pulmonary hypertension

Introduction

Chronic disorder with mean pulmonary artery pressure of > 20-25 mm Hg at rest or > 30 mm Hg with exercise & a pulmonary capillary wedge pressure < 15 mm Hg measured during right heart catheterization.*

* see Differential diagnosis: below for causes of acute elevation in pulmonary artery pressure.

Etiology

• left atrial hypertension*
  • valvular heart disease
    • mitral stenosis
  • heart failure
    • LV systolic dysfunction
    • LV diastolic dysfunction (most common in elderly, USA) (28%)
      • left ventricular end-diastolic pressure (LVEDP) > 15 mm Hg
    • congenital heart disease
• hypoxemia*
  • chronic lung disease
    • COPD
    • interstitial lung disease
    • pulmonary fibrosis
    • chronic pulmonary embolism
  • severe nocturnal hypoxemia (sleep apnea)
  • high altitude, chronic mountain sickness
  • obesity hypoventilation syndrome
• left to right shunts - atrial septal defect
• vascular diseases of the lung
  • chronic thromboembolism
    • chronic thromboembolic pulmonary hypertension
• connective tissue disease
  • systemic lupus erythematosus
  • systemic sclerosis
• HIV1 infection
• portal hypertension, portopulmonary hypertension
• schistosomiasis (world-wide most common cause)
• chronic hemolytic anemia
  • sickle cell disease (older patients)
• familial, congenital heart disease (see Genetics below)
  • persistent pulmonary hypertension of the newborn
• pharmaceutical agents: analeptics
• toxin exposure
• idiopathic (primary pulmonary hypertension, group 1) (14%)

* left heart disease & hypoxemia due to chronic lung disease most common causes

* see causes of pulmonary hypertension for more detail

Pathology

• vascular
  • elevated mean pulmonary artery pressure due to increased pulmonary vascular resistance
  • arterial intimal proliferation & arteriolar constriction secondary to alveolar hypoxia
    • disease localized to small pulmonary arterioles resulting in high pulmonary vascular resistance is primary pulmonary arterial hypertension
  • increased pulmonary blood flow from left to right shunts
  • increased pulmonary venous pressure from left heart failure*
  • > 50% of the vascular bed must be occluded to produce clinical pulmonary hypertension
• perivascular parenchymal changes resisting blood flow
  • pulmonary fibrosis
  • pulmonary edema
• intravascular obstruction
  • thromboembolism
  • parasitic disease (schistosomiasis)
• cor pulmonale may result from right ventricular overload

* increased mean pulmonary artery pressure with elevated pulmonary artery capillary wedge pressure indicates pulmonary venous hypertension

Genetics

• ALK1 mutation
• endoglin mutation
• BMPR2 mutation

Clinical manifestations

(also see primary pulmonary hypertension)

• exertional dyspnea
• fatigue
• syncope
• peripheral edema
• persistent unexplained hoarseness
• right ventricular heave
• loud pulmonic valve component of the 2nd heart sound P2
  • widely split S2
• systolic murmur best heard at the left sternal border that increases with inspiration
• diastolic murmur of tricuspid regurgitation
• right-sided S3 gallop or S4 gallop heart sound
  • S3 gallop best heard at the left sternal border with the patient supine
    • listen during inspiration, murmur increases with inspiration
• jugular venous distension with a large a wave
• lungs are clear to auscultation
• chest pain
• Raynaud phenomenon suggesting connective tissue disease (see etiology)

Laboratory

• antinuclear antibody (ANA)
• HIV testing
• serum pro-BNP improves predictive value in patients with sickle cell disease
• serum ALT, serum AST
• arterial blood gas (hypoxemia, hypercapnia)

Diagnostic procedures

• echocardiography (initial diagnostic test of choice)
  • elevated pulmonary artery pressure
    • mean pulmonary artery pressure > 25 mm Hg at rest
    • normal range: 15-30/5-13 (mean 10-18) mm Hg
    • echocardiography may underestimate true pulmonary artery pressure
    • right ventricular hypertrophy, right ventricular dilation, right ventricular failure
  • rule out mitral stenosis
  • bubble-contrast or transesophageal echocardiogram for congenital heart disease
• electrocardiogram: (EKG)
  • right ventricular hypertrophy
  • RVH by EKG found in only 1/3 of patients with COPD & cor pulmonale
  • RBBB often occurs
  • right axis deviation
  • T wave changes
• pulmonary function testing
  • isolated decrease in DLCO with normal TLC, FEV & FEV1
  • SaO2 during sleep (overnight pulse oximetry) & with exertion 6-minute walk may determine need for oxygen therapy
  • 6-minute walk improves predictive value in patients with sickle cell disease
• polysomnography
  • if suspected sleep disordered breathing
  • rule out severe nocturnal hypoxemia
    • overnight pulse oximetry may suffice
• pulmonary artery catheterization with vasodilator test
  • indications
    • suspected pulmonary artery hypertension suggested by clinical presentation not confirmed by echocardiography
    • allows measurement of mean pulmonary artery pressure > 20 mm Hg (diagnostic)
    • most patients with confirmed pulmonary hypertension
      • not indicated in pulmonary hypertension due to heart failure
    • patients with connective tissue disease or other disorder associated with pulmonary parenchymal disease
  • IV vasodilator (adenosine, epoprostenol)
  • inhaled nitric oxide
  • vasoreactivity verified by
    • reduction in mean pulmonary artery pressure of at least 10 mm of Hg to a value <= 40 mm Hg
    • no decrease in cardiac output with vasodilation
• acute vasoreactivity study
  • assess response to vasodilator(s)
• left heart catheterization & coronary angiography to exclude LV dysfunction
• open lung biopsy may be indicated

Radiology

• chest radiograph
  • enlarged right ventricle
  • dilated pulmonary arteries
  • reduced peripheral pulmonary vascularity
• CT angiography if acute pulmonary embolism suspected
• ventilation perfusion scan (V/Q scan) prior to pulmonary angiography in patients with
  • suspected pulmonary embolism
  • suspected chronic thromboembolic pulmonary hypertension
• pulmonary angiography may be appropriate if VQ scan is equivoval
• findings on chest CT can identify patients with pulmonary hypertension due to left heart failure

Complications

• hypoxia
• cor pulmonale
• even borderline pulmonary hypertension associated with 31% increased risk of all-cause mortality
• complications associated with elective non-cardiac surgery include myocardial ischemia, venous thromboembolism, cardiogenic shock, & dysrhythmias

* mean pulmonary artery pressure of 19-24 mm Hg

Differential diagnosis

• acute onset pulmonary hypertension due to pulmonary embolism
  • non-collapsing inferior vena cava
  • right ventricular dilation with septal bowing & preserved ejection fraction

Management

• treat underlying cause
  • steroids for connective tissue disease, COPD
  • treatment of left heart failure with vasodilator may overload left ventricle worsening congestive heart failure
  • treatment of lung disease with vasodilator may worsen VQ mismatch
  • see for guidelines treating pulmonary hypertension in children
• supplemental oxygen in patients that are hypoxemic
  • 6 minute walk & overnight pulse oximetry may qualify patients for oxygen therapy (SaO2 < 88%)
• anticoagulation with warfarin unless contraindicated
  • this recommendation in the absence of thromboembolism not well understood
• calcium channel antagonists
  • invasive hemodynamic monitoring required prior to initiating therapy to verify vasoreactivity (see primary pulmonary hypertension)
  • effective in some patients with primary pulmonary hypertension (pulmonary Raynaud's phenomenon)
  • adverse effect of possibly worsening gas exchange
  • nifedipine 120-240 mg QD
  • diltiazem 540-900 mg QD
• phosphodiesterase-5 inhibitors
  • sildenafil
    • sildenafil improves exercise capacity, WHO functional class, & hemodynamics in patients with mild pulmonary hypertension
    • recommended adult dose of 20 mg TID
    • 5 mg TID non-inferior to 80 mg TID
  • tadalafil
  • riociguat in place of PDE-5 inhibitor may be of benefit
  • useful for patients with negative vasoreactivity testing
  • does not facilitate elective surgery in high-risk patients
• endothelin receptor antagonists
  • bosentan
  • ambrisentan
  • macitentan (Opsumit)
    • macitentan/tadalafil (Opsynvi) improves exercise capacity
  • useful for patients with negative vasoreactivity testing
• prostacyclin analogues
  • treprostinil intravenous
  • epoprostenol intravenous
  • inhaled iloprost
  • reserved for patients whose disease has progressed despite oral therapy with phosphodiesterase-5 inhibitor or endothelin receptor antagonist
  • only prostacyclin analogues reduce mortality
• triple therapy of PDE-5 inhibitor, endothelin receptor antagonist & prostacyclin analogue may be better than monotherapy
• other treatment options
  • sotatercept (Winrevair) improves exercise capacity FDA-approved March 2024
  • industry-sponsored study suggests benefit for initial therapy with ambrisentan (Letairis) 10 mg + tadalafil (Adcirca) 40 mg) PO QD
  • nitrates may have short-term benefit
  • treatment with vascodilator not curative but improves survival
  • diuretics
  • consider digoxin
• chronic pulmonary embolism
  • anticoagulation if pulmonary embolism suspected
  • surgical thromboendarterectomy if indicated in patients with pulmonary embolism
  • chronic anticoagulation
  • inferior vena cava interruption (Greenfield filter)
• consider exercise training
• delay or cancel elective surgery for patients with high risk pulmonary hypertension
• patients with severe pulmonary hypertension or right ventricular dysfunction should be referred to pulmonary hypertension center
• lung or heart/lung transplantation
• advise against pregnancy if severe; maternal mortality 30-50%
• screen for portal hypertension prior to liver transplantation
• screening:
  • 1st degree relatives of patients with familial pulmonary hypertension
  • congenital heart disease with systemic-to-pulmonary shunt

More general terms

• cardiopulmonary disease
• arterial disease
• sign/symptom

More specific terms

• chronic thromboembolic pulmonary hypertension (CTEPH)
• portopulmonary hypertension
• primary pulmonary hypertension (PPH)
• pulmonary venous hypertension

Additional terms

• causes of pulmonary hypertension
• pulmonary artery pressure (PAP)
• right ventricular failure; right heart failure
• right ventricular hypertrophy (RVH)