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Pulmonary Hypertension

Chapter 294 | Part 6: Disorders of the Cardiovascular System · Part 6 – Cardiovascular Disorders · Chapter 294

Key Clinical Points

  1. Pulmonary hypertension (PH) is defined by mean pulmonary artery pressure (mPAP) >20 mmHg, pulmonary vascular resistance (PVR) >2.0 Wood units (WU), and pulmonary artery wedge pressure (PAWP) ≤15 mmHg for precapillary cases.
  2. Pulmonary arterial hypertension (PAH) is a distinct subset characterized by obliterative arteriopathy and high mortality if untreated.
  3. The BMPR2 gene mutation is the primary genetic driver of heritable PAH.
  4. Right ventricular failure in PAH results from both increased after pressure and impaired sarcomere function due to chronic inflammation.
  5. Echocardiography serves as the initial screening tool; Right Heart Catheterization (RHC) is the gold standard for diagnosis.
  6. Vasoreactivity testing (inhaled nitric oxide or epoprostenol) identifies patients eligible for calcium channel blocker therapy (mPAP decrease ≥10 mmHg to ≤40 mmHg).
  7. Treatment targets include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin pathway agents.
  8. Prognosis is stratified by risk groups based on hemodynamics, functional capacity, and NT-proBNP levels.
  9. Systemic manifestations of right heart failure include hepatic congestion, renal impairment, and multi-organ involvement.
  10. CTEPH requires specific management including lifelong anticoagulation (warfarin preferred) and potential surgical endarterectomy.

DEFINITION & OVERVIEW

• Definition: Pulmonary hypertension (PH) is a heterogeneous disease involving pathogenic remodeling of the pulmonary vasculature, which increases pulmonary artery pressure and pulmonary vascular resistance (PVR). • Hemodynamic Criteria: ◦ Diagnosis of PH: mPAP >20 mmHg. ◦ Precapillary PH: PVR >2.0 Wood units (WU) and PAWP ≤15 mmHg. ◦ Postcapillary PH: Characterized by high PAWP (>15 mmHg). ◦ Combined Pre-/Post-capillary PH: High PVR (>2.0 WU) and high PAWP (>15 mmHg). • Pulmonary Arterial Hypertension (PAH): ◦ Distinct subset characterized by obliterative arteriopathy. ◦ Symptoms: Dyspnea, chest pain, and syncope. ◦ Mortality: High if untreated due to decompensated right heart failure. • Clinical Classification (Table 294-1): ◦ Group 1 (PAH): Includes idiopathic, heritable, drug/toxin-associated, and connective tissue disease-associated cases. ◦ Group 2: PH associated with left heart disease (e.g., heart failure, valvular disease). ◦ Group 3: PH associated with lung diseases and/or hypoxia. ◦ Group 4: PH associated with pulmonary artery obstructions (e.g., CTEPH). ◦ Group 5: PH with unclear and/or multifactorial mechanisms.

EPIDEMIOLOGY

• Idiopathic PAH (IPAH): ◦ Favors women to men by ~3.1-fold. ◦ Men typically present with more severe hemodynamics and a less favorable prognosis. • Heritable PAH: ◦ BMPR2 mutation leads to younger age at diagnosis, more severe hemod hemodynamics, and higher clinical risk. ◦ Conversion rate for carriers without symptoms: ~2.3% per year. • HIV-Associated PAH: ◦ Significant cause of mortality in the HIV population. ◦ No correlation between stage of HIV infection and development of PAH. ◦ Correlation: Inverse correlation between CD4+ count and ePASP; positive correlation between viral load and ePASP.

ETIOLOGY & PATHOPHYSIOLOGY

• Core Mechanisms: ◦ Pro-proliferative vs. anti-proliferative imbalance. ◦ Remodeling: Hypertrophic, fibrotic, and plexogenic remodeling of distal (small) pulmonary arterioles. ◦ Extracellular matrix expansion (collagens, fibronectin) leading to vessel stiffening. • Genetic Drivers: ◦ BMPR2: Most common cause of heritable PAH; part of the TGF-β receptor superfamily. ◦ Other Genes: TBX4 and SOX17 (regulate activation of FGF-10 and HGF). • Epigenetics: ◦ Increased DNA damage in pulmonary artery endothelial cells and circulating blood mononuclear cells. ◦ Mechanisms: Methylation/demethylation involving TET2 and DNMT3B. ◦ Targets: Bromodomain-containing 4; HDAC-1 and HDAC-5 inhibition. • Hypoxia & Metabolism: ◦ HIF-2α: Pathogenic pathway; inhibited by PT2567 to improve hemodynamics. ◦ JAK2: Overactivated in PAH; inhibited by ruxolitinib. ◦ MMP-8: Protective against PAH by stabilizing FAK-YAP/TAZ. • Endothelial-Mesenchymal Transition (End-MT): ◦ Linked to loss of BMPR2 expression; characterized by migration and gain of smooth muscle actin fibers.

CLINICAL FEATURES

• Presentation: ◦ Common: Dyspnea and/or fatigue. ◦ Advanced: Edema, chest pain, presyncope, and syncope. • Physical Examination: ◦ Early phase: Often unrevealing. ◦ Late stage (Right Heart Failure): Elevated JVP, lower extremity edema, and ascites. ◦ Cardiovascular: Accentuated P component of S2, right-sided S or S4, and a holosystolic tricuspid regurgitant murmur. • Associated Signs: ◦ Clubbing (chronic lung disease). ◦ Sclerodactyly and telangiectasia (scleroderma/CREST). ◦ Crackles and systemic hypertension (left heart failure). • Systemic Manifestations (Figure 4): ◦ Eyes: Glaucoma, retinal detachment, venous stasis retinopathy. ◦ Brain: Cognitive dysfunction, depression, anxiety. ◦ Thyroid: Hypo/hyperthyroidism, Grave's disease. ◦ Liver: Congestive hepatopathy, fibrosis, cardiac cirrhosis. ◦ Kidneys: Low perfusion injury, congestive nephropathy, renal fibrosis. ◦ Muscle (Sarcopenia): Multi-factorial; reduced strength, type I to type II fiber switching, and decreased capillary density.

DIFFERENTIAL DIAGNOSIS

• Common Pitfalls: ◦ Overlooked due to non-specific symptoms overlapping with asthma, HFpEF, and deconditioning. ◦ Misconception that PH in lung/heart disease is just an extension of the primary disease. • Key Diagnostic Indicators: ◦ Echocardiogram: High quality; absence of tricuspid regurgitation makes estimation impossible. ◦ Pulmonary Function: Isolated reduction in DLCO is a classic finding in PAH. ◦ Imaging (CT): Identifies pulmonary artery enlargement, RV enlargement, and peripheral pruning. ◦ Specific conditions: Valvular disease, LV dysfunction, LA enlargement, and intracardiac shunt.

INVESTIGATIONS & DIAGNOSIS

  1. Initial Screening: • Echocardiography with agitated saline (bubble) study. • Indicators: Estimated pulmonary artery systolic pressure >35 mmHg, notched waveform on RV outflow tract, or hypertrophied/dilated RV.
  2. Advanced Imaging: • High-resolution CT (HRCT): Evaluates pulmonary artery size, RV size, and identifies features like peripheral pruning or venous congestion. • Pulmonary Function Tests: Assess for restrictive or obstructive lung disease.
  3. Gold Standard Assessment: • Right Heart Catheterization (RHC) to determine mPAP, PVR, and PAWP.
  4. Vasoreactivity Testing (Reserved for Idiopathic/Heritable PAH): • Agents: Inhaled nitric oxide or inhaled epoprostenol. • Criteria for Positive Response: mPAP decrease ≥ 10 mmHg to an absolute level ≤ 40 mmHg without a decrease in cardiac output. → Positive result → Eligibility for calcium channel blocker therapy.
  5. Additional Screening: • Biomarkers: NT-proBNP (correlates with RV dysfunction and serves as a marker for treatment response). • Laboratory: HIV test, ANA, RF, anti-Scl-70 (rheumatoid screen), liver function/hepatitis serology.
  6. Definitive Procedure for CTEPH: • Digital subtraction pulmonary angiography to identify webbing, stricture, and tapering.
  7. Diagnostic Algorithm (Flowchart 2):
  8. Unexplained Dyspnea / Suspected PH → General Practitioner Assessment.
  9. "Causes other than PH identified?"
  10. Yes → Manage Accordingly.
  11. No → Assess "PH probability".
  12. "PH probability" assessment:
  13. Low → Further Evaluation.
  14. Intermediate or High → Refer to PH Center.
  15. Fast Track Referral: If -PAH, -CTEPH, or Warning Signs (rapid progression, severe symptoms, presyncope/syncope on mild exertion) are present → Refer to PH Center.
  16. Heart Assessment Branch: Echocardiography and CPET → Rapid Cross-Referral as Needed or direct referral based on findings.

MANAGEMENT & TREATMENT

  1. Initial Risk Stratification (based on high-risk findings): • Identify High-Risk Features: $p ext{VRO} < 11 ext{ mL/kg/min}, ext{NT-proBNP} > 1000 ext{ ng/mL}$, moderate pericardial effusion, or cardiac output < 2.0.
  2. Pharmacologic Selection (based on risk profile): • Vasoreactivity Positive: If mPAP decrease ≥ 10 mmHg to ≤ 40 mmHg without a decrease in cardiac output → Initiate Oral Calcium Channel Antagonist Therapy. • Vasoreactivity Negative + High-Risk Findings: Initial combination: treprostinil (IV or SC) + tadalafil + ambrisentan. • Vasoreactivity Negative + No High-Risk Findings: Initial combination: tadalafil + (ambrisentan or macitentan).
  3. CTEPH Specific Management (Flowchart 4): • Initial Step: Lifelong anticoagulation (warfarin preferred). • Assessment: Multidisciplinary team evaluates for surgical operability (PVR > 12 WU, NYHA FC IV, etc.). • If Operable → Pulmonary Endarterectomy. • If Non-Operable → Riociguat (sildenafil, treprostinil) ± BPA.
  4. Drug Classes (Table 2): • Prostacyclin derivatives: Epoprostenol (IV/Inhaled), Treprostinil (IV/SC/Inhaled/Oral). • Endothelin receptor antagonists: Bosentan, Ambrisentan, Macitentan. • PDE5 inhibitors: Sildenafil, Tadalafil. • Soluble guanylyl cyclase stimulator: Treprostinil.

PROGNOSIS & COMPLICATIONS

• Prognosis Factors: ◦ Severity of RV dysfunction (NT-proBNP levels). ◦ Functional capacity (6-minute walk distance). ◦ Presence of high-risk features at diagnosis. • Complications: ◦ Right heart failure → multi-organ congestion (hepatopathy, nephropathy). ◦ Sarcopenia and muscle atrophy (reduced strength, type I to type II fiber switching, decreased capillary density). ◦ Respiratory impairment due to myopathy.

SPECIAL CONSIDERATIONS

• HIV-Associated PAH: ◦ Significant cause of mortality in HIV patients. ◦ No correlation between HIV stage and development of PAH. • Congenital Heart Disease (CHD): ◦ Can lead to pulmonary vascular remodeling; requires specific consideration for underlying cardiac anatomy.

KEY PEARLS & CLINICAL TRAPS

• mPAP Threshold: Lowered from ≥ 25 mmHg to > 20 mmHg. • PVR Threshold: Lowered from ≥ 3 to > 2 Wood units (WU). • Vasoreactivity: Only ~5% of patients are responders; they have a significantly better prognosis. • CTEPH Identification: Look for 'webbing' and 'stricture' on angiography; these are pathognomonic for CTEPH. • Sarcopenia: In PAH, muscle loss is multi-factorial (deconditioning + metabolic changes).

Reference Tables

TABLE 294-1 World Symposium on Pulmonary Hypertension Clinical Classification GROUP 1 Pulmonary arterial hypertension…

Harrison's 22e, p.2191

  • GROUP 1 Pulmonary arterial hypertension (PAH)
    1.1 Idiopathic
    1.1.1 Non-responders at vasoreactivity testing
    1.1.2 Acute responders at vasoreactivity testing
    1.2 Heritablea
    1.3 Associated with drugs and toxinsa
    1.4 Associated with:
    1.4.1 Connective tissue disease
    1.4.2 HIV infection
    1.4.3 Portal hypertension
    1.4.4 Congenital heart disease
    1.4.5 Schistosomiasis
    1.5 PAH with features of venous/capillary (PVOD/PCH) involvement
    1.6 Persistent PH of the newborn
  • GROUP 2 PH associated with left heart disease
    2.1 Heart failure:
    2.1.1 with preserved ejection fraction
    2.1.2 with reduced or mildly reduced ejection fractionb
    2.2 Valvular heart disease
    2.3 Congenital/acquired cardiovascular conditions leading to post-capillary PH
  • GROUP 3 PH associated with lung diseases and/or hypoxia
    3.1 Obstructive lung disease or emphysema
    3.2 Restrictive lung disease
    3.3 Lung disease with mixed restrictive/obstructive pattern
    3.4 Hypoventilation syndromes
    3.5 Hypoxia without lung disease (e.g. high altitude)
    3.6 Developmental lung disorders
  • GROUP 4 PH associated with pulmonary artery obstructions
    4.1 Chronic thrombo-embolic PH
    4.2 Other pulmonary artery obstructionsc
  • GROUP 5 PH with unclear and/or multifactorial mechanisms
    5.1 Hematological disordersd
    5.2 Systemic disorderse
    5.3 Metabolic disordersf
    5.4 Chronic renal failure with or without hemodialysis
    5.5 Pulmonary tumor thrombotic microangiopathy
    5.6 Fibrosing mediastinitis

TABLE 294-2 FDA-Approved Therapies for the Treatment of Pulmonary Arterial Hypertension

Harrison's 22e, p.2197

GENERIC NAME ROUTE OF
ADMINISTRATION		 DRUG CLASS INDICATION
Epoprostenol IV Prostacyclin derivative Treatment of PAH to improve exercise capacity
Inhaled Prostacyclin derivative
Treprostinil IV or SC Prostacyclin derivative Treatment of PAH to diminish symptoms associated with exercise
Inhaled Prostacyclin derivative
Treprostinil Oral Prostacyclin derivative Treatment of PAH to improve exercise ability
Oral Selective IP receptor agonist
Bosentan Oral Endothelin receptor antagonist Treatment of PAH to improve exercise capacity and to decrease clinical worsening
Oral Endothelin receptor antagonist
Macitentan Oral Endothelin receptor antagonist Treatment of PAH to improve a composite endpoint of delay of clinical worsening
Oral or IV PDE5 inhibitor
Tadalafil Oral PDE5 inhibitor Treatment of PAH to improve exercise ability
Oral Soluble guanylyl cyclase stimulator