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python3 << 'EOF' import pdf2image import pytesseract import os base = '/home/da…

~/Pulmonary_Hypertension_Notes.txt

================================================================================
         PULMONARY HYPERTENSION - COMPLETE NOTES
         (Compiled from 4 Sources: Definition & Pathogenesis | Classification |
          Evaluation & Stratification | Treatment)
================================================================================


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PART 1: DEFINITION AND PATHOGENESIS
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1. DEFINITION
─────────────
- Pulmonary Hypertension (PH) = pressures in pulmonary circulation exceed a
  specific threshold (analogous to systemic hypertension).
- Normal pulmonary circulation is a LOW-PRESSURE system:
    • Systolic PAP:  15-20 mmHg
    • Diastolic PAP:  5-8 mmHg
    • Mean PAP (mPAP): 10-12 mmHg
- DIAGNOSIS of PH: mPAP > 20 mmHg at rest (measured by right heart
  catheterization).


2. FUNDAMENTAL HEMODYNAMIC FORMULA
────────────────────────────────────
  Flow = Delta Pressure (AP) / Resistance

  Applied to pulmonary circulation:
    - Flow          = Cardiac Output (CO)
    - Delta P (AP)  = PAP - Left Atrial Pressure (LAP)
    - Resistance    = Pulmonary Vascular Resistance (PVR)

  => CO = (PAP - LAP) / PVR

  Rearranged to solve for PAP:
  *** PAP = (CO x PVR) + LAP ***

  KEY IMPLICATION: Rising PAP must be due to increase in one or more of:
    1. Cardiac Output (CO)
    2. Pulmonary Vascular Resistance (PVR)
    3. Left Atrial Pressure (LAP)


3. FACTORS CAUSING INCREASED PAP
──────────────────────────────────

  A. INCREASE IN PULMONARY VASCULAR RESISTANCE (PVR)
     Resistance depends on length and circumference of vessel.
     Normal: thin walls, unobstructed lumen.

     Three mechanisms:
     (i) Obliterative PH
         - Increased vessel wall THICKNESS
         - Decreases circumferential area for blood flow
         - Examples: PAH-associated vascular remodeling

     (ii) Obstructive PH
         - Obstruction WITHIN the lumen
         - Examples: thrombus, tumor, infective body

     (iii) Vasoconstrictive (Constrictive) PH
         - Pulmonary vessels extremely sensitive to HYPOXIA
         - Hypoxia => vasoconstriction => reduced vessel diameter => increased PVR
         - Occurs with: lung disease, high altitude, hypoventilation disorders

  B. INCREASE IN LEFT ATRIAL PRESSURE (LAP)
     - Pulmonary veins drain directly into left ventricle/left atrium
     - Increased LAP (due to ineffective LV pumping) => blood stagnation in
       pulmonary circulation
     - Indicates: left heart failure OR mitral valve disease
     - This is POST-CAPILLARY PH (pressure backs up from left side)

  C. INCREASE IN CARDIAC OUTPUT (CO)
     - More blood through pulmonary circulation increases pressure
     - Physiological: exercise, anemia, pregnancy (usually accompanied by drop
       in PVR, so PH mild)
     - Pathological:
         • Left-to-right shunts: VSD, PDA, ASD (high CO without change in PVR)
           => Hyperkinetic pulmonary hypertension
         • Cirrhosis / Portal hypertension:
           - Increased NO causes vasodilation initially
           - Elevated CO and elevated PAP


4. IMPORTANT HEMODYNAMIC MEASUREMENTS
────────────────────────────────────────
  - PAP (Pulmonary Arterial Pressure): measured by right heart catheterization
  - PCWP (Pulmonary Capillary Wedge Pressure):
      • Measured by balloon catheterization in pulmonary capillaries
      • Approximates Left Atrial Pressure (LAP)
      • Normal PCWP: < 15 mmHg
  - PVR = (mPAP - PCWP) / Cardiac Output


5. SUBCLASSIFICATION BY HEMODYNAMICS
──────────────────────────────────────
  - Pre-capillary PH:
      • mPAP > 20 mmHg
      • PCWP ≤ 15 mmHg (normal)
      • Elevated PVR
      • Problem is BEFORE the capillaries (in pulmonary arteries)
      • Groups: 1, 3, 4, and some of 5

  - Post-capillary PH:
      • mPAP > 20 mmHg
      • PCWP > 15 mmHg (elevated -- reflects elevated LAP)
      • Normal PVR
      • Problem is AFTER the capillaries (left heart disease)
      • Group 2

  - Combined Pre- and Post-capillary PH:
      • mPAP > 20 mmHg
      • PCWP > 15 mmHg
      • PVR also elevated (both problems present)
      • Some Group 2 or Group 5 cases


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PART 2: CLASSIFICATION OF PULMONARY HYPERTENSION
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PH is classified into 5 GROUPS based on etiology and hemodynamic pattern:

────────────────────────────────────────────────────────────────────
GROUP 1: PULMONARY ARTERIAL HYPERTENSION (PAH)
────────────────────────────────────────────────────────────────────
- Hemodynamics: PRE-CAPILLARY (mPAP > 20, PCWP ≤ 15, elevated PVR)
- Problem: OBLITERATIVE -- vessel wall thickening/remodeling
- Causes:
    • Idiopathic PAH (no known cause)
    • Heritable PAH (BMPR2 gene mutation most common -- 80% of heritable cases)
    • Drug/toxin-induced:
        - Appetite suppressants (fenfluramine, aminorex)
        - Methamphetamine / amphetamines
        - Dasatinib (tyrosine kinase inhibitor)
    • Associated conditions (APAH):
        - Connective Tissue Diseases (CTD):
            * Systemic sclerosis (most common CTD cause of PAH)
            * SLE, MCTD, Sjogren's, RA
        - Congenital Heart Disease (CHD): left-to-right shunts (ASD, VSD, PDA)
            * Initially hyperkinetic PH
            * Chronically: Eisenmenger syndrome (reversed shunt, cyanosis)
        - HIV infection
        - Portal hypertension
        - Schistosomiasis (embeds in arterial wall -- Group 1, NOT Group 4)

- Note: In systemic sclerosis -- LIMITED type (lcSSc) more commonly causes
  Group 1 PAH; DIFFUSE type (dcSSc) more commonly causes ILD => Group 3.


────────────────────────────────────────────────────────────────────
GROUP 2: PH DUE TO LEFT HEART DISEASE
────────────────────────────────────────────────────────────────────
- Hemodynamics: POST-CAPILLARY (mPAP > 20, PCWP > 15, normal PVR)
- Problem: Increased LAP backs up into pulmonary circulation
- Causes:
    • Heart failure with reduced EF (HFrEF)
    • Heart failure with preserved EF (HFpEF) -- most common overall
    • Valvular heart disease: mitral stenosis, mitral regurgitation,
      aortic stenosis
    • Cardiomyopathies
- Treatment: address underlying left heart disease (NOT PH-specific drugs)


────────────────────────────────────────────────────────────────────
GROUP 3: PH DUE TO LUNG DISEASE AND/OR HYPOXIA
────────────────────────────────────────────────────────────────────
- Hemodynamics: PRE-CAPILLARY (mPAP > 20, PCWP ≤ 15, elevated PVR)
- Mechanism: VASOCONSTRICTIVE -- hypoxia causes pulmonary vasoconstriction
- Causes:
    • COPD (most common lung disease causing PH)
    • Interstitial Lung Disease (ILD):
        - All types including UIP/IPF, NSP, etc.
        - Systemic sclerosis with ILD (diffuse type)
    • Combined Pulmonary Fibrosis and Emphysema (CPFE)
    • Hypoventilation-Related:
        - Obesity Hypoventilation Syndrome (OHS)
        - Neuromuscular diseases
        - NOTE: Isolated OSA (without other disease) generally does NOT cause
          PH. If obese OSA patient has PH => investigate HFpEF or CTEPH
    • High Altitude exposure
    • Developmental disorders
    • Lymphangioleiomyomatosis (LAM) -- previously Group 5, now Group 3
- Severity note: Lung disease (ILD/COPD) usually causes MILD to MODERATE PH.
  If SEVERE PH in lung disease patient => investigate other groups (1, 4, 5).


────────────────────────────────────────────────────────────────────
GROUP 4: PH DUE TO PULMONARY ARTERY OBSTRUCTION
────────────────────────────────────────────────────────────────────
- Hemodynamics: PRE-CAPILLARY (mPAP > 20, PCWP ≤ 15, elevated PVR)
- Mechanism: OBSTRUCTIVE -- physical obstruction within pulmonary artery lumen
- Causes:
    • Chronic Thromboembolic PH (CTEPH): MOST COMMON
        - Chronic thromboembolism or in-situ thrombosis
        - 3-5% of acute PE patients develop CTEPH
        - All acute PE patients should be re-evaluated at 3-6 months
        - History of acute PE may be ABSENT in 30-40% of CTEPH patients
    • Tumors:
        - Primary: Angiosarcoma of pulmonary artery (most common)
        - Metastatic: From solid organs
    • Arteritis (non-CTD):
        - Behcet's disease
        - Takayasu's arteritis (can also cause pulmonary arterial aneurysms)
    • Hydatidosis:
        - Echinococcus cysts entering pulmonary circulation
        - Contrast with schistosomiasis (embeds in wall = Group 1)
    • Congenital stenosis of the pulmonary artery


────────────────────────────────────────────────────────────────────
GROUP 5: PH WITH UNCLEAR OR MULTIFACTORIAL MECHANISMS
────────────────────────────────────────────────────────────────────
- Hemodynamics: Variable -- pre-capillary, post-capillary, or combined
- Definition: Cannot be categorized into Groups 1-4, OR multifactorial
- Causes:
    • Hematologic disorders:
        - Chronic hemolytic anemia (e.g., sickle cell disease, thalassemia)
        - Myeloproliferative disorders
        - Splenectomy
    • Systemic and metabolic disorders:
        - Sarcoidosis
        - Pulmonary histiocytosis
        - Neurofibromatosis
        - Glycogen storage diseases
        - Gaucher's disease
        - Thyroid disorders (hypo- or hyperthyroidism)
    • Complex congenital heart disease
    • Chronic renal failure on dialysis

SUMMARY TABLE: Groups at a Glance
────────────────────────────────────
 Group | Main Mechanism    | mPAP  | PCWP  | PVR      | Key Example
 ──────┼───────────────────┼───────┼───────┼──────────┼─────────────────
   1   | Obliterative      |  ↑    | normal|  ↑       | Idiopathic PAH
   2   | Post-capillary    |  ↑    |  ↑    | normal   | HFpEF
   3   | Vasoconstrictive  |  ↑    | normal|  ↑       | COPD, ILD
   4   | Obstructive       |  ↑    | normal|  ↑       | CTEPH
   5   | Multifactorial    |  ↑    | varies| varies   | Sarcoidosis


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PART 3: EVALUATION AND RISK STRATIFICATION
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1. CLINICAL PRESENTATION
──────────────────────────

  Symptoms (non-specific, can mimic other diseases):
    • Exertional dyspnea (most common early symptom)
    • Exercise intolerance / fatigue
    • Exertional chest pain or syncope (late, ominous signs)
    • Palpitations
    • Disease-specific symptoms (based on underlying cause)

  Signs:
    • Evidence of right ventricular hypertrophy (RVH):
        - Parasternal heave at left sternum
        - Loud P2 (pulmonary component of S2)
        - Murmurs of pulmonary regurgitation (PR) in severe cases
        - Right-sided S4 (late, RVH)
        - Right-sided S3 (end stage, right heart failure)
        - Left shift of apex (due to RVH)
    • Signs of right heart failure (late stages):
        - Elevated JVP (jugular venous pressure)
        - Peripheral edema
        - Ascites
    • Disease-specific signs (e.g., skin changes in scleroderma)


2. SCREENING -- WHO IS SCREENED?
──────────────────────────────────
  Annual echocardiographic screening indicated for:
    • Patients with systemic sclerosis (ALL types)
    • Patients with portal hypertension (being evaluated for liver transplant)
    • Patients with known BMPR2 gene mutations
    • HIV patients
    • Patients with congenital heart disease


3. DIAGNOSTIC TESTS
─────────────────────

  A. ECHOCARDIOGRAPHY (ECHO) -- First-line investigation
     - Primarily measures SYSTOLIC PAP (sPAP) via tricuspid regurgitation
       velocity (TRV)
     - Formulas:
         sPAP = 4 x TRV² + Right Atrial Pressure
         mPAP = (0.6 x sPAP) + 2

     Probability of PH based on TRV:
     ┌──────────────────────┬───────────────────────────────┐
     │  TRV (m/s)           │  Probability                  │
     ├──────────────────────┼───────────────────────────────┤
     │  < 2.8               │  LOW probability              │
     │  2.8 - 3.4           │  INTERMEDIATE probability     │
     │  > 3.4               │  HIGH probability             │
     └──────────────────────┴───────────────────────────────┘

     sPAP-based probability:
     ┌──────────────────────┬───────────────────────────────┐
     │  sPAP (mmHg)         │  Probability                  │
     ├──────────────────────┼───────────────────────────────┤
     │  < 34                │  LOW                          │
     │  34 - 50             │  INTERMEDIATE                 │
     │  > 50                │  HIGH                         │
     └──────────────────────┴───────────────────────────────┘

     Other echo features used to adjust probability:
     - Ventricles: Flattening of interventricular septum (LVEI > 1.1 in
       systole and/or diastole)
     - Pulmonary artery & RA: Early diastolic pulmonary regurgitation
       velocity > 2.2 m/s
     - Inferior vena cava: Dilated IVC
     - RA: RA area at end-systole > 18 cm²

     Combining features:
       Low + other features      => Intermediate
       Intermediate + features   => High probability
       High probability          => proceed to RHC
       Intermediate              => follow up
       Low                       => evaluate other causes

     IMPORTANT: Echo is NOT gold standard; results can be falsely high or low.

  B. ELECTROCARDIOGRAM (ECG)
     - Reflects RVH and right heart failure
     - Early: Normal ECG
     - Late findings:
         • RVH features
         • Right ventricular strain or ischemia
         • Right axis deviation (Lead I negative, Leads II and III positive)
         • Right bundle branch block pattern
         • T-wave inversions in anterior leads (V1-V3) -- RV strain
         • ST segment depression in V1-V3 -- RV strain
         • Tachycardia
         • Atrial fibrillation (due to RA dilation)
     - Note: These findings are NOT specific to PH; can be seen in any RVH.

  C. RIGHT HEART CATHETERIZATION (RHC) -- GOLD STANDARD
     - Definitive diagnosis of PH
     - Procedure: Catheter via femoral vein -> IVC -> RA -> RV ->
       pulmonary arteries
     - Measurements:
         • Exact PAP (systolic, diastolic, mPAP)
         • PCWP (approximates LAP)
         • Cardiac output
         • PVR = (mPAP - PCWP) / Cardiac Output
     - Benefits:
         • Confirms PH diagnosis
         • Subclassifies: pre-capillary / post-capillary / combined
     - When done: when echo results ambiguous (intermediate or high probability
       but features don't match), OR when initiating treatment

  D. VASOREACTIVITY TESTING (During RHC)
     - Purpose: Similar to bronchodilator reversibility in spirometry
     - Drugs used: IV adenosine, IV epoprostenol, OR inhaled nitric oxide
     - Procedure: Measure PAP -> administer vasodilator -> re-measure PAP
     - POSITIVE response criteria (ALL three must be met):
         1. mPAP falls by ≥ 10 mmHg
         2. mPAP falls TO a value < 40 mmHg
         3. No drop in cardiac output
     - Significance: Positive responders may be prescribed CALCIUM CHANNEL
       BLOCKERS for long-term treatment (major clinical implication)
     - Indications for vasoreactivity testing:
         • Idiopathic PAH
         • Heritable PAH
         • Drug/toxin-induced PAH
         (NOT indicated for other groups or associated PAH)

  E. ADDITIONAL INVESTIGATIONS
     - Blood tests: CBC, LFTs, TFTs, ANA, anti-Scl-70, anti-dsDNA (for CTD
       screening), HIV serology, BMPR2 genetics, NT-proBNP/BNP
     - 6-Minute Walk Distance (6MWD): functional assessment
     - Pulmonary function tests (PFTs): to diagnose underlying lung disease
     - HRCT chest: ILD, emphysema, vascular changes
     - V/Q scan: preferred over CT-PA for CTEPH screening
     - Polysomnography: if OSA/OHS suspected
     - Liver function + portal hypertension workup (Doppler ultrasound)


4. RISK STRATIFICATION (Initial Assessment)
────────────────────────────────────────────
  Used to guide treatment intensity at diagnosis.
  Based on three main tools:

  THREE-STRATA CLASSIFICATION (Low / Intermediate / High risk):
  Used at INITIAL diagnosis, focusing on:

    Variable              | Low Risk        | High Risk
    ──────────────────────┼─────────────────┼───────────────
    Symptoms              | Mild (FC I-II)  | Severe (FC IV)
    6MWD                  | > 440 m         | < 165 m
    NT-proBNP             | < 300 ng/L      | > 1400 ng/L
    BNP                   | < 50 ng/L       | > 300 ng/L
    PCWP / mPAP           | Lower           | Higher
    Cardiac Index         | Maintained      | < 2.0 L/min/m²
    Mixed Venous O2 Sat   | ≥ 65%           | < 60%
    WHO Functional Class  | I-II            | IV
    Right atrial pressure | < 8 mmHg        | > 14 mmHg

  Risk also influenced by:
    - Presence/absence of syncope
    - Rapid vs slow disease progression
    - Echo RV function

  FOUR-STRATA CLASSIFICATION (Follow-up):
  Used at FOLLOW-UP and reassessment after treatment.
  Categories: Low / Intermediate-Low / Intermediate-High / High risk
  Variables used: WHO Functional Class + 6MWD + NT-proBNP
  Frequency: Every 3-6 months, adjust treatment based on results.

  SIMPLIFIED (for follow-up -- uses easily measured variables):
    - Low cardiac output = HIGH risk
    - Avoids complex invasive investigations at follow-up


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PART 4: TREATMENT OF PULMONARY HYPERTENSION
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1. GENERAL PRINCIPLES
───────────────────────
  - PH-SPECIFIC therapies are approved ONLY for GROUP 1 (PAH).
  - Groups 2, 3, and 5: Treatment = address UNDERLYING cause.
  - Group 4 (CTEPH): surgical/interventional treatment (see below).
  - Example: Systemic sclerosis with ILD (Group 3) => treat ILD, not PH.
             Systemic sclerosis without ILD but PAH (Group 1) => PH therapy.


2. THREE PATHWAYS TARGETED BY PH DRUGS
────────────────────────────────────────
  All PH drugs aim to REDUCE PVR by causing VASODILATION via three pathways:

  A. PROSTACYCLIN PATHWAY
     - Normal: Prostacyclin (PGI2, PGH2) causes vasodilation
     - Drugs:
       (i) Prostacyclin Analogs (directly replenish prostacyclin):
           • Epoprostenol: very short half-life; IV route ONLY
           • Iloprost: inhaled route
           • Treprostinil: IV, inhaled, OR subcutaneous routes

       (ii) Prostacyclin Receptor Agonists (PRAs):
            • Selexipag: acts via prostacyclin receptor (not prostacyclin itself)

  B. NITRIC OXIDE (NO) PATHWAY
     - Normal: NO activates guanylate cyclase => increases cGMP => vasodilation
     - cGMP is metabolized by PDE5 (phosphodiesterase 5)
     - Drugs:
       (i) PDE5 Inhibitors (prevent cGMP breakdown):
           • Sildenafil
           • Tadalafil

       (ii) Guanylate Cyclase Stimulators (directly stimulate NO pathway):
            • Riociguat
            (Note: Riociguat + PDE5 inhibitors CONTRAINDICATED together)

  C. ENDOTHELIN PATHWAY
     - Normal: Endothelins bind receptors => vasoconstriction
     - Drugs: Endothelin Receptor Antagonists (ERAs):
       (i) Non-selective (blocks both A and B endothelin receptors):
           • Bosentan -- HEPATOTOXICITY risk (monitor LFTs)
           • Macitentan

       (ii) Selective (A receptor only):
            • Ambrisentan


3. NOVEL DRUG: SOTATERCEPT
────────────────────────────
  - Mechanism: Blocks TGF-beta pathway; inhibits pulmonary fibrosis AND treats PH
  - Evaluated in the STELLAR trial (effective for PAH)
  - Administration: Subcutaneous injectable
  - Side effects: Thrombocytopenia, epistaxis, dizziness
  - FDA approval: Approved (as of 2024)


4. TREATMENT ALGORITHM FOR GROUP 1 PAH
────────────────────────────────────────

  STEP 1: Confirm Group 1 PH

  STEP 2: Vasoreactivity Testing (if idiopathic, heritable, or drug-induced PAH)
    - POSITIVE result => CALCIUM CHANNEL BLOCKERS (CCBs) as long-term treatment
         (e.g., nifedipine, diltiazem, amlodipine)
    - NEGATIVE result => proceed to risk stratification-guided therapy

  STEP 3: Risk Stratification
    Low to Intermediate Risk:
      => COMBINATION THERAPY as initial treatment
      => ERA + PDE5 inhibitor (most studied: Ambrisentan + Tadalafil)
      => Supported by AMBITION trial

    High Risk:
      => Triple combination therapy
      => Include IV prostacyclin (epoprostenol) + ERA + PDE5 inhibitor
      => Consider early referral for lung transplant evaluation

  STEP 4: Follow-up Reassessment (every 3-6 months, 4-strata model)
    - If not at low risk => escalate therapy
    - Add sotatercept if not responding to standard triple therapy


5. TREATMENT OF OTHER GROUPS
──────────────────────────────

  GROUP 2 (Left Heart Disease):
    - Treat underlying cause: optimize HF therapy (ACE inhibitors, beta-
      blockers, diuretics), valve repair/replacement
    - PH-specific drugs are NOT indicated and may be HARMFUL

  GROUP 3 (Lung Disease/Hypoxia):
    - Treat underlying lung disease (bronchodilators, steroids, antifibrotics)
    - Long-term oxygen therapy if hypoxemic
    - Treprostinil inhaled approved for ILD-associated PAH (Group 3.4)
    - Otherwise PH-specific drugs not routinely used

  GROUP 4 (CTEPH):
    - Surgical: Pulmonary Endarterectomy (PEA) -- DEFINITIVE treatment
        • Removes organized thrombus from pulmonary arteries
        • Potentially curative
    - Interventional: Balloon Pulmonary Angioplasty (BPA) -- for inoperable cases
    - Medical (inoperable or residual PH after PEA):
        • Riociguat (guanylate cyclase stimulator) -- APPROVED for CTEPH
        • Anticoagulation (lifelong)
    - NOTE: Riociguat is the only PH-specific drug approved for Group 4

  GROUP 5 (Multifactorial):
    - Address underlying condition
    - PH-specific drugs used on case-by-case basis


6. GENERAL/SUPPORTIVE MEASURES (ALL Groups)
─────────────────────────────────────────────
  - Diuretics: for fluid overload / right heart failure
  - Anticoagulation: especially CTEPH (Group 4); consider in Group 1
  - Oxygen supplementation: for hypoxemia
  - Digoxin: for RV failure or AF
  - Supervised exercise rehabilitation
  - Avoid: pregnancy (high maternal mortality), high altitude, strenuous
    activities, NSAIDs (worsen fluid retention)
  - Vaccinations: influenza, pneumococcal
  - Psychosocial support


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QUICK REVISION: HIGH-YIELD FACTS
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 1. PH definition:    mPAP > 20 mmHg (new 2022 ESC/ERS threshold, changed
                      from old >25 mmHg)
 2. Gold standard:    Right Heart Catheterization (RHC)
 3. First-line test:  Echocardiography
 4. Most common PH:   Group 2 (left heart disease, especially HFpEF)
 5. Most common PAH:  Idiopathic PAH (Group 1)
 6. BMPR2 mutation:   Heritable PAH -- 80% of familial cases
 7. CTD most PAH:     Systemic sclerosis (especially limited/lcSSc)
 8. OSA alone:        Does NOT cause PH (investigate HFpEF or CTEPH if found)
 9. Schistosomiasis:  Group 1 (embeds in wall); Hydatidosis: Group 4 (in lumen)
10. CTEPH: 3-5%       of acute PE patients; re-evaluate all PE at 3-6 months
11. Vasoreactivity:   Only for idiopathic/heritable/drug-induced Group 1 PAH
12. CCBs:             Only for vasoreactivity-POSITIVE patients
13. PDE5i + Riociguat: CONTRAINDICATED (both in NO pathway)
14. Riociguat:        Only PH drug approved for Group 4 (CTEPH)
15. Bosentan:         Hepatotoxic; monitor LFTs
16. AMBITION trial:   Ambrisentan + Tadalafil as initial combination for PAH
17. STELLAR trial:    Sotatercept evaluated for PAH
18. Epoprostenol:     IV only (shortest half-life)
19. Treprostinil:     Most versatile -- IV, subcutaneous, inhaled
20. Group 3 severity: Mild-moderate; if severe => suspect Group 1, 4, or 5
21. LAM:              Reclassified from Group 5 to Group 3
22. Sotatercept:      Blocks TGF-beta; subcutaneous; side effects: 
                      thrombocytopenia, epistaxis
23. PEA surgery:      Definitive treatment for operable CTEPH (Group 4)
24. Follow-up:        4-strata model (Low/Int-Low/Int-High/High); every 3-6 months

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End of Notes
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