Pulmonary Hypertension

Jessica Reed

Classification

WHO Group

Pathophysiology

Etiologiesm
Group 1. Pulmonary arterial hypertension Proliferation and hyperplasia of vascular wall leading to increased pulmonary vascular resistance Idiopathic, heritable (BMPR2 mutation), druginduced/ toxin-induced (methamphetamine, Fen-Phen), connective tissue disease (scleroderma), HIV, portal HTN, congenital heart disease (ASD, VSD, PDA), schistosomiasis (#1 cause of PAH worldwide), Pulmonary veno-occlusive disease (PVOD) Pulmonary capillary hemangiomatosis
Group 2. Left heart disease Elevated end diastolic filling pressure. Increased PCWP. HFrEF, HFpEF, aortic/mitral valve disease, stiff LA
Group 3. Lung diseases or chronic hypoxemia Hypoxic pulmonary vasoconstriction leads to vascular bed remodeling COPD, ILD, OSA, chronic high-altitude exposure, developmental lung disorders, chronic alveolar hypoventilation
Group 4. Chronic thromboembolic pulmonary hypertension (CTEPH) Chronic pulmonary embolism. Incomplete fibrinolysis and organization of thrombus Thrombotic and non-thrombotic emboli (parasites, foreign bodies, tumor)
Group 5. Multifactorial Varied Hematologic disorders (sickle cell disease), chronic hemolytic anemia, sarcoidosis, pulmonary Langerhans cell histiocytosis, fibrosing mediastinitis, ESRD

Presentation 

  • Symptoms: Exertional dyspnea, presyncope, fatigue, exertional chest pain, edema, syncope (concern for severe PH)
  • Physical Exam Findings: JVD, RV Heave, Widely split S2, tricuspid regurg murmur, Hepatomegaly, ascites, rales (pulmonary edema), LE edema
  • Presentation can be variable and depends on group, underlying etiology and functional class at time of presentation. Main chief complaint for admission: volume overload secondary to RV failure and/or hypoxia

Evaluation 

  • Labs: CBC with diff (assess for anemia, polycythemia), BNP, CMP, blood gas to assess for chronic hypercarbia
    • If suspected but undiagnosed: TSH, HIV, rheumatologic serologies (ANA w/reflex ENA, RF/CCP, ANCA, Scl-70, Ro/La)
  • Imaging:
    • CXR: Possible Cardiac enlargement, PA dilation, hilar fullness
    • TTE with bubble: RVSP >35-40 is concerning for PH. TTE can show evidence of RV dilation and dysfunction (TAPSE <1.6cm), RA dilation, septal flattening, pericardial effusion, bubble study for shunt, LV dysfunction
    • CT angiogram: evaluates for acute and chronic thrombi using contrast media; consider V/Q scan in setting of AKI and advanced CKD (discuss risk and benefits)
    • V/Q scan: better performance in evaluating small chronic embolism in contrast to CTA
    • High-res CT: for better evaluation of lung parenchyma in patients with ILD
  • Additional Testing
    • EKG: right atrial enlargement (peaked P waves), RBBB, RV hypertrophy
    • 6-min walk test: important for prognostication, baseline exertional capacity, and to evaluate treatment response
    • PFT: rule out obstructive and restrictive disease; isolated DLCO reduction can be seen with PAH
    • Sleep study: evaluation for chronic hypoxemia from OSA; if low suspicion for OSA/CSA, can start with overnight oximetry
    • RHC (see below)

Diagnosis and Diagnostic Algorithm

1. Clinical Suspicion of PH (see presentation) → 2. Initial Non-Invasive Testing (TTE, CXR, Labs, PFTs, EKG) → 3. Further Imaging (CT Chest/V/Q scan) → 4. Referral to PH Center*→ 5. Confirmatory Testing (RHC is diagnostic) → 6. Additional Tests 

  • May be suspected from clinical presentation and echo
  • A right heart catheterization is the gold standard for PH diagnosis and will differentiate between precapillary and postcapillary PH
    • Nitric oxide challenge during RHC assesses for drug response
    • Fluid challenge with 500ml LR during RHC assesses left heart compliance
  • Referral to PH Center is particularly recommended for suspected PAH (Group 1), CTEPH (Group 4), or severe PH with RV dysfunction
  • RHC: required for diagnosis and to determine therapeutic options; measures mPAP, PWP, PVR, CO, CI
    • Acute vasoreactivity testing (AVT) - Nitric oxide challenge during RHC assesses for drug response and possible therapeutic options
      • Positive: mPAP decreases by ≥ 10 mmHg and mPAP reaches ≤ 40 mmHg, no decrease in cardiac output
    • Fluid challenge with 500ml LR during RHC assesses left heart compliance
      • Negative Fluid Challenge: PCWP remains ≤ 15 mmHg

Definitions

Characteristics

Causes
Pre-capillary PH mPAP > 20 mmHg
PWP ≤ 15 mmHg
PVR ≥ 2 WU		 Groups 1, 3, 4, 5
Post-capillary PH mPAP > 20 mmHg
PWP > 15 mmHg
PVR < 2 WU		 Group 2
Combined pre- and postcapillary PH mPAP > 20 mmHg
PWP > 15 mmHg
PVR ≥ 2 WU		 Group 2, 5

General Management 

  • Immunizations: Strong recommendations for yearly influenza, COVID-19, and pneumococcal vaccinations
  • Pregnancy Counseling: recommend patients avoid pregnancy due to high maternal and fetal risks (RH failure, increased mortality).
  • Treatment Goals: Focus on preventing right heart failure, maximizing PH therapies, symptom relief, quality of life, and functional class improvement (NYHA class) as below
  • Oxygenation Goal: Maintain oxygen saturation >90%.
  • Volume/Hemodynamic Management: try to avoid giving fluids, especially if significant RV dysfunction as this is more likely to throw off Frank-Starling curve than over-diuresis
    • Classic teaching of pre-load dependence is more accurate for acute RV dysfunction than chronic and diuresis is often warranted during episodes of RHF
  • Specialist Consultation: Consult pulmonary hypertension specialists when considering starting, holding, or changing PH medications; Do not change therapy at VUMC without PH consult
  • Regular Follow-Up: Q3-6M visits, assessment of NYHA functional Class for treatment escalation, serial echocardiograms, 6minute walk and RHC if clinically indicated,

Disease Specific Therapeutics and Interventions

Therapy

MOA/Rationale

Patient Population/Considerations
Oral CCBs (Nifedipine, diltiazem, amlodipine) Induce vasodilation by inhibiting calcium influx in pulmonary artery smooth muscle, promoting muscle relaxation Used ONLY in pts w/ Group 1 PH who had a positive vasoreactivity challenge on RHC as above
Anticoagulation (DOAC, VKA) Prevent new thrombus formation and promoting the resolution of any existing acute thrombi
  • For pts with confirmed CTEPH (Group 4)
  • Should be worked up for hypercoagulability including antiphospholipid syndrome.
PAH-specific medications (in order of escalation)
Endothelin receptor antagonists (e.g., bosentan, ambrisentan, macitentan) Block endothelin-1 receptors, reducing vasoconstriction and proliferation
  • All therapies given under the direction of PH specialist
Important Notes on Prostacyclin Based Therapies:
  • Side effects include jaw pain, flushing, arthralgias, and diarrhea
  • IV formulations are administered through a continuous pump. Never stop IV prostacyclin therapy inpatient since even brief pauses can cause rebound vasoconstriction and death.
  • Epoprostenol: IV (Veletri) or inhaled (Flolan); half-life 4 minutes
  • Treprostinil: IV/subcutaneous/inhaled/PO; half-life 4 hours
  • Selexipag (Uptravi): PO, half-life hours
Phosphodiesterase- 5 inhibitors (e.g., sildenafil, tadalafil) Inhibit PDE-5, increasing cGMP levels and promoting vasodilation
Prostacyclin analogs (e.g., epoprostenol, treprostinil) Mimic prostacyclin, leading to vasodilation and inhibition of platelet aggregation
Prostacyclin receptor agonists (e.g., selexipag) Activate prostacyclin receptors, causing vasodilation
Soluble guanylate cyclase stimulators (e.g., riociguat) Stimulate sGC, increasing cGMP independent of nitric oxide leading to vasodilation
Sotatercept An activin receptor type IIA-Fc fusion protein, works by binding to free activins, restoring balance between the activin proliferative and BMP antiproliferative pathways in the pulmonary arteries. Used as add on therapy in Group 1 PH to enhance exercise capacity, improve functional class, and reduce clinical worsening
  • Treatment escalation is based on a pt’s risk stratification
  • Procedural Considerations
  • Atrial septostomy: creation of a R->L shunt to offload the RV
  • VA ECMO can be used as bridge to medical therapy or for lung transplant.
  • Lung transplantation can be considered for pts who are candidates and failing maximal medical therapy

Poor prognostic factors 

  • NYHA Functional Class III and IV: Indicates severe symptoms and significant limitations in physical activity
  • 6-minute walk test less than 300 meters: correlates with worse functional capacity and right ventricular dysfunction
  • AKI and/or hyponatremia: AKI and hyponatremia are markers of severe right heart failure and systemic congestion, indicating poor renal perfusion and neurohormonal activation, both of which are associated with increased mortality
  • Low SBP (SBP < 90): reflects poor cardiac output and advanced right ventricular failure,
  • Poor hemodynamics on RHC (right atrial pressure > 20 mmHg; cardiac index less than 2)
  • TTE findings: tricuspid annular plane systolic excursion (TAPSE, marker of global RV function) < 1.8, pericardial effusion, and severe RV dysfunction
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