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PULMONARY HYPERTENSION - COMPLETE NOTES

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SECTION 1: DEFINITION AND PATHOGENESIS

Definition and Normal Physiology of Pulmonary Hypertension

• Pulmonary hypertension (PH) occurs when the pressures in the pulmonary circulation exceed a specific threshold.
• This is analogous to systemic hypertension, where pressure in systemic vessels (aorta and branches) is above a threshold (systolic > 140, diastolic > 90).
• The pulmonary circulation is normally a low-pressure circulation.
  • In normal conditions:
    1. Systolic pulmonary artery pressure is typically 15-20 mmHg.
    2. Diastolic pulmonary artery pressure is usually 5-8 mmHg.
    3. Mean pulmonary arterial pressure (mPAP) is normally 10-12 mmHg.
• A patient is labeled as having pulmonary hypertension if their mPAP is greater than 20 mmHg at rest.

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Pathogenesis of Pulmonary Hypertension: The Fundamental Formula

• The flow across a vessel depends on two main factors:
  • Delta pressure (AP): the pressure difference between the starting and ending points.
  • Resistance of the vessel.
• The relationship is expressed as: Flow = AP / Resistance
• Applying this formula to pulmonary circulation:
  • Flow in pulmonary circulation is equivalent to cardiac output (CO), as both the left and right sides of the heart have equal cardiac outputs.
  • Delta pressure (AP) is the pressure difference from the right ventricle (starting point) to the left atrium (ending point). This can be written as pulmonary arterial pressure (PAP) minus left atrial pressure (LAP).
  • Resistance is the pulmonary vascular resistance (PVR).
• Thus, the equation becomes: Cardiac Output = (Pulmonary Arterial Pressure - Left Atrial Pressure) / Pulmonary Vascular Resistance
• Rearranging this formula: PAP = (Cardiac Output x PVR) + Left Atrial Pressure
• This means if pulmonary artery pressure is rising, it must be due to an increase in one or more of these three components: cardiac output (CO), pulmonary vascular resistance (PVR), or left atrial pressure (LAP).

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Factors Contributing to Increased Pulmonary Arterial Pressure

• Resistance depends on the length and circumference of the vessel.
• Pulmonary vessels normally have extremely thin walls and a lumen free of obstruction.
• PVR can increase through three mechanisms:
  • Obliterative PH: Occurs when there is an increase in the thickness of the vessel wall. This decreases the circumferential area available for blood flow, thereby increasing PVR.
  • Obstructive PH: Occurs due to obstruction within the lumen of the pulmonary vessels. Examples include a thrombus, a tumor, or an infective body inside the lumen.
  • Vasoconstrictive (Constrictive) PH: Pulmonary vessels are extremely sensitive to hypoxia. When hypoxia occurs, the vessels vasoconstrict, increasing resistance and PVR.

• A rise in CO increases PAP. This happens in high-output states such as:
  • Left-to-right cardiac shunts (e.g., ASD, VSD, PDA)
  • Hyperthyroidism
  • Severe anemia

• Elevated LAP causes back-pressure into the pulmonary circulation, raising PAP.
• Causes include:
  • Left ventricular dysfunction (HFpEF, HFrEF)
  • Mitral or aortic valve disease
  • Left ventricular outflow obstruction

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Normal Pulmonary Circulation Anatomy

• The right ventricle ejects blood into the pulmonary arteries (main, right, and left branches).
• Blood passes through the pulmonary capillary bed for gas exchange.
• Oxygenated blood returns to the left atrium via pulmonary veins.
• The mean pulmonary arterial pressure (mPAP) is measured at the level of the pulmonary artery.

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Hemodynamic Definitions

• Pre-capillary PH: Occurs at pulmonary arteries. Definition: mPAP > 20 mmHg, High PVR, Normal PCWP (< 15 mmHg)
• Post-capillary PH: Occurs beyond capillaries. Definition: High mPAP, High PCWP (> 15 mmHg), Normal PVR (< 3 Wood units)
• Combined Pre- and Post-capillary PH: Increased PCWP and PVR

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SECTION 2: CLASSIFICATION OF PULMONARY HYPERTENSION

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Group 1: Pulmonary Arterial Hypertension (PAH)

• Definition: The primary problem is at the level of the pulmonary arteries, specifically the arterial walls, which become thickened. This leads to an increase in PVR. It is characterized as pre-capillary pulmonary hypertension.

1. Idiopathic PAH: The cause is unknown. Characterized by increased wall thickness of pulmonary vessels, increased PVR, and increased mPAP. Biopsies often show plexiform fibrosis, intimal fibrosis, and medial hypertrophy, leading to narrowed lumens. Can be categorized into responders and non-responders to vaso-reactivity testing.
2. Heritable PH: Caused by single gene mutations, most commonly in the Bone Morphogenetic Protein Receptor 2 (BMPR2) gene. Mutations lead to increased activity of transforming growth factor beta (TGF-beta), causing fibrosis. Other genes include SMAD, Endoglin, Activin receptor-like kinase. These patients are often young females with a family history.
3. Drugs and Toxins:
   • Dasatinib: A tyrosine kinase inhibitor used for CML
   • Amphetamines: Sympathomimetic drugs that cause vasoconstriction
   • Proteasome Inhibitors: Like bortezomib, used for multiple myeloma
   • Anti-Hepatitis C drugs
4. Connective Tissue Disease (CTD): Includes systemic sclerosis (most common), RA, myositis. Various pathways lead to pulmonary vascular involvement.
5. Porto-Pulmonary Hypertension: 1-10% incidence; not tied to cirrhosis severity; is a contraindication for liver transplant.
6. HIV: 1-5% of HIV cases; late manifestation; treated with ART.
7. Pulmonary Veno-Occlusive Disease (PVOD) / Pulmonary Capillary Hemangiomatosis (PCH): Genetic disease; obstruction in pulmonary capillaries; lung transplant is the treatment.
8. Congenital Heart Disease: Congenital heart disorders (ASD, VSD, PDA); causes increased pressure in pulmonary circulation (Eisenmenger syndrome).
9. Schistosomiasis: Tissue reaction in pulmonary arteries; 1-5% incidence; diagnosis via symptoms and eggs in stool/urine.

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Group 2: PH Associated with Left Heart Disease

• Left heart problem leads to increased back pressure and elevated left atrial pressure.
• Normal PVR initially; can evolve to combined pre- and post-capillary hypertension.
• Most common type of pulmonary hypertension.
• Causes:
  • HFpEF, HFrEF, HFmrEF
  • Mitral and aortic valve disease
  • Conditions affecting left ventricular function

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Group 3: PH Secondary to Lung Disease or Hypoxia

• Secondary to lung disease or hypoxia; vasoconstriction leads to increased PVR.
• Causes:
  • Obstructive lung disease: COPD, bronchiolitis
  • Restrictive/fibrotic lung disease: Interstitial Lung Diseases (ILDs)
  • Combined Pulmonary Fibrosis with Emphysema (CPF-E)
  • Hypoventilation: OHS (obesity hypoventilation syndrome), neuromuscular diseases
  • High-altitude hypoxia
  • Previously Group 5 sleep apnea, now moved to Group 3

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Group 4: PH Associated with Pulmonary Artery Obstruction

• Obstruction in pulmonary artery lumen; leads to increased PVR.
• Causes:
  • Chronic Thromboembolic PH (CTEPH): Developed from pulmonary thromboembolism (most important)
  • Tumors: Primary (angiosarcoma) or metastatic tumors
  • Vasculitis/Arteritis: Inflammation of arterial walls; Behcet's disease, Takayasu's arteritis
  • Hydatid cysts: Echinococcus cysts causing obstruction
  • Congenital stenosis of pulmonary artery

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Group 5: PH with Unclear/Multifactorial Mechanisms

• Unexplained PH; multifactorial issues.
• Causes:
  • Hematologic disorders: Myeloproliferative neoplasms, autoimmune hemolytic anemia
  • Systemic disorders: Sarcoidosis, Pulmonary Langerhans Cell Histiocytosis (PLCH)
  • Metabolic disorders: Neurofibromatosis, Gaucher's disease
  • Chronic kidney disease (CKD)

• Group 2 (PH associated with left heart disease) is the most common type of pulmonary hypertension.
• Group 3 (PH secondary to lung disease) is the second most common.
• Groups 1, 4, and 5 are relatively uncommon.

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SECTION 3: EVALUATION AND STRATIFICATION

Symptoms of Pulmonary Hypertension

• PH is most commonly a silent or slowly progressive disease.
• Initial symptoms:
  • Exertional dyspnea (most common presenting symptom)
  • Fatigue
  • Reduced exercise tolerance
• Later/Advanced symptoms (signs of right heart failure):
  • Exertional chest pain (angina-like, from RV ischemia)
  • Exertional syncope or near-syncope
  • Palpitations
  • Peripheral edema (leg swelling)
  • Abdominal distension (ascites)

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Physical Examination Findings

• Signs of RV enlargement and failure

• Loud P2 (pulmonary component of the second heart sound) - due to forceful closure of pulmonary valve
• Right ventricular heave (parasternal heave)
• Tricuspid regurgitation murmur (pansystolic at left lower sternal border)
• Pulmonary regurgitation murmur (Graham-Steell murmur)
• Jugular venous distension (JVD)
• S3 or S4 gallop (right-sided)

• Peripheral edema
• Hepatomegaly
• Ascites

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Initial Investigations

• Right axis deviation
• Right ventricular hypertrophy (tall R wave in V1, deep S wave in V5/V6)
• Right bundle branch block (RBBB)
• P pulmonale (tall peaked P waves in lead II)

• Enlargement of central pulmonary arteries
• Peripheral vascular pruning (loss of small peripheral vessels)
• Right ventricular enlargement (RV fills retrosternal space on lateral view)
• Loss of retrosternal space

• BNP (B-type natriuretic peptide) / NT-proBNP: Elevated in right heart failure; used for prognosis and monitoring
• Troponin: Elevated in severe disease with RV ischemia
• Uric acid: Elevated, marker of poor perfusion

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Echocardiography (2D Echo) - Key Screening Tool

• First-line non-invasive test for suspected PH
• Provides estimated RVSP (Right Ventricular Systolic Pressure) using TR jet velocity (modified Bernoulli equation: RVSP = 4v² + RAP)
• Echo findings suggesting PH:
  • Tricuspid regurgitation (TR) jet velocity > 2.8 m/s
  • Dilated right ventricle and right atrium
  • Flattening of interventricular septum ("D-sign" on parasternal short axis)
  • Reduced RV function (TAPSE < 17 mm)
  • Pericardial effusion (sign of severe disease)
  • RV:LV ratio > 1

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Right Heart Catheterization (RHC) - Gold Standard Diagnostic Test

• Required for definitive diagnosis of PH
• Performed via right internal jugular or femoral vein
• Direct measurement of:
  • mPAP (mean pulmonary artery pressure)
  • PCWP (pulmonary capillary wedge pressure)
  • Cardiac output (by thermodilution or Fick method)
  • PVR calculation: PVR = (mPAP - PCWP) / CO

• mPAP > 20 mmHg = PH
• mPAP > 20 mmHg + PVR > 2 Wood units + PCWP < 15 mmHg = Pre-capillary PH
• mPAP > 20 mmHg + PCWP > 15 mmHg = Post-capillary PH

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Vaso-Reactivity Testing (Done During RHC)

• Performed in: Idiopathic PH, heritable PH, drug-induced PH only
• Agent used: Inhaled nitric oxide (iNO), inhaled iloprost, or IV adenosine
• Positive response criteria:
  • mPAP falls by ≥ 10 mmHg
  • Absolute value of mPAP drops to < 40 mmHg
  • No drop in cardiac output
• Significance: Positive response may lead to calcium channel blockers for long-term treatment

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Etiological Evaluation After PH Confirmation (Based on Group)

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Radiological Investigations

• Pulmonary Artery (PA) size > 3 cm (30 mm)
• Pulmonary artery to aorta ratio ≥ 1
• Right Ventricle (RV) to Left Ventricle (LV) ratio > 1
• Interventricular septum flattened or pushed towards the left ventricle
• Egg and Banana Sign (specific to Group 1 PH):
  1. Egg = dilated pulmonary artery trunk
  2. Banana = arch of the aorta
  3. Normally, the pulmonary trunk is not visible at the level of the aortic arch. In PH, the dilated pulmonary artery is pushed upwards, becoming visible at the same level as the aortic arch on CT

• Dilatation of the pulmonary bay (bulge at the left heart border representing the pulmonary artery)
• Prominence of the right descending pulmonary artery

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Other Investigations

• For Group 1 PH:
  1. Normal spirometry (airway resistance and lung compliance unchanged)
  2. Isolated low DLCO (diffusion capacity for carbon monoxide) due to increased wall thickness impairing gas diffusion
  3. This pattern (normal spirometry + isolated low DLCO) is suggestive of a pulmonary vascular problem and warrants 2D echocardiography
• For Group 3 PH: Spirometry varies depending on whether obstructive, restrictive, or mixed disease

• Assesses exercise capacity and identifies limiting factors
• Findings suggestive of PH:
  1. Low exercise capacity
  2. Low heart rate reserve (heart rate spikes quickly to maximum at low activity)
  3. Oxygen desaturation with exercise
  4. Low oxygen pulse (VO2/HR ratio) - indicator of stroke volume

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Risk Stratification of PH Patients

• Prognosis: Low risk = 1-year mortality < 5%; Intermediate = 5-20%; High = > 20%

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SECTION 4: TREATMENT OF PULMONARY HYPERTENSION

General Principles

• Treatment targets the underlying cause and the specific PH group.
• Group 1 (PAH) has the most targeted pharmacologic therapies.
• Groups 2 and 3 are primarily managed by treating the underlying condition.
• Group 4 (CTEPH) has specific interventional and pharmacologic options.

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Supportive/General Measures (All Groups)

• Oxygen supplementation: For hypoxic patients (SpO2 < 90% at rest). Especially important in Group 3.
• Diuretics: For right heart failure with fluid overload (edema, ascites).
• Anticoagulation: Historically used in Group 1 (idiopathic PAH), but evidence is weak and current guidelines do not strongly recommend routine use. Still used in Group 4 (CTEPH) - warfarin preferred.
• Digoxin: Occasionally used for rate control in atrial arrhythmias.
• Avoid: Pregnancy (high mortality risk), strenuous exercise, high altitude travel.
• Vaccinations: Influenza and pneumococcal vaccines recommended.

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Specific Drug Treatments for Group 1 PAH

1. Prostacyclin Pathway (Pro-vasodilation)

2. Nitric Oxide (NO) Pathway (Pro-vasodilation)

• Note: PDE5 inhibitors and guanylate cyclase stimulators CANNOT be used together (synergistic hypotension risk).

3. Endothelin Pathway (Pro-vasoconstriction - blocked)

• Key side effect of ERAs: Hepatotoxicity (monitor LFTs)
• Bosentan is teratogenic - monthly pregnancy tests required

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Newer Drug: Sotatercept

• Mechanism: Blocks the TGF-beta pathway. Mutations in BMPR2 gene lead to increased TGF-beta activity causing pulmonary fibrosis. Sotatercept inhibits this pathway.
• Trial: Evaluated in the STELLAR trial - effective in patients with pulmonary arterial hypertension.
• Administration: Subcutaneous injectable.
• Important Side Effects: Thrombocytopenia, epistaxis, dizziness.
• Status: Not yet FDA approved; not in common use. The other five drug classes are in common use.

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Treatment Algorithm for Group 1 PH

• Determine if it is Group 1 PH.
• If idiopathic, heritable, or drug-induced PH → perform vaso-reactivity testing.
  1. If vaso-reactivity testing positive → treat with calcium channel blockers (long-term). Only these three indications with positive testing are approved for CCBs.
  2. If vaso-reactivity testing negative (or patient does not have one of these three types) → treatment depends on initial risk stratification.

• Low to Intermediate Risk:
  1. Combination therapy
  2. Typically: ERA + PDE5 inhibitor (e.g., ambrisentan + tadalafil)
  3. The AMBITION trial supported this combination, showing lower hospitalization rates, improved 6-minute walk distance, and reduced mortality.
• High Risk:
  1. Triple therapy
  2. ERA + PDE5 inhibitor + prostacyclin analog (e.g., epoprostenol or treprostinil - IV or subcutaneous)

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Reassessment and Treatment Escalation

• After initiating management, patients are reassessed every 3 to 6 months.
• Reassessment parameters: 6-minute walk distance, BNP, WHO functional class.
• Risk categories at reassessment: Low / Intermediate-Low / Intermediate-High / High

• Ongoing reassessment every 3-6 months. If patient on triple therapy remains high risk → lung transplant is considered.

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Treatment of Group 2 PH (Left Heart Disease)

• Treat the underlying left heart condition.
• Optimize management of HFpEF, HFrEF, or valvular disease.
• PAH-specific drugs (ERAs, PDE5 inhibitors, prostacyclins) are NOT indicated and may be harmful.
• Exception: Riociguat has some evidence in post-capillary PH.

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Treatment of Group 3 PH (Lung Disease / Hypoxia)

• Treat the underlying lung disease (COPD, ILD, etc.).
• Oxygen therapy is the most important intervention - corrects hypoxia-driven vasoconstriction.
• Inhaled treprostinil (Tyvaso) has been approved specifically for PH associated with ILD.
• PAH-specific vasodilators are generally avoided (risk of worsening V/Q mismatch).

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Treatment of Group 4 PH - CTEPH

1. Anticoagulation (warfarin) - lifelong, to prevent further thrombus
2. Surgical: Pulmonary Endarterectomy (PEA) - treatment of choice for accessible proximal disease; can be curative
3. Balloon Pulmonary Angioplasty (BPA) - for patients not eligible for surgery (inoperable CTEPH)
4. Riociguat (Adempas) - only PAH drug specifically approved for CTEPH; improves exercise capacity and PVR
5. Macitentan - also has evidence in inoperable CTEPH

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Calcium Channel Blockers in PAH

• Only used when vaso-reactivity test is positive
• Indications: Idiopathic PAH, heritable PAH, drug-induced PAH (with positive vaso-reactivity)
• Drugs used: Amlodipine, nifedipine, diltiazem
• Verapamil is avoided (negative inotropy harmful to RV)
• Must be reassessed at 3-6 months; if not at low risk, switch to combination therapy

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Lung Transplant

• Considered in end-stage disease
• Indications: High-risk patients refractory to maximal medical therapy (triple therapy)
• Types: Single lung transplant, bilateral lung transplant, or heart-lung transplant
• Porto-pulmonary hypertension is a contraindication for liver transplant (but patients may be considered for combined liver-lung transplant)

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