Pulmonary Hypertension

Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Patients typically present with shortness of breath initially during exercise and then at rest. Diagnosis may involve an echocardiogram, ECG, chest X-ray, pulmonary function tests, a ventilation-perfusion scan, laboratory testing for conditions associated with PAH, and/or cardiac catheterization. Management is often complex and aimed at treating the underlying etiology. Several classes of vasodilatory agents may be used for patients with primary PAH, including calcium channel blockers and vasoactive prostaglandins.

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Overview

Definition

Pulmonary hypertension (PH) is defined as elevated pulmonary arterial pressure. 

  • Elevated pulmonary arterial pressure consistent with PH:
    • ≥ 25 mm Hg at rest
    • ≥ 30 mm Hg during exercise
  • Normal pulmonary arterial pressure: 10–14 mm Hg
  • May be primary (uncommon) or secondary (common):
    • Primary PH is referred to as pulmonary arterial hypertension (PAH).
    • Secondary PH may be due to chronic heart, lung, or systemic diseases.

Epidemiology

Secondary PH is much more common than the primary variant. The epidemiology of secondary PH is similar to the underlying condition. 

Primary PH/PAH:

  • Prevalence: approximately 15 cases in 1 million adults
  • Schistosomiasis is the most common cause worldwide.
  • In areas without endemic schistosomiasis:
    • 50% of cases are idiopathic.
    • 10% of cases are familial.
  • Gender bias: women > men
  • Most common age at presentation: 4th–5th decades
  • Mortality rate: approximately 5.4 per 100,000

Anatomy review

Blood flow through the cardiac and pulmonary circulation takes the following path:

  • Deoxygenated systemic blood returns to the right side of the heart through the superior and inferior venae cavae. 
    • Vena cava → right atrium → tricuspid valve → right ventricle → pulmonary valve → pulmonary trunk
    • Pulmonary arteries → pulmonary capillaries (blood is oxygenated) → pulmonary veins 
  • Oxygenated blood returns to the left side of the heart.
    • Pulmonary veins → left atrium → mitral valve → left ventricle → aortic valve → aorta
    • The aorta leads blood into the systemic arterial circulation.
Anatomy review for pulmonary hypertension

Blood flow through the cardiac and pulmonary circulation

Image by Lecturio.

Classification and Etiology

The WHO has classified PH into 5 categories based on the etiology:

Group 1: PAH

Group 1 refers to cases of increased pulmonary arterial pressure in the absence of underlying heart or lung disease and was previously called (and can still be conceptualized as) primary PH. The etiologies of group 1 include:

  • Idiopathic PAH (most common cause of PAH)
  • Familial PAH: due to mutations in the bone morphogenic protein-receptor-2 (BMPR2) gene, several other rare mutations, or unknown causes
  • Drugs or toxins:
    • Appetite suppressants:
      • Amphetamines
      • Fenfluramine
      • Aminorex
    • Rapeseed oil
    • Cocaine
  • Associated with:
    • Connective tissue disease (primarily scleroderma)
    • HIV infection
    • Portal hypertension
    • Congenital left-to-right shunts
    • Schistosomiasis (among the most common causes of PAH worldwide)
  • Pulmonary veno-occlusive disease
  • Pulmonary capillary hemangiomatosis (PCH)
  • Persistent PH of the newborn

Group 2: PH due to left heart disease

Left-sided heart disease can cause pressure backup through the pulmonary vasculature leading to PH, and is the most common cause of PH overall. Etiologies include:

  • Left-sided atrial or ventricular heart disease
  • Left-sided valvular heart disease
  • Obstruction of the left heart inflow or outflow tracts (congenital or acquired)
  • Congenital cardiomyopathies

Group 3: PH due to chronic lung disease and/or hypoxia

Hypoxia leads to physiological vasoconstriction of the pulmonary vasculature to prevent ventilation-perfusion mismatch. As a result, chronic hypoxia, as well as destructive lung diseases, can lead to chronic PH. Etiologies include:

  • Chronic obstructive pulmonary disease (COPD) (most common)
  • Interstitial lung disease
  • Pulmonary diseases with mixed restrictive and obstructive patterns
  • Sleep-disordered breathing (e.g., obstructive sleep apnea)
  • Alveolar hypoventilation disorders:
    • Obesity hypoventilation syndrome
    • Congenital central alveolar hypoventilation syndrome
    • Hypothalamic dysfunction
  • Chronic exposure to high altitude

Group 4: PH due to chronic thromboembolic disease

Group 4 cases are diagnosed when there is an increase in pulmonary arterial pressure with documentation of pulmonary arterial obstruction. Etiologies include:

  • Chronic pulmonary thromboembolism
  • Nonthrombotic pulmonary embolism:
    • Tumor embolisms (late-stage manifestations of certain malignancies with embolization of tumor particles themselves)
    • Foreign material (most commonly silicone, after surgical injection)

Group 5: PH due to unclear or multifactorial causes

Pulmonary hypertension is classified as Group 5 when the elevation in pulmonary arterial pressure is associated with a systemic disease, where a causal relationship is not clearly understood or thought to be multifactorial. Etiologies include:

  • Hematological disorders:
    • Chronic hemolytic anemias:
      • Sickle cell disease
      • Thalassemia
      • Spherocytosis
    • Chronic myeloproliferative disorders
    • Splenectomy
  • Systemic disorders:
    • Sarcoidosis
    • Pulmonary histiocytosis
    • Lymphangioleiomyomatosis
  • Metabolic disorders:
    • Glycogen storage disease
    • Gaucher disease
    • Thyroid disorders
  • Others:
    • Tumoral obstruction
    • Fibrosing mediastinitis
    • Chronic renal failure

Pathophysiology

Overview

  • ↑ Pulmonary arterial pressure leads to:
    • Enlarged proximal pulmonary arteries
    • Right ventricular hypertrophy
    • Tricuspid regurgitation
    • Right atrial dilation
    • Ultimately results in cor pulmonale (right-sided heart failure).
  • Mean pulmonary arterial pressure = (Q x PVR) + pulmonary capillary wedge pressure
    • Q: right-sided cardiac output
    • PVR: pulmonary vascular resistance
    • Pulmonary capillary wedge pressure estimates left atrial pressure.
  • ↑ Pulmonary arterial pressure may be due to:
    • ↑ Pulmonary vascular resistance (most common)
    • ↑ Flow through the pulmonary vasculature
    • ↑ Left-sided pressures

Increased pulmonary vascular resistance

Increased pulmonary vascular resistance is the primary cause of PH in most cases and may be due to:

  • Occlusive vasculopathies of the small pulmonary arteries/arterioles: remodel the vasculature and alter the tone (e.g., idiopathic PAH)
  • ↓ In the area of the pulmonary vascular bed: 
    • Pulmonary emboli
    • Interstitial lung disease
  • Hypoxic vasoconstriction:
    • Hypoventilation syndromes
    • Parenchymal lung disease
  • ↑ Pulmonary venous pressure:
    • Mitral valve disease
    • Left ventricular dysfunction
    • Constrictive pericarditis
    • Restrictive cardiomyopathy
    • Pulmonary venous obstruction

Increased flow through the pulmonary vasculature

Typically, increased flow triggers vasodilation of the pulmonary vasculature. In cases where this increase in flow is chronic, PH may develop. Chronic increases in flow can also induce vascular changes leading to increased pulmonary vascular resistance.

  • Congenital heart defects with left-to-right shunt:
    • Atrial septal defects
    • Ventricular septal defects
    • Patent ductus arteriosus
  • Liver cirrhosis
  • Chronic anemia
  • Arteriovenous malformations

Genetic mutations

Familial PAH is most commonly due to mutations in the BMPR2 gene.

  • BMPR2
    • 80% of familial cases are due to an inactivating mutation in BMPR2.
    • BMPR2 normally inhibits vascular smooth muscle proliferation.
    • With BMPR2 inactivated, patients are unable to prevent vascular smooth muscle proliferation → PAH
  • Several other rare mutations have been identified.

Pathogenesis by classification group

Table: Pathogenesis of PH by classification group
Group 1: “primary”
  • Vasoconstriction of the pulmonary arterial system
  • Vascular cell proliferation
  • Fibrosis
Group 2: due to left-sided heart disease
  • ↑ Left-sided pressures (↑ pulmonary capillary wedge pressure) → ↑ mean pulmonary arterial pressure
  • Pulmonary vascular remodeling
  • Reduced compliance of the pulmonary vasculature
Group 3: due to lung or hypoxic disease
  • Hypoxia triggers pulmonary vasoconstriction to prevent ventilation-perfusion mismatch via the following mechanisms:
    • ↓ NO production (a vasodilator)
    • Impaired voltage-gated potassium channels → contraction of pulmonary smooth muscles
    • ↑ Activity of phospholipase A2 → increase in vasoconstrictive substances: vasoconstrictive prostaglandins, thromboxanes, leukotrienes
    • ↑ Endothelin (a vasoconstrictor)
  • Vascular destruction due to progressive parenchymal fibrosis
  • Vascular inflammation
Group 4: due to chronic thromboemboli Similar to group 3

Clinical Presentation

History

  • Symptoms:
    • Dyspnea on exertion leading to dyspnea at rest (primary symptom)
    • Fatigue
    • Chest pain (angina) 
    • Exertional syncope
  • Considerations from past medical history:
    • COPD/emphysema
    • Interstitial lung disease
    • Heart disease
    • Sickle cell anemia
    • Travel to regions with endemic schistosomiasis 
    • Hypercoagulable states/history of thromboembolic disease

Physical exam

Exam findings consistent with PH include:

  • Raised jugular venous pulsation (JVP)
  • Heart sounds:
    • Pronounced 2nd heart sound (due to a louder P2 component)
    • Fixed splitting of S2
    • Presence of extra right-sided heart sounds:
      • S3: can be heard in ventricular volume overload and congestive heart failure (CHF)
      • S4: ↑ resistance to ventricular filling due to ↓ ventricular compliance
  • Murmurs:
    • Tricuspid regurgitation: pansystolic murmur heard at the left sternal border
    • Mitral valve stenosis: diastolic murmur heard at the apex
    • Aortic stenosis: midsystolic murmur heard best at the right 2nd intercostal space, radiating to the carotids
  • Signs of right-sided heart failure:
    • Peripheral edema
    • Ascites
    • Pleural effusion
    • Hepatomegaly

Diagnosis

Diagnosis of group 1 PAH is typically one of exclusion, after ruling out etiologies in groups 2–5, which can be made by the following tests:

  • Echocardiography
    • Best initial test
    • Allows for assessment of:
      • Ventricular and atrial size and function
      • Valve function (e.g., presence of stenosis or regurgitation)
      • Evidence of volume overload on either side
    • Findings may include:
      • ↑ Thickness of ventricular walls
      • Ventricular hypokinesis
      • Valvular regurgitation
  • ECG:
    • Important for:
      • Ruling out PH due to left-sided heart disease
      • Assessing right-sided heart function
    • Findings of right heart disease may include:
      • Tachycardia
      • Right axis deviation
      • Upright R waves in V1–V3 
  • Chest X-ray findings:
    • Enlargement of central pulmonary arteries and the main branches 
    • Tapering of distal vessels
    • Findings consistent with heart disease: cardiomegaly, pulmonary edema
    • Findings consistent with lung disease: COPD, interstitial lung disease
    • Note: Chest X-ray is often normal or with minimal findings.
  • Ventilation-perfusion lung scan:
    • Helps differentiate group 3 (lung/hypoxic disease) from group 4 (chronic thromboembolic disease)
    • Findings may include:
      • Group 3: diffuse mottled perfusion
      • Group 4: segmental mismatched defects
  • Pulmonary function tests:
    • Useful in diagnosing lung and/or hypoxic disorders
    • Obstructive patterns: COPD
    • Restrictive patterns: interstitial lung disease
  • Right-sided cardiac catheterization:
    • Most accurate test for confirming the diagnosis, especially in idiopathic cases of PAH
    • Invasive procedure
    • Allows for evaluation of:
      • Hemodynamics of the cardiac chambers and large vessels
      • Cardiac output
      • Cardiac shunting
      • Other causes of dyspnea or angina
    • Allows for testing of vasoreactivity in patients with group 1 PAH:
      • Administer a short-acting vasodilatory substance (e.g., inhaled NO) and assess response.
      • Important for managing patients with group 1 PAH
  • Laboratory tests: can help identify other causes of PH
    • CBC: to rule out anemia
    • Liver function tests: to rule out liver disease as a cause of symptoms
    • HIV testing 
    • ANA: test to screen for scleroderma
    • Assays for schistosomiasis
Color doppler image of tricuspid regurgitation

Tricuspid regurgitation:
Tricuspid regurgitation approximates 4.2 m/sec, indicating a peak tricuspid regurgitation pressure gradient of approximately 70 mm Hg (moderate pulmonary hypertension)
A: Color Doppler image of tricuspid regurgitation
B: Continuous Doppler (CW) image from the left apical 4-chamber view optimized for the right ventricle

LA: left atrium
LV: left ventricle
RA: right atrium
RV: right ventricle
TR: tricuspid regurgitation (orange arrow)

Image: “Tricuspid regurgitation” by J.A. Jaffey et al. License: CC BY 4.0

Management

For groups 2–5, management should be directed at treating the underlying condition. In addition, management should focus on maintaining/improving oxygenation. Patients should be referred to specialists at tertiary centers for management, which is often complex.

Vasodilatory agents

  • Calcium channel blockers (CCBs):
    • Only effective in patients who are vasoreactive
    • CCBs block the inward movement of calcium into:
      • Endothelial cells → vasodilation
      • Sinoatrial (SA) and atrioventricular (AV) nodes → ↓ cardiac conduction and contractility
    • Dihydropyridines:
      • Primarily vasodilators at therapeutic doses
      • Examples: amlodipine, nifedipine
    • Non-dihydropyridines:
      • Have inhibitory effects at the SA and AV nodes
      • Examples: diltiazem, verapamil
    • High doses may produce a dramatic reduction in pulmonary artery pressure.
  • Vasodilatory prostaglandins: 
    • Prostacyclin (PGI2) is a natural vasodilatory substance.
    • PGI2 analogs: epoprostenol, treprostinil
  • Endothelin receptor antagonists:
    • Endothelins are natural vasoconstrictors.
    • Competitively antagonize endothelin receptors → ↓ pulmonary vascular resistance
    • Examples: bosentan, ambrisentan
  • Phosphodiesterase inhibitors (PDE-5 inhibitors):
    • PDE-5 degrades cGMP.
    • PDE-5 inhibitors ↓ degradation of cGMP → ↑ cGMP → ↑ smooth muscle relaxation 
    • Results in ↑ pulmonary and systemic vasodilation
    • Examples: sildenafil (Viagra), tadalafil
  • Guanylate cyclase activators
    • Soluble guanylate cyclase (sGC) is an intracellular receptor for NO.
    • sGC ↑ cGMP within the cell → vasodilation
    • Examples: cinaciguat, riociguat
Vasodilatory agents for treatment of pulmonary hypertension

Vasodilatory agents for the treatment of pulmonary hypertension:
A stimulus triggers NO synthase (NOS) in the endothelial cells to convert L-arginine into NO. The NO then moves into the smooth muscle, where it stimulates the activity of guanylate cyclase (also known as guanylyl cyclase), which converts guanosine triphosphate into cGMP. Cyclic GMP then induces smooth muscle relaxation, resulting in vasodilation.

Image by Lecturio.

Other nonsurgical management options

  • Supportive measures:
    • Oxygen therapy
    • Low-sodium diet 
    • Physical therapy/supervised exercise to improve functional capacity
    • Influenza vaccination
    • Birth control to prevent pregnancy due to high risk of maternal mortality associated with PH in pregnancy
  • Diuretics:
    • Indication: patients with right-sided volume overload (edema, ascites)
    • Avoid hypovolemia (patients with right-sided heart failure are preload dependent).
    • Loop diuretics are typically 1st-line drugs (e.g., furosemide).
  • Anticoagulation:
    • Indications:
      • Group 4 (PH due to chronic thromboembolic disease)
      • Group 1 PAH that is either idiopathic or familial
      • Atrial fibrillation
    • Warfarin is usually the drug of choice.
  • Digoxin:
    • Indications: 
      • Heart failure due to systolic dysfunction 
      • Certain supraventricular tachyarrhythmias
    • Effects:
      • Positive inotrope
      • Can reduce sympathetic activation

Surgical options

  • Lung transplantation:
    • Indications for referral:
      • Rapidly progressive disease on therapy
      • Use of parenteral prostaglandins
      • Known or suspected pulmonary venoocclusive disease
    • Procedures of choice: 
      • Bilateral lung transplant
      • Heart-lung transplant
  • Creation of a right-to-left shunt
    • Can be temporizing (as a bridge to transplant) or palliative
    • Procedures:
      • Atrial septostomy
      • Transcatheter Potts shunt: placement of a shunt between the left pulmonary artery and the descending aorta
  • Endovascular thrombectomy: in patients with chronic thromboembolism and a known source

Prognosis

  • PAH is progressive and may be fatal if left untreated.
  • Untreated, group 1 PAH has the worst prognosis:
    • 1-year survival: 85%
    • 3-year survival: 68%
    • 5-year survival: 57%
  • Prognosis depends on the underlying cause.
  • The main cause of death is right ventricular failure.
  • Patients should be monitored by a specialist to assess for a decline in functional status.

Clinical Relevance

  • CHF: the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Congestive heart failure can lead to group 2 PH. Echocardiography can confirm the diagnosis and provide information about the EF. Treatment is directed at the removal of excess fluid and decreasing oxygen demand of the heart. 
  • Coronary artery disease: occurs due to a stenosis of the coronary arteries, leading to ischemia of the heart. Symptoms include chest pain and dyspnea. Diagnosis is based on history, ECG findings, cardiac stress tests, and/or cardiac catheterizations. Treatment is primarily based on reducing oxygen demand of the heart and increasing the delivery of oxygen.
  • Tricuspid regurgitation (TR): a valvular defect that allows the backflow of blood from the right ventricle to the right atrium during systole. Tricuspid regurgitation may be asymptomatic or present with systemic venous congestion due to increased right atrial and venous pressures. Tricuspid regurgitation can also result from PH, but intrinsic valve disease should be considered in the differential diagnosis of PH. Echocardiography can help establish the diagnosis. Treatment focuses on heart failure management, and surgery is reserved for severe disease.
  • Pulmonary fibrosis: a rapidly progressive interstitial lung disease with few available therapies. As pulmonary fibrosis progresses, group 3 PH can develop. The average life expectancy is 3–4 years from diagnosis. Lung transplantation is the only curative intervention, provided candidacy. 
  • COPD: a lung disease usually caused by smoking, and characterized by progressive, largely irreversible airflow obstruction secondary to chronic inflammation. Chronic obstructive pulmonary disease is one of the primary causes of group 3 PH and the symptoms include progressive dyspnea and chronic cough. The diagnosis is confirmed with a pulmonary function test. Management includes smoking cessation, pulmonary rehabilitation, and pharmacotherapy.
  • Pulmonary embolism: a result of the intraluminal obstruction of the main pulmonary artery or its branches by certain components (e.g., thrombus, cholesterol, air, amniotic fluid, or fat). The most common presenting symptom is dyspnea. Initial management is supportive (focusing on restoring oxygenation and hemodynamic stability), which is followed by systemic anticoagulation and interventional therapies. Chronic thromboembolic events can lead to group 4 PH.

References

  1. Oldroyd, S.H., Bhardwaj, A. Pulmonary Hypertension. (2021). StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482463/
  2. Simonneau, G., Gatzoulis, M.A., Adatia, I., Celermajer, D., Denton, C., Ghofrani, A., Gomez Sanchez, M.A., Krishna Kumar, R., Landzberg, M., Machado, R.F., Olschewski, H., Robbins, I.M., Souza, R. (2013). Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology, 62(25 Suppl), D34–D41. https://doi.org/10.1016/j.jacc.2013.10.029
  3. Hopkins, W., Rubin, L. (2020). Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy. In Finlay, G. (Ed.), UpToDate. Retrieved April 6, 2021, from https://www.uptodate.com/contents/treatment-of-pulmonary-arterial-hypertension-group-1-in-adults-pulmonary-hypertension-specific-therapy
  4. Rubin, L., and Hopkins, W. (2020). The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1). In Finlay, G. (Ed.), UpToDate. Retrieved April 6, 2021, from https://www.uptodate.com/contents/the-epidemiology-and-pathogenesis-of-pulmonary-arterial-hypertension-group-1

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