does not reverse established PAH
• PAH-specific therapy effective (similar to IPAH)
• Bosentan: interaction with antiretrovirals (CYP3A4)
• Prognosis: worse than IPAH; similar to CTD-PAH

15.5 CTEPH - Special Considerations

• 3-5% of acute PE patients develop CTEPH
• Underdiagnosed - median delay to diagnosis 14 months
• 2022 ESC/ERS: All acute PE patients should have structured follow-up at 3-6 months (TTE assessment)
• V/Q scan preferred over CTPA for CTEPH screening
• Anticoagulation: lifelong in all CTEPH patients regardless of PEA
• DOACs: widely used for anticoagulation in CTEPH (rivaroxaban, apixaban); less data than VKA but acceptable

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SECTION 16: COMPLICATIONS

16.1 Right Ventricular Failure

• Most common cause of death in PAH
• Features: ↑ JVP, hepatomegaly, ascites, peripheral edema, ↓ BP, poor peripheral perfusion
• Management of acute RV failure in PAH:
  • Optimize volume: cautious diuresis (avoid over-diuresis)
  • Optimize preload: small IV fluid challenge if underfilled
  • Vasopressors: norepinephrine (vasopressor of choice in cardiogenic shock with PH)
  • Avoid: tachycardia, hypotension, hypoxia, acidosis, hypercarbia (all worsen RV)
  • IV epoprostenol: initiate or escalate
  • Consider VA-ECMO as bridge to transplantation in refractory cases

16.2 Arrhythmias

• Supraventricular tachycardias (SVT, atrial flutter, AF): poorly tolerated in PH
• Loss of atrial "kick" → acute ↓ CO → hemodynamic collapse
• Management: urgent electrical cardioversion if hemodynamically unstable
• Rate control: digoxin or amiodarone (avoid β-blockers - worsen RV failure)
• Anticoagulation: balance between CTEPH protection and bleeding risk

16.3 Hemoptysis

• Occurs in advanced PAH, CTEPH, Eisenmenger syndrome, PVOD
• Mechanism: rupture of dilated bronchial artery collaterals, plexiform lesions
• Management: bronchial artery embolization; avoid anticoagulation escalation acutely

16.4 Syncope

• Exertional syncope = ominous sign → WHO FC IV
• Mechanism: inability to augment CO with exercise → cerebral hypoperfusion
• Requires immediate escalation of therapy + listing for transplantation

16.5 Sudden Cardiac Death

• Occurs in 5-10% of PAH patients
• Mechanism: arrhythmia (VT/VF from RV hypertrophy/ischemia), acute RV failure
• ICD: no evidence of benefit in PAH (unlike SCD prevention in HFrEF)

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SECTION 17: PROGNOSIS

17.1 Historical vs Modern Survival

17.2 Poor Prognostic Factors

• WHO FC IV at diagnosis
• 6MWD <165 m
• NT-proBNP >1400 ng/L or BNP >200 pg/mL
• RA area >26 cm²
• TAPSE/sPAP <0.19 mm/mmHg
• CI <2.0 L/min/m²
• SvO₂ <60%
• RVEF <37%
• Pericardial effusion (moderate-large)
• Syncope on exertion
• Rapid progression
• No response to vasoreactivity testing
• CTD-PAH (especially SSc) vs IPAH

17.3 Good Prognostic Factors

• Vasoreactivity positive → long-term CCB responder
• Low-risk profile on 2022 ESC/ERS stratification
• FC I-II, 6MWD >440 m, BNP <50 pg/mL
• Young age, IPAH (vs APAH)
• Achievement of low-risk status on follow-up

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SECTION 18: IMPORTANT TABLES

Table 1: Hemodynamic Definitions Summary

Table 2: WHO Classification Summary

Table 3: Drug Comparison for PAH

Table 4: CTEPH vs PAH - Key Differences

Table 5: Pre-Capillary vs Post-Capillary PH

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SECTION 19: FLOWCHARTS

Flowchart 1: Diagnostic Approach

CLINICAL SUSPICION
(Unexplained dyspnea, known associated condition)
                    ↓
          STEP 1: INITIAL EVALUATION
          - ECG, CXR, Pulse oximetry
          - BNP/NT-proBNP
          - CBC, LFTs, TFTs, ANA, anti-Scl-70
          - HIV, hepatitis serology
                    ↓
        STEP 2: ECHOCARDIOGRAM (Screening)
               ↓               ↓               ↓
         Low probability    Intermediate     High probability
         PH unlikely        probability      PH likely
                 ↓               ↓               ↓
          Consider other   PFTs + DLCO      Refer to PH center
          diagnoses        HRCT chest
                           V/Q scan                ↓
                           Sleep study      STEP 3: RHC (Gold Standard)
                                                    ↓
                    ┌───────────────────────────────────────────┐
                    │        HEMODYNAMIC CLASSIFICATION         │
                    ├──────────────┬──────────────┬────────────┤
                    │ Pre-capillary│ Post-capillary│  Combined  │
                    │ PAWP ≤15     │ PAWP >15      │  PAWP >15  │
                    │ PVR >2       │ PVR ≤2        │  PVR >2    │
                    ├──────────────┼──────────────┼────────────┤
                    │Groups 1,3,4,5│   Group 2,5   │  Group 2,5 │
                    └──────────────┴──────────────┴────────────┘
                    ↓
          FURTHER DIAGNOSTIC WORK-UP PER GROUP:
          Group 1 (PAH): V/Q, CTD screen, genetics
          Group 2: Echo, coronary angiography, LHD optimization
          Group 3: PFTs, HRCT, ABG
          Group 4 (CTEPH): V/Q, CTPA, DSA, operability assessment
          Group 5: Specific work-up per underlying condition

Flowchart 2: Pathophysiology of PAH

TRIGGER (Genetic predisposition: BMPR2 + environmental/immune trigger)
                                    ↓
                    ENDOTHELIAL DYSFUNCTION
                    ↙           ↓           ↘
           ↓ NO/PGI₂      ↑ Endothelin-1    Platelet activation
               ↓                 ↓                 ↓
        Vasoconstriction    Vasoconstriction    In situ thrombosis
        + proliferation     + proliferation
               ↓                 ↓                 ↓
              ___________________________________________
                                  ↓
                    PULMONARY VASCULAR REMODELING
                    (Intimal proliferation, medial hypertrophy,
                     adventitial fibrosis, plexiform lesions)
                                  ↓
                      PROGRESSIVE ↑ PVR + ↑ mPAP
                                  ↓
                     RV PRESSURE OVERLOAD
                         ↙                 ↘
              ADAPTIVE (early)         MALADAPTIVE (late)
           RV hypertrophy              RV dilatation
           ↑ RV systolic P             Septal D-shift
           Normal CO                  TR, ↓ CO
                                       Venous congestion
                                       Multi-organ failure → DEATH

Flowchart 3: Treatment Algorithm (2022 ESC/ERS)

NEWLY DIAGNOSED PAH (after RHC confirmation)
                    ↓
         GENERAL MEASURES + SUPPORTIVE CARE
         (O₂, diuretics, anticoagulation per indication,
          exercise rehabilitation, contraception, vaccinations)
                    ↓
         VASOREACTIVITY TESTING?
         (IPAH/Heritable PAH only)
              ↙                    ↘
         POSITIVE               NEGATIVE
        (<5%)                  (>95%)
            ↓                      ↓
      CALCIUM CHANNEL         RISK STRATIFICATION
      BLOCKERS (CCB)          (WHO FC + 6MWD + BNP + Echo + hemodynamics)
            ↓                        ↙               ↓              ↘
      Reassess 3-6 months       LOW RISK         INT RISK         HIGH RISK
      Adequate? → continue     (FC I-II)         (FC III)          (FC IV)
      Inadequate? → PAH therapy      ↓                ↓                 ↓
                           Oral combination    Oral combination    Triple combo:
                           ERA + PDE5i        ERA + PDE5i          ERA + PDE5i
                           (Macitentan +      or ERA + riociguat    + IV Epoprostenol
                            Tadalafil)         ± selexipag         or IV Treprostinil
                                  ↓                ↓                    ↓
                         REASSESS AT 3-6 MONTHS (Risk stratification)
                                        ↓
                             ACHIEVED LOW RISK? → Continue
                                        ↓
                                   NO → Escalate:
                                   Add third agent (selexipag)
                                   or switch prostanoid to IV
                                        ↓
                             STILL HIGH RISK?
                                        ↓
                                LUNG TRANSPLANT LISTING
                                (bilateral or heart-lung)

Flowchart 4: CTEPH Management

DOCUMENTED CTEPH (RHC + V/Q + CTPA)
                    ↓
         LIFELONG ANTICOAGULATION (all patients)
                    ↓
        MULTIDISCIPLINARY TEAM ASSESSMENT
        (Surgeons + Interventionalists + PH specialists)
              ↙                           ↘
         OPERABLE                    INOPERABLE
              ↓                      (distal disease, comorbidities)
    PULMONARY ENDARTERECTOMY                ↓
    (PEA) - Surgery of choice         RIOCIGUAT (Class I)
         ↓                              +/- BPA (multiple sessions)
    Reassess at 6 months                     ↓
    Persistent PH?                     Reassess response
         ↓                                   ↓
    → Riociguat                        Transplantation if refractory
    → BPA (for residual distal disease)

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SECTION 20: HIGH-YIELD EXAM PEARLS

20.1 Harrison's Key Points (22nd Edition)

1. mPAP >20 mmHg (not ≥25 mmHg) is the current threshold for PH diagnosis
2. Normal mPAP = 14 ± 3.3 mmHg; upper limit of normal = ~20 mmHg
3. RHC is the gold standard for PH diagnosis
4. BMPR2 mutations are found in ~75% familial PAH and ~25% sporadic IPAH; incomplete penetrance (15-20%)
5. Vasoreactivity testing in IPAH/heritable PAH only; positive = ↓mPAP ≥10 mmHg to ≤40 mmHg without ↓CO
6. Only <5% of IPAH are vasoreactive
7. Epoprostenol IV is the ONLY PAH drug proven to improve survival in a landmark RCT
8. Schistosomiasis affects >230 million globally; 5% develop PAH → one of the most common causes worldwide
9. SCD (sickle cell disease): PH in 6-10% of patients
10. CTEPH (Group 4): organized thrombus, not fresh PE; V/Q scan preferred screening tool
11. PEA (pulmonary endarterectomy) can be curative for CTEPH
12. PAH in SSc accounts for 30% of SSc deaths
13. Pregnancy is CONTRAINDICATED in PAH; maternal mortality ~30-50%
14. PAH-specific drugs NOT indicated in Group 2 (IpcPH); riociguat caused harm in HFpEF
15. Riociguat - ONLY PAH drug approved for both PAH and CTEPH
16. EIF2AK4 biallelic mutations are specific to PVOD/PCH

20.2 2022 ESC/ERS Guideline Updates vs Previous (2015)

20.3 Frequently Asked MD/DNB/DM Examination Questions

20.4 Clinical Pearls

1. "Loud P2" is the most consistent physical sign of PH - heard at left upper sternal border (not apex)
2. Pre-syncope or syncope on exertion = WHO FC IV = urgent treatment escalation/transplant referral
3. PVOD/PCH: suspect when DLCO severely reduced, HRCT shows GGO + septal lines + lymphadenopathy. Avoid standard PAH vasodilators - risk of fatal pulmonary edema
4. Portopulmonary PH: β-blockers used for portal hypertension management should be stopped if significant PH develops (worsen RV function)
5. Diltiazem preferred over nifedipine in vasoreactive patients with tachycardia (diltiazem slows HR)
6. V/Q BEFORE CTPA in all unexplained PH patients to exclude CTEPH
7. D-shaped interventricular septum on echo/CT = RV pressure overload (pushes septum into LV in systole)
8. TAPSE/sPAP ratio is the key RV-PA coupling parameter: <0.19 mm/mmHg = high risk (RV uncoupled from PA)
9. The "silent zone" of PH: RHC abnormal, echo inconclusive - always trust RHC over echo
10. Macitentan (SERAPHIN trial) was the first PAH trial to use morbidity AND mortality as primary endpoint (previously only 6MWD)

20.5 Mnemonics

• E - Endothelin receptor antagonists (bosentan, ambrisentan, macitentan)
• P - PDE-5 inhibitors (sildenafil, tadalafil)
• I - IP receptor agonist (selexipag)
• C - Calcium channel blockers (vasoreactive only)
• S - Soluble guanylate cyclase stimulators (riociguat)
• (+ Prostanoids: epoprostenol, treprostinil, iloprost)

• Drop in mPAP by ≥10 mmHg
• Absolute mPAP ≤40 mmHg
• NO decrease in cardiac output

• P - PAH (Group 1 - Pulmonary Arterial)
• A - Left hEArt disease (Group 2)
• L - Lung disease/hypoxia (Group 3)
• E - pulmonary artEry Emboli/CTEPH (Group 4)
• Mix - Miscellaneous (Group 5)

• S - Syncope on exertion, Severe RV failure signs
• P - Poor 6MWD (<165 m), Pericardial effusion
• E - Elevated BNP/NT-proBNP, Ejection fraction of RV <37%
• E - Elevated RAP >14, Elevated PVR
• D - Decreased CI (<2.0 L/min/m²), Decreased SvO₂ (<60%)

---

SUMMARY BOX: "TOP 20 EXAM-READY FACTS"

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PULMONARY HYPERTENSION

Comprehensive PG Notes — MD/DM/DNB Internal Medicine

---

1. DEFINITION

Current Hemodynamic Definition (2018 WSPH / 2022 ESC/ERS)

PH = mPAP > 20 mmHg at rest, measured by right heart catheterization (RHC)

Normal Values

Hemodynamic Definitions

Changes from Previous (2015) Guidelines

Gray zone: mPAP 21-24 mmHg with PVR 2-3 WU = meets new criteria but no approved therapies yet

---

2. EPIDEMIOLOGY

• Overall PH prevalence: 99-127 per 100,000 population
• Group 2 (LHD) = most common form (~80% of all PH)
• PAH (Group 1): prevalence 15-50 per million; rarest form
• IPAH comprises ~50% of PAH; CTD-PAH ~25%
• Women > Men (especially PAH); female:male ratio ~2-4:1
• PH may be as common as multiple sclerosis, twice as common as IPF

• 1-year: ~82% | 3-year: ~67% | 5-year: ~58%
• Pre-treatment era: median survival ~2.8 years from diagnosis

---

3. ETIOLOGY — WHO CLASSIFICATION (6th WSPH / 2022 ESC/ERS)

GROUP 1 - PULMONARY ARTERIAL HYPERTENSION (PAH)
  1.1 Idiopathic (IPAH)
      1.1.1 Non-vasoreactive
      1.1.2 Vasoreactive (long-term CCB responders) ← NEW subcategory
  1.2 Heritable (BMPR2, ALK1, ENG, SMAD9, CAV1, KCNK3, EIF2AK4, TBX4)
  1.3 Drug/toxin-induced (fenfluramine, dasatinib, amphetamines)
  1.4 Associated PAH:
      1.4.1 Connective tissue disease (SSc, SLE, MCTD)
      1.4.2 HIV
      1.4.3 Portal hypertension
      1.4.4 Congenital heart disease (Eisenmenger)
      1.4.5 Schistosomiasis
  1.5 CCB long-term responders (NEW separate category)
  1.6 PVOD / PCH (overt venous/capillary involvement)
  1.7 Persistent PH of the newborn (PPHN)

GROUP 2 - LEFT HEART DISEASE
  HFpEF (most common), HFrEF, Mitral/aortic valve disease

GROUP 3 - LUNG DISEASE / HYPOXIA
  COPD, IPF/ILD, OSA, alveolar hypoventilation, high altitude

GROUP 4 - PA OBSTRUCTIONS
  CTEPH (most common), angiosarcoma, arteritis, congenital PA stenosis

GROUP 5 - MISCELLANEOUS / MULTIFACTORIAL
  Sickle cell (6-10%), sarcoidosis, myeloproliferative, LAM, thyroid disease

Key Genetic Mutations

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4. PULMONARY CIRCULATION PHYSIOLOGY

• Ratio of RV contractility (Ees) to arterial elastance (Ea)
• Ees/Ea ≥1.5 = coupled (normal); <0.8 = uncoupled (maladaptive)
• Echo surrogate: TAPSE/sPAP >0.32 = low risk; <0.19 = high risk

---

5. PATHOPHYSIOLOGY

Three Core Pathways

ENDOTHELIAL DYSFUNCTION
        ↙              ↓               ↘
  ↓ NO / ↑ PDE5    ↑ Endothelin-1    ↓ PGI₂ / ↑ TXA₂
  (vasoconstriction  (vasoconstriction  (vasoconstriction
   + proliferation)   + proliferation)   + thrombosis)
        ↘              ↓               ↙
           PULMONARY VASCULAR REMODELING
     (medial hypertrophy, intimal fibrosis, plexiform lesions)
                        ↓
              ↑ PVR → ↑ mPAP → RV overload
                        ↓
        ┌───────────────────────────────┐
        │ ADAPTIVE          MALADAPTIVE │
        │ RV hypertrophy    RV dilatation│
        │ Normal CO         ↓ CO, TR     │
        │                  Organ failure │
        └───────────────────────────────┘

↑ PVR → RV hypertrophy → RV dilatation → D-shaped septum
→ ↓ LV filling → ↓ CO → venous congestion → death

---

6. WHO FUNCTIONAL CLASS

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7. CLINICAL FEATURES

Symptoms (by progression)

• Early: Exertional dyspnea (most common first symptom), fatigue
• Intermediate: Chest pain (RV ischemia), pre-syncope on exertion
• Late: Exertional syncope (= FC IV, ominous), orthopnea, edema, ascites, hemoptysis

Physical Signs

Red Flag Features (immediate referral)

• Syncope on mild exertion
• Rapid symptom progression
• 6MWD <165 m
• Signs of right heart failure
• Estimated mPAP >50 mmHg on echo

---

8. DIAGNOSTIC APPROACH

Three-Step Algorithm (2022 ESC/ERS)

STEP 1 — SUSPICION (GP/Physician)
↓
ECG + CXR + O₂ saturation + basic bloods
↓
STEP 2 — DETECTION (Echocardiogram)
↓
TRV ≤2.8 m/s → Low probability
TRV 2.9-3.4 m/s ± signs → Intermediate
TRV >3.4 m/s OR 2.9-3.4 + signs → High
+ PFTs, HRCT, V/Q scan, sleep study
↓
STEP 3 — CONFIRMATION (PH Center)
Right Heart Catheterization (GOLD STANDARD)
+ vasoreactivity testing if indicated

Investigation Findings

V/Q BEFORE CTPA in all unexplained PH - higher sensitivity for CTEPH

Vasoreactivity Testing

• Who: IPAH and heritable PAH only (NOT CTD-PAH, CTEPH, APAH)
• Agent: Inhaled NO (10-20 ppm) or inhaled epoprostenol (preferred)
• Positive (Sitbon criteria): ↓mPAP ≥10 mmHg → absolute ≤40 mmHg, no ↓CO
• Significance: <5% are positive → eligible for long-term CCBs

Blood Investigations

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9. RISK STRATIFICATION (2022 ESC/ERS)

Four-Strata Model

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10. TREATMENT

General Measures

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11. PAH-SPECIFIC PHARMACOTHERAPY

Drug Classes Summary

Critical Contraindications

• PDE5i + riociguat = ABSOLUTELY CONTRAINDICATED (synergistic hypotension)
• CCBs in non-vasoreactive patients = risk of acute RV failure/death
• PAH-specific drugs in Group 2 IpcPH = no benefit; riociguat caused harm in HFpEF trials
• ERAs in pregnancy = teratogenic (Category X)

Treatment Algorithm

NEW PAH DIAGNOSIS (confirmed by RHC)
            ↓
VASOREACTIVITY TEST? (IPAH/Heritable only)
    ↙ POSITIVE             ↘ NEGATIVE
  (<5%)                      (>95%)
      ↓                           ↓
Long-term CCB            RISK STRATIFICATION
      ↓                    ↙          ↓          ↘
Reassess 3-6 m       LOW/INT       INT-HIGH      HIGH/FC IV
Adequate→continue    RISK          RISK          RISK
Inadequate→switch        ↓              ↓             ↓
                   Oral dual     Oral dual      Triple combo:
                 combination  combination +   ERA + PDE5i +
                 ERA + PDE5i  consider add-on  IV Epoprostenol
                 (Macitentan    (Selexipag)
                 + Tadalafil)
                             ↓
            REASSESS AT 3-6 MONTHS
                    ↓              ↓
           ACHIEVED LOW RISK    NOT ACHIEVED
           → Continue           → Escalate / Add 3rd agent
                                → Lung transplant listing

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12. MANAGEMENT BY WHO GROUP

Group 1 (PAH)

• Confirm by RHC → vasoreactivity test (IPAH/heritable) → risk stratify → combination oral therapy
• FC IV / high risk: IV epoprostenol first-line
• SSc-PAH: annual screening; worse prognosis than IPAH
• Congenital/Eisenmenger: bosentan (BREATHE-5); avoid systemic vasodilators that drop SVR without ↓PVR
• Portopulmonary: stop β-blockers if PH significant; mPAP >50 or PVR >5 WU = contraindication to liver transplant

Group 2 (Left Heart Disease)

• Optimize underlying LHD (diuretics, ACEi, β-blocker, valve surgery)
• NO PAH-specific drugs for isolated post-capillary PH
• Mitral valve surgery may resolve PH

Group 3 (Lung Disease/Hypoxia)

• Optimize lung disease + supplemental O₂
• Inhaled treprostinil: approved for ILD-associated PH (INCREASE trial: ↑6MWD +21 m)
• Avoid systemic vasodilators → worsen V/Q mismatch → worsening hypoxemia
• Severe "out-of-proportion" PH: refer to specialist center

Group 4 (CTEPH)

CTEPH CONFIRMED
      ↓
LIFELONG ANTICOAGULATION (all patients)
      ↓
MULTIDISCIPLINARY ASSESSMENT
    ↙                     ↘
OPERABLE               INOPERABLE
    ↓                       ↓
PULMONARY               RIOCIGUAT (Class I)
ENDARTERECTOMY          + BPA (multiple sessions)
(PEA) — curative
70-80% normalize PVR
Op mortality ~4-5%
    ↓
Residual PH at 6 months?
→ Riociguat + BPA

Group 5 (Miscellaneous)

• Treat underlying condition; PAH therapy case-by-case; no RCT data

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13. SPECIAL SITUATIONS

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14. COMPLICATIONS

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15. PROGNOSIS

• S — Syncope on exertion, Signs of RV failure
• P — Poor 6MWD (<165 m), Pericardial effusion
• E — Elevated BNP (>200), RVEF <37%
• E — Elevated RAP >14 mmHg, Elevated PVR
• D — Decreased CI (<2.0 L/min/m²), Decreased SvO₂ (<60%)

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16. HIGH-YIELD EXAM PEARLS

Must-Know Facts

1. PH threshold changed from ≥25 to >20 mmHg in 2022; normal mPAP = 14 ± 3.3 mmHg
2. BMPR2 — 75% familial PAH; incomplete penetrance 15-20%
3. EIF2AK4 — specific to PVOD/PCH; biallelic, autosomal recessive
4. Vasoreactive = <5% of IPAH; criteria: ↓mPAP ≥10 mmHg → absolute ≤40 mmHg, no ↓CO
5. Epoprostenol IV = only PAH drug with RCT mortality benefit
6. Riociguat = only drug approved for both PAH AND CTEPH
7. V/Q scan preferred over CTPA for CTEPH screening (sensitivity ~97%)
8. PEA = curative in 70-80% of operable CTEPH
9. Pregnancy = CONTRAINDICATED in PAH (maternal mortality 30-50%)
10. PAH drugs in Group 2 IpcPH = NO; riociguat caused harm in HFpEF trials
11. PDE5i + riociguat = ABSOLUTELY CONTRAINDICATED
12. Schistosomiasis — 5% of >230 million infected develop PAH (major global cause)
13. SSc-PAH = 30% of SSc deaths; screen ALL SSc annually
14. CTEPH: lifelong anticoagulation in ALL patients regardless of PEA
15. TAPSE/sPAP <0.19 mm/mmHg = RV-PA uncoupling = high risk
16. Portopulmonary PH: mPAP >50 or PVR >5 WU = contraindication to liver transplant
17. Initial 2022 ESC/ERS therapy = oral combination (ERA + PDE5i) not monotherapy
18. Inhaled treprostinil approved for ILD-associated PH (Group 3; INCREASE trial)
19. D-shaped septum on echo = RV pressure overload pushing into LV in systole
20. PVOD/PCH: severely reduced DLCO + GGO on HRCT + risk of fatal edema with vasodilators

Common Viva Questions

Mnemonics

• ERA (bosentan, ambrisentan, macitentan)
• PDE5i (sildenafil, tadalafil)
• IP receptor agonist (selexipag)
• CCB (vasoreactive only)
• SGC stimulator (riociguat)
• Prostanoids (epoprostenol, treprostinil, iloprost)

• PAH (Group 1)
• Aleft heart disease (Group 2)
• Lung disease (Group 3)
• Embolic/CTEPH (Group 4)
• Miscellaneous (Group 5)

• Drop ≥10 mmHg, absolute ≤40 mmHg, CO does not drop

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SUMMARY TABLE: Pre-Capillary vs Post-Capillary PH

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MANAGEMENT BY WHO GROUP — DETAILED DRUG THERAPY

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GROUP 1 — PULMONARY ARTERIAL HYPERTENSION (PAH)

Treatment Goal

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Step 1 — Vasoreactivity Testing (IPAH/Heritable PAH only)

• Nifedipine ER: 30-240 mg/day (preferred if HR ≤100)
• Diltiazem: 240-720 mg/day (preferred if HR >100, slows rate)
• Amlodipine: 2.5-20 mg/day (good tolerability)
• Re-assess at 3-6 months; if inadequate response → switch to PAH-specific drugs
• Verapamil AVOIDED — negative inotropic effect worsens RV function

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Step 2 — Risk-Stratified Initial Therapy (2022 ESC/ERS)

A. Patients WITHOUT Cardiopulmonary Comorbidities

AMBITION trial: Ambrisentan 10 mg + Tadalafil 40 mg → 50% ↓ composite endpoint (death, lung transplant, hospitalization, disease worsening) vs. monotherapy. Benefit mainly from delay in first hospitalization. No increase in adverse events.

B. Patients WITH Cardiopulmonary Comorbidities (e.g., obesity, OSA, HFpEF features)

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Step 3 — Sequential Escalation at Follow-Up (3-6 months)

REASSESS AT 3-6 MONTHS POST-INITIATION
(WHO FC + 6MWD + BNP/NT-proBNP + Echo + Hemodynamics)
                    ↓
         ACHIEVED LOW RISK?
         ↙                   ↘
        YES                   NO
     Continue               ESCALATE:
     same regimen           Add 3rd agent
                                  ↓
                     If on ERA + PDE5i:
                     Add SELEXIPAG (1600 µg BD max)
                     or switch to IV PROSTANOID
                                  ↓
                     If already on triple oral:
                     Switch to IV/SC prostanoid
                     (Epoprostenol IV preferred)
                                  ↓
                     STILL HIGH RISK?
                     → LUNG TRANSPLANT LISTING
                     (Bilateral or heart-lung)

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Detailed Drug-by-Drug Pharmacology

PROSTANOIDS

SELECTIVE IP RECEPTOR AGONIST

Harrison's 22E: Selexipag was studied in WHO FC II-III patients on background ERA or PDE5i or both. Active metabolite has prolonged half-life vs prostanoid analogues → twice-daily dosing practical.

ENDOTHELIN RECEPTOR ANTAGONISTS (ERAs)

SERAPHIN key message: Macitentan 10 mg OD → HR 0.55 (45% risk reduction) for combined death or disease progression. Significant benefit even on background therapy. Now preferred ERA in combination regimens.

• Teratogenic — mandatory contraception (Category X)
• Peripheral edema (ET-B blockade → fluid retention)
• Hepatotoxicity (bosentan > macitentan ≈ ambrisentan)
• Drug interactions via CYP3A4 induction (bosentan most significant — reduces levels of cyclosporine, warfarin, statins, sildenafil)

PDE-5 INHIBITORS

sGC STIMULATOR

• PDE-5 inhibitors (ABSOLUTE)
• Pregnancy
• Severe hepatic impairment
• NOT for Group 2 PH (LEPHT/DILATE trials showed harm — ↑ adverse events, no benefit)

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NOVEL AGENT — SOTATERCEPT (Harrison's 22E)

Exam Pearl: Sotatercept represents the 4th therapeutic pathway in PAH — the activin/BMP axis. It is the first drug with a completely novel mechanism approved in PAH in over a decade. Approved by FDA in 2024.

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Summary: Approved PAH Drug Classes and Pathways

PATHWAY 1 - ENDOTHELIN            PATHWAY 2 - NO/cGMP
Bosentan    (ERA, Dual)            Sildenafil  (PDE5i)
Ambrisentan (ERA, ET-A select.)    Tadalafil   (PDE5i)
Macitentan  (ERA, Dual, tissue)    Riociguat   (sGC stimulator)*

PATHWAY 3 - PROSTACYCLIN/cAMP     PATHWAY 4 - ACTIVIN/BMP (NEW)
Epoprostenol (IV prostanoid)       Sotatercept (Activin inhibitor)
Treprostinil (IV/SC/inh/oral)
Iloprost     (Inhaled)
Selexipag    (IP receptor agonist)

*Riociguat also approved for CTEPH (inoperable/post-PEA)
CCBs: Vasoreactive patients ONLY (<5% IPAH)

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GROUP 2 — LEFT HEART DISEASE (PH)

Principle: Treat the underlying left heart disease. PAH-specific drugs are not indicated.

• Pulmonary vasodilators → ↓ PA pressure WITHOUT reducing elevated PAWP
• Net result: fluid redistribution → alveolar flooding → acute pulmonary edema
• Riociguat trials (LEPHT, DILATE-1): ↑ adverse events, no benefit, potential harm in HFpEF
• Sildenafil (RELAX trial in HFpEF): no improvement in 6MWD or outcomes

Harrison's 22E: HFpEF-PH — "The focus of care should be to optimize contemporary treatment of HFpEF including SGLT-2 therapy, mineralocorticoid therapy, diuretics, and encouraging regular exercise to promote weight loss and conditioning."

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GROUP 3 — PH DUE TO LUNG DISEASE / HYPOXIA

Principle: Treat the underlying lung disease. Targeted PAH therapy only in selected severe cases.

Warning: Systemic vasodilators in Group 3 can worsen V/Q mismatch by increasing blood flow to poorly ventilated lung regions → worsening hypoxemia. This is why inhaled route (treprostinil, iloprost) is preferred — delivers drug preferentially to ventilated lung units.

• Refer to specialist PH centre
• Exclude concomitant PAH or CTEPH
• Careful trial of PAH therapy with monitoring
• Lung transplantation for advanced refractory disease

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GROUP 4 — CTEPH (Chronic Thromboembolic PH)

Principle: Multimodal — Surgery + Interventions + Drugs

• Warfarin (VKA): historically preferred; target INR 2-3
• DOACs (rivaroxaban, apixaban): increasingly used; validated in VTE; less data specific to CTEPH but acceptable

CTEPH CONFIRMED (RHC + V/Q + CTPA/DSA)
              ↓
MULTIDISCIPLINARY TEAM (Expert CTEPH Centre)
    ↙                           ↘
OPERABLE                    INOPERABLE or REFUSES
(proximal disease,          (distal/microvascular disease,
technically accessible)      high surgical risk)
    ↓                               ↓
PULMONARY                    RIOCIGUAT 2.5 mg TDS
ENDARTERECTOMY (PEA)         (Class I Recommendation)
• Median sternotomy + CPB         +
• Deep hypothermic arrest    BALLOON PULMONARY
• Curative in 70-80%         ANGIOPLASTY (BPA)
• Op mortality ~4-5%         (4-6 sessions, wires/balloons)
• Normalises PVR in most         ↓
    ↓                    Combination: Riociguat + BPA
REASSESS at 6 MONTHS     increasingly standard of care
    ↓
RESIDUAL PH POST-PEA?
    ↓
→ Riociguat (CHEST-1)
→ BPA for distal residual disease
→ Macitentan (MERIT-1 trial): modest benefit

• 261 patients; inoperable CTEPH or persistent PH after PEA
• Riociguat 2.5 mg TDS: ↑ 6MWD +46 m vs -6 m placebo (p<0.001)
• ↓ PVR -226 dyn·sec·cm⁻⁵; improved WHO FC
• Class I, Level B recommendation

• Multiple sessions (typically 4-6), targeting 1-2 segments per session
• Complication: reperfusion pulmonary edema, haemoptysis, vessel injury
• Improvements: ↓ PVR, ↑ exercise capacity, improved RV function
• Now combined with riociguat for optimal results

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GROUP 5 — MISCELLANEOUS

No approved specific PAH therapy — manage underlying condition

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INVASIVE / PROCEDURAL OPTIONS (ALL GROUPS)

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COMBINATION THERAPY — EVIDENCE SUMMARY

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CONTRAINDICATIONS MATRIX

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MONITORING ON PAH THERAPY