Pulmonary hypertension and cor pulmonale

Pulmonary hypertension (PH) is defined by an elevated mean pulmonary arterial pressure (mPAP) > 20 mm Hg at rest. PH is divided into five groups based on the underlying causes: pulmonary arterial hypertension (PAH), left heart disease, chronic lung disease, pulmonary artery obstruction (e.g., due to chronic thromboembolic disease), and unclear multifactorial mechanisms. Over time, the increase in right ventricular pressure may result in structural changes (e.g., dilation or hypertrophy) or impaired function of the right ventricle, a cardiac condition known as cor pulmonale. While PH is often asymptomatic in the early stages, symptoms such as dyspnea on exertion, fatigue, cyanosis, and syncope appear in later stages. Echocardiograms are used as an initial noninvasive test to estimate pulmonary artery pressure and to evaluate for right ventricular dysfunction. Right heart catheterization provides a definite diagnosis by measuring mPAP but is not always required. Treatment mainly consists of managing the underlying cause of PH and preventing disease progression. Patients with PAH (i.e., Group 1 PH) usually benefit from treatment with calcium channel blockers and other pulmonary vasodilators, while their benefit is unclear for other groups. In most cases, evaluation by a PH specialist and referral to specialized centers is recommended. Acute decompensated pulmonary hypertension is a high-mortality complication that can occur and is very challenging to treat, typically requiring intensive care, and in some cases, ECMO and lung transplant. Some patients can develop acute or chronic cor pulmonale, which requires treatment of the underlying cause and, in some cases, acute stabilization.

This article focuses primarily on adult PH. See “Persistent pulmonary hypertension of the newborn (PPHN)” for information on PH in infants.

• Pulmonary hypertension (PH) ^[1][2][3]
  • An elevated mean pulmonary arterial pressure (mPAP) > 20 mm Hg at rest (normal: 10–14 mm Hg) ^[1][4][5][6]
  • Subtypes
    • Precapillary pulmonary hypertension
      • Pulmonary vascular remodeling leads to increased pulmonary vascular resistance.
      • Caused by pulmonary arterial hypertension, chronic lung disease, chronic thromboembolism, or certain multifactorial mechanisms
      • Right heart catheterization shows increased pulmonary vascular resistance (≥ 3 Wood units) and reduced pulmonary capillary wedge pressure (PCWP).
    • Postcapillary pulmonary hypertension
      • Results from increased pulmonary venous pressure
      • Caused by left heart disease and certain multifactorial mechanisms
      • Right heart catheterization shows increased PCWP; pulmonary vascular resistance is typically normal.
• Pulmonary arterial hypertension (PAH): a type of precapillary pulmonary hypertension characterized by loss and obstructive remodeling of the pulmonary vascular bed that results in increased pulmonary arterial pressure (See “Etiology” for underlying causes) ^[7]

Pulmonary arterial hypertension is a cause of pulmonary hypertension. However, not all pulmonary hypertension is caused by pulmonary arterial hypertension.

• PAH: more commonly affects female individuals

Epidemiological data refers to the US, unless otherwise specified.

The following etiologies are grouped according to the World Health Organization (WHO) classification system for pulmonary hypertension. ^[7][8][9]

Pulmonary arterial hypertension (Group 1 PH)

• Idiopathic
• Hereditary (e.g., BMPR2 loss-of-function mutation)
  • Encodes a set of inhibitors of vascular smooth muscle cell proliferation
  • Associated with a poor prognosis
• Drug-induced ^[8]
  • Methamphetamine (and possibly amphetamines and cocaine)
  • Sympathomimetic appetite suppressants (e.g., diethylpropion, fenfluramine)
  • Chemotherapeutic agents, e.g., dasatinib
• Associated conditions
  • Connective tissue diseases, e.g., systemic sclerosis
  • Portopulmonary hypertension
  • Congenital heart disease (e.g., left-to-right shunt, Eisenmenger syndrome)
  • HIV infection
  • Schistosomiasis
• PPHN

Left heart disease (Group 2 PH)

• Congestive heart failure (CHF): e.g., HFrEF, HFpEF
• Valvular heart diseases, e.g., aortic valve stenosis, mitral valve stenosis
• Other acquired or congenital heart diseases causing postcapillary PH (e.g., hypoplastic left heart, aortic coarctation, HCM, LVOT obstruction)

Chronic lung diseases (Group 3 PH)

• Obstructive lung diseases
  • COPD, emphysema
  • Obstructive sleep apnea
• Restrictive lung diseases: e.g., interstitial lung disease
• High altitude (e.g., high-altitude pulmonary hypertension)
• Others: e.g., developmental lung disorders, mixed obstructive and restrictive lung diseases

Pulmonary artery obstruction (Group 4 PH) ^[8]

• Chronic thromboembolic pulmonary hypertension (CTEPH): Chronic thromboembolic occlusion of the pulmonary vessels
  • Recurrent microthrombi narrow the cross-sectional area of pulmonary vessels.
  • Affected individuals are at high risk for pulmonary embolism.
• Other causes of pulmonary artery (PA) obstruction: extrinsic compression by mediastinal tumors or masses, arteritis involving PAs, congenital PA stenoses, fibrosing mediastinitis ^[10]

Unclear multifactorial mechanisms (Group 5 PH)

• Hematologic disorders (e.g., sickle cell disease, MPNs, chronic hemolytic anemias)
• Systemic disorders (e.g., sarcoidosis, neurofibromatosis, Langerhans cell histiocytosis)
• Metabolic disorders (e.g., metabolic syndrome, chronic kidney disease, Gaucher disease)
• Complex congenital heart disease ^[11]

Conditions at high risk of PH ^[12]

Periodic screening and monitoring for clinical features of PH is suggested for patients with any of the following:

• Family history of PAH
• Genetic screening positive in the patient or 1st-degree relative (e.g., for BMPR2)
• Exposure to drug or toxin known to cause PH (e.g., methamphetamine, fenfluramine)
• Scleroderma
• Mixed connective tissue diseases
• HIV
• Portal hypertension
• Recent (e.g., within the last 3–6 months) surgical repair of a congenital left-to-right shunt

• Increased pulmonary vascular resistance
  • Occlusive vasculopathy (e.g., idiopathic pulmonary arterial hypertension, connective tissue diseases)
  • Hypoxic pulmonary vasoconstriction: chronic hypoxic pulmonary vasoconstriction → airway smooth muscle hypertrophy (medial hypertrophy) and pulmonary vascular bed destruction → ↑ pulmonary vascular resistance (e.g., COPD, obstructive sleep apnea)
  • Increased pulmonary vessel pressure → right heart hypertrophy → right heart failure (cor pulmonale) and arrhythmias → death
  • Inflammation (e.g., COPD) → ↑ inflammatory cell infiltration of intima → thickened endothelial wall → intimal fibrosis
  • PAH associated with endothelial dysfunction: ↑ endothelin and ↓ vasodilators (e.g., NO, prostacyclins) → vasoconstriction → arteriosclerosis, plexiform lesions ^[13]
• Increased pulmonary venous pressure: volume or pressure overload from left-sided heart disease (e.g. mitral valve regurgitation)
• Increased pulmonary blood flow
  • Left-to-right shunt (e.g., ASD, VSD, PDA)
  • Portopulmonary hypertension
  • Sickle cell anemia: Individuals with SCD have an anemia-induced increase in cardiac output.

Increased pressure in pulmonary circuit → ↑ right ventricular afterload → dilatation and/or hypertrophy of the right heart → right heart failure and arrhythmias → death.

Patients with early PH may be asymptomatic.

• Common clinical features
  • Dyspnea and/or syncope on exertion
  • Chest pain
  • Fatigue
  • Cyanosis
  • Clinical features of underlying etiology (e.g., COPD, OSA, PE)
• Less common clinical features
  • Hoarseness
  • Cough, hemoptysis
• Physical examination
  • Loud and palpable second heart sound (often split)
  • Jugular vein distention
  • Symptoms of right heart failure (e.g., palpitations, peripheral edema, hepatojugular reflux)
  • Nail clubbing
  • Parasternal heave

Clinical symptoms may be inconspicuous, especially in the early stages when symptoms of underlying diseases such as COPD may eclipse those of PH.

Approach ^[4][14]

Due to overlapping clinical features, PH is often diagnosed during the evaluation of more common differential diagnoses and etiologies of dyspnea, chest pain, and fatigue (e.g., COPD, CHF, cardiomyopathy, PE, OSA), or identified during screening echocardiography or cardiac catheterization (e.g., preoperative assessment).

• Screen and monitor patients with conditions at high risk of PH for suggestive clinical features. ^[12]
• If clinical suspicion is high for PH, perform transthoracic echocardiography (TTE) to noninvasively identify markers of elevated pulmonary artery pressure.
• If TTE suggests PH and the etiology is not yet known, begin evaluation for the most common underlying causes.
  • Identify clinical evidence of left heart disease and/or chronic lung disease and consider supportive investigations (e.g., ECG, CXR, BNP, PFTs) as directed by clinical suspicion.
  • If these are inconclusive, perform a V/Q scan to evaluate for thromboembolic disease.
• If the etiology remains unclear, TTE is equivocal, and/or severe PH is identified (see “Severity assessment”):
  • Consult a PH specialist.
  • Refer for confirmatory right heart catheterization.
  • Consider more advanced investigations, e.g., genetic screening.

Right heart catheterization can typically be deferred if echocardiography strongly suggests PH, the underlying etiology is clear (e.g., COPD), and the disease is nonsevere.

CXR, ECG, and laboratory studies are not required to diagnose pulmonary hypertension, but they may support the diagnosis and help identify the underlying etiology.

Transthoracic echocardiography (TTE) ^[4][7]

For clinical purposes, noninvasive estimates of mPAP and its surrogate markers, pulmonary artery systolic pressure (PASP) and right ventricular systolic pressure (RVSP), are typically accurate enough to make a diagnosis of PH and guide therapy. ^[15]

• Indication: first-line study in all patients with suspected PH ^[7]
• Findings: A combination of findings can be used to estimate PASP, RVSP, and mPAP. ^[16][17]
  • ↑ Tricuspid regurgitation velocity (TRV)
  • Right ventricular pressure overload
    • Flattening of the interventricular septum
    • Hypertrophy of the right ventricle
    • Dilation of the coronary sinus ^[18][19]
  • Right ventricular failure
    • Dilation and hypokinesis of the right ventricle
    • Right atrial dilation
  • Underfilled left heart chambers
  • Evidence of underlying cardiovascular disease
    • Left ventricular dysfunction
    • Mitral regurgitation
    • Mitral stenosis
    • Thrombus in the right heart, pulmonary artery, or IVC

Echocardiography can also be used to screen patients at high risk for early features of pulmonary hypertension.

Right heart catheterization ^[1][4]

Obtain right heart catheterization in consultation with a PH specialist to ensure that individual patient-specific questions are addressed.

• Indications
  • Confirmatory test for pulmonary hypertension
  • Detailed assessment of other cardiac diseases (e.g., valvular heart disease, coronary artery disease)
• Findings: mPAP > 20 mm Hg at rest is considered diagnostic for PH. ^[1][4]
  • Precapillary pulmonary hypertension, e.g., PAH
    • Pulmonary vascular resistance ≥ 3 Wood units (normal: 0.25–1.6 Wood units)
    • PCWP ≤ 15 mm Hg
  • Postcapillary pulmonary hypertension and mixed pre- and postcapillary pulmonary hypertension, e.g., secondary to left heart disease
    • Pulmonary vascular resistance is variable.
    • PCWP > 15 mm Hg

ECG ^[20]

• Typically shows nonspecific changes secondary to increased right ventricular workload
  • Right ventricular hypertrophy
  • Right-axis deviation
  • P pulmonale
  • Incomplete or complete right bundle branch block
  • S1Q3T3
• May also show signs of underlying etiology, e.g., ischemic heart disease

Chest x-ray ^[14][21]

Chest x-ray findings may help to support the diagnosis of PH. ^[21]

• Right heart hypertrophy
  • Prominent right heart border
  • Lateral view: loss of retrosternal space due to right ventricular enlargement
• Vascular changes
  • Enlarged central pulmonary arteries
  • Reduction in number and size of vessels of the peripheral pulmonary vasculature (referred to as pulmonary vascular pruning)
• Signs of the underlying cause (e.g., nodular opacities in interstitial lung disease, hyperinflation in COPD, pulmonary venous congestion in left heart disease)

Investigations of the underlying cause

Consider adding the following based on clinical suspicion of the underlying etiology:

• Left heart disease: NT-proBNP (See also “Diagnostics” in “CHF” and “Mitral regurgitation.”)
• Chronic lung disease (See also "Diagnostics" in “COPD,” “ILD,” and “OSA.”)
  • Arterial blood gas
  • Pulmonary function tests
  • Diffusion capacity for carbon monoxide
  • Consider CT chest and sleep studies.
• Chronic pulmonary thromboembolism: V/Q scan (See also “ PE diagnostics.”)
• Others: Consider if etiology remains unclear after investigations for left-heart disease, chronic lung disease, and CTEPH. ^[22]
  • Drug-induced: e.g., urine drug screen
  • Portopulmonary hypertension: Send liver chemistries, consider ultrasound liver.
  • Infection (based on risk factors): e.g., screen for HIV and schistosomiasis.
  • Connective tissue disease (most commonly systemic sclerosis): e.g., antinuclear antibodies, anticentromere antibodies, anti-Scl-70 and anti-RNA polymerase III
  • Sarcoidosis: e.g., inflammatory markers, serum calcium, ACE levels
  • Hereditary: e.g., genetic testing

If PH is not explained by left heart disease or chronic lung disease, perform a V/Q scan to exclude CTEPH. ^[7]

Approach

• Treat acute decompensated PH urgently, if present.
• Determine functional severity and screen for high-risk features; consult PAH specialist and strongly consider admission to PAH specialty center if present.
• Tailor treatment according to WHO PH group (see “Long-term management”).
  • Start supportive treatment to reduce symptoms and slow progression.
  • Consider directed therapies for Group I PH (i.e., PAH): e.g., CCBs and/or other pulmonary vasodilators.
  • Treat the underlying cause of PH (e.g., CPAP for patients with OSA, CHF treatment, anticoagulation for PE).

Therapy should be initiated early before irreversible changes in the pulmonary vessels occur.

Pulmonary vasodilators are not typically beneficial for patients with Group 2 PH (left heart disease) or Group 3 PH (chronic lung disease).

Severity assessment

WHO functional class for PH (WHO-FC) ^[23]

The WHO-FC system for pulmonary hypertension is widely used to help guide therapy. ^[12][24]

• WHO-FC I: No limitations in physical activity; no significant symptoms during most regular ADLs and IADLs
• WHO-FC II: Slightly limited physical activity; no rest symptoms, but some symptoms during IADLs
• WHO-FC III: Noticeably limited physical activity; consistent symptoms during basic ADLs
• WHO-FC IV: Severely limited physical activity; frequent and/or progressive symptoms with almost any activity or even at rest

High-risk features ^[24]

The presence of any of the following features typically warrants admission to a PAH specialty center for evaluation and treatment. Stabilization in an ICU setting may be required in some cases.

• Rapidly progressing symptoms
• Unclear PH etiology
• Thromboembolic disease
• Severe PH (e.g., WHO-FC III-IV)
• Significantly elevated NT-proBNP
• RV dysfunction

All patients

• Assess for shock (e.g., cardiogenic shock or obstructive shock).
• Consult a PH specialist.
• Admit to ICU and start continuous monitoring.
• Identify and treat any precipitating factors.
  • Supraventricular arrhythmias
  • Intravascular catheter infection
  • Pulmonary embolism
  • Sepsis
  • Missed or interrupted medical treatment, e.g., IV prostacyclin pump failure

Respiratory support ^[26][27]

• Target SpO₂ > 90%; consider HFNC for patients with high oxygen demand. ^[4]
• If possible, avoid intubation and positive pressure ventilation (PPV).
• Extreme caution and specialist consultation is advised if mechanical ventilation is unavoidable. ^[27]

Do not attempt to intubate or mechanically ventilate patients with acute decompensated PH without guidance from specialists in critical care and pulmonary hypertension.

Hemodynamic support ^[26]

Consult a PH specialist to guide therapy and tailor treatment to individual needs.

• General treatment goals
  • Targeting euvolemia
    • Requires very close assessment of volume status and fluid balance monitoring as both hypovolemia and hypervolemia are harmful to cardiac function.
    • Typically involves careful balancing of IV diuretics for volume overload and IV fluid challenges for hypovolemia.
  • RV afterload reduction: e.g., with pulmonary vasodilators (prescribed by a PH specialist) ^[28]
  • Optimizing cardiac output and peripheral perfusion: typically with a combination of inodilators (e.g., dobutamine) and other vasopressors (e.g, norepinephrine)
• Refractory right heart failure: Consider extracorporeal life support as a bridge to urgent lung or heart-lung transplant. ^[26]
• Patients with an IV prostacyclin pump (e.g., epoprostenol) ^[29]
  • Consult the patient's PAH specialist immediately for any mechanical issues (e.g., suspected device failure or problems with tube patency).
  • Do not stop the infusion or adjust dosage or flow rates without guidance from the treating specialist.

Management of acute decompensated PH is extremely challenging and should take place in a specialized center whenever possible. Consult a PAH specialist immediately for any issues with IV prostacyclin pumps. ^[29]

Consider individualized treatment based on the underlying condition and patient characteristics under the guidance of an appropriate specialist (e.g., cardiology, pulmonology). Calcium channel blockers and other pulmonary vasodilators are the mainstay of treatment for Group I PH (i.e., PAH), while treatment of the underlying cause is the primary focus for the other WHO PH groups.

Supportive care ^[24][30][31]

• Oxygen therapy for patients with COPD and a PaO₂ < 60 mm Hg
• Diuretics for volume overload
• Immunizations
• Psychosocial support
• Exercise training ^[32]
• Avoidance of the following, whenever possible: ^[12]
  • Pregnancy: Offer counseling on contraception options. ^[4]
  • High altitude
  • Nonessential surgeries
• Consider referral to palliative care for patients with advanced PH and distressing symptoms.

Overdiuresis may reduce right ventricular preload, resulting in decreased cardiac output and subsequent complications, e.g., prerenal failure.

Patients who have a normal oxygen saturation at rest may desaturate with exercise or while sleeping; perform exercise and nocturnal oximetry and treat accordingly.

Group 1 PH: PAH ^[12][33]

Refer all patients to a specialist PAH center for assessment and vasoreactivity testing prior to starting pulmonary vasodilator therapy aimed at decreasing pulmonary vascular resistance.

• Vasoreactivity testing: A test performed during right heart catheterization to identify responsiveness to calcium channel blocker (CCB) therapy; mPAP is measured after administration of a vasodilator (e.g., inhaled nitric oxide) ^[33]
  • Vasoreactive: Treat with CCBs.
  • Nonvasoreactive: Consider other pulmonary vasodilator therapies.
• Calcium channel blockers: First-line pulmonary vasodilator therapy for patients with PAH and positive vasoreactivity testing and no signs of RHF or other contraindications to CCBs ^[12]
• Other pulmonary vasodilator therapies: typically second-line agents, the choice of which depends on symptom severity (e.g., WHO-FC) and should be guided by a PAH specialist. ^[7][12]
  • Most patients (e.g., WHO-FC II-III) receive initial combination oral therapy (e.g., PDE-5 inhibitor PLUS endothelin receptor antagonist).
  • Most high-risk patients (e.g., WHO-FC III-IV or rapidly progressive disease) are treated with parenteral prostacyclins (either as first-line or in combination)

• Surgical therapy for refractory PAH
  • Atrial septostomy (right-to-left shunt)
  • Heart-lung/bilateral lung transplantation ^[37][38]

Group 2 PH: Left-sided heart disease ^[7][14]

• Treat systemic hypertension (see “Hypertension management”).
• Provide CHF treatment as needed.
  • Consider diuretics to manage volume overload.
  • Restrict sodium intake.
• Consider replacement or repair of damaged valves (see “Aortic valve stenosis”, “Aortic regurgitation, “Mitral valve stenosis”, and “Mitral regurgitation”).
• Aggressively treat any atrial fibrillation (see “Management of Afib with RVR” and “Management of Afib in CHF”).
• Treat comorbidities, e.g., diabetes, obesity, management of ASCVD.

Group 3 PH: Chronic lung disease ^[7][14]

• Start long-term oxygen therapy.
• Optimize treatment of underlying COPD or interstitial lung disease.
• Consider lung transplantation.

Group 4 PH: PA obstruction

• CTEPH ^[39]
  • Pulmonary endarterectomy is the first-line treatment.
  • Consider balloon pulmonary angioplasty if the patient is ineligible for pulmonary endarterectomy or if PH persists or recurs.
  • Consider certain pulmonary vasodilators in select cases.
  • Treat associated hypoxia and heart failure.
  • Lifelong anticoagulation
• Extrinsic compression (rare): Consider treatment tailored to the individual extrinsic etiology. ^[10]

Group 5 PH: Multifactorial diseases ^[40]

• Direct initial therapy at the underlying cause of PH.
• Consider pulmonary vasodilator therapy on a case-by-case basis.

Definition ^[41]

Altered structure (i.e., hypertrophy, dilation) or impaired function of the right ventricle due to pulmonary hypertension resulting from a primary disorder of the respiratory or pulmonary artery system

Cor pulmonale is also known as pulmonary heart disease because it is caused by right ventricular dysfunction resulting from lung disease, not cardiac disease. ^[22]

Acute cor pulmonale ^[22]

• Pathophysiology: a sudden increase in right ventricular afterload results in right ventricular dilation and dysfunction
• Etiology: : includes acute massive pulmonary embolism (most common) and ARDS ^[42]
• Clinical features: acute onset, chest pain, shortness of breath, hypotension, tachycardia, syncope, symptoms of deep vein thrombosis

Chronic cor pulmonale ^[22]

• Pathophysiology: Increased right ventricular afterload leads to progressive right ventricular hypertrophy that over time results in right ventricular dilation and dysfunction.
• Etiology: caused by diseases of the lung parenchyma and pulmonary vasculature or disorders of chronic hypoxia
  • Lung parenchyma: COPD , interstitial lung disease, bronchiectasis
  • Pulmonary vasculature: PAH, chronic thromboembolic pulmonary hypertension
  • Chronic hypoxia: obesity hypoventilation syndrome, obstructive sleep apnea, kyphoscoliosis, neuromuscular disorders
• Clinical features
  • Similar to clinical features of pulmonary hypertension.
  • Prominent symptoms of right heart failure

Diagnostics ^[41]

• Echocardiogram shows right ventricular dilation, hypertrophy, or dysfunction.
• Further workup depends on the suspected underlying cause; see “Diagnostics” of “Pulmonary hypertension.”
• For patients with suspected acute cor pulmonale, urgently perform diagnostic studies for PE.

Treatment

• Treatment depends on the underlying cause (see “Treatment of pulmonary hypertension”).
• Patients with acute cor pulmonale typically require:
  • Stabilization (see “Acute decompensated PH”)
  • Intensive management of the underlying cause (see “Treatment of PE”, “Massive PE” and “Treatment of ARDS”).