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Pulmonary Hypertension

By Mark T. Gladwin, MD, Jack D. Myers Professor and Chair, Department of Medicine;Director, University of Pittsburgh School of Medicine;Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute ; Andrea Levine, MD, Fellow, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center

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Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels become constricted and/or obstructed. Severe pulmonary hypertension leads to right ventricular overload and failure. Symptoms are fatigue, exertional dyspnea, and, occasionally, chest discomfort and syncope. Diagnosis is made by finding elevated pulmonary artery pressure (estimated by echocardiography and confirmed by right heart catheterization). Treatment is with pulmonary vasodilators and diuretics. In some advanced cases, lung transplantation is an option. Prognosis is poor overall if a treatable secondary cause is not found.

Pulmonary hypertension is defined as a mean pulmonary arterial pressure 25 mm Hg at rest and a normal (≤ 15 mm Hg) pulmonary artery occlusion pressure (pulmonary capillary wedge pressure) as measured by right heart catheterization.

Etiology

Many conditions and drugs cause pulmonary hypertension. The most common overall causes of pulmonary hypertension are

Pulmonary hypertension is currently classified into 5 groups (see Table: Classification of Pulmonary Hypertension) based on a number of pathologic, physiologic, and clinical factors. In the first group (pulmonary arterial hypertension), the primary disorder affects the small pulmonary arterioles.

A small number of cases of pulmonary arterial hypertension (PAH) occur sporadically, unrelated to any identifiable disorder; these cases are termed idiopathic pulmonary arterial hypertension. Hereditary forms of PAH (autosomal dominant with incomplete penetrance) have been identified; 75% of cases are caused by mutations in bone morphogenetic protein receptor type 2 (BMPR2). Other identified mutations include activin-like kinase type 1 receptor (ALK-1), caveolin 1 (CAV1), endoglin (ENG), potassium channel subfamily K member 3 (KCNK3), and mothers against decapentaplegic homologue 9 (SMAD9) but are much less common, occurring in ~1% of cases. In about 20% of cases of hereditary pulmonary arterial hypertension, the causative mutations are unidentified. A newly identified mutation in the EIF2AK4 gene has been linked to pulmonary veno-occlusive disease, a form of PAH Group 1' (1).

Certain drugs and toxins are risk factors for PAH. Those definitely associated with PAH are appetite suppressants (fenfluramine, dexfenfluramine, aminorex), toxic rapeseed oil, and benfluorex. SSRIs taken by pregnant women are a risk for development of persistent pulmonary hypertension of the newborn (PPHN). Drugs that are likely associated with PAH are amphetamines, methamphetamines, L-tryptophan, and dasatinib (2).

Patients with hereditary causes of hemolytic anemia, such as sickle cell disease, are at high risk of developing pulmonary hypertension (10% of cases based on right heart catheterization criteria). The mechanism is related to intravascular hemolysis and release of cell-free Hb into the plasma, which scavenges nitric oxide, generates reactive oxygen species, and activates the hemostatic system. Other risk factors for pulmonary hypertension in sickle cell disease include iron overload, liver dysfunction, thrombotic disorders, and chronic kidney disease.

Classification of Pulmonary Hypertension

Group

Type

Specific Disorders

1

Pulmonary arterial hypertension (PAH)

Idiopathic PAH

Heritable PAH:

  • BMPR2

  • ALK-1, ENG, SMAD9, CAV1, KCNK3

  • Unknown

Drug- and toxin-induced PAH

Disorders associated with PAH:

  • Connective tissue disorders

  • HIV infection

  • Portal hypertension

  • Congenital heart disorders

  • Schistosomiasis

1'

Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis

Immune mediated:

  • Connective tissue disorders

Heritable PVOD:

  • EIF2AK4

Infectious:

  • Measles

  • Epstein-Barr virus (EBV)

  • Cytomegalovirus (CMV)

  • HIV

Drug- and toxin- induced PVOD

Coagulopathic

1"

Persistent pulmonary hypertension of the newborn (PPHN)

2

Pulmonary hypertension with left-heart disease

Left heart systolic dysfunction

Left heart diastolic dysfunction, including left heart failure with preserved ejection fraction

Valvular heart disorders

Congenital or acquired left heart inflow or outflow tract obstruction and congenital cardiomyopathies

3

Pulmonary hypertension associated with lung disorders, hypoxemia, or both

Alveolar hypoventilation disorders

COPD

Chronic exposure to high altitude

Developmental abnormalities

Interstitial lung disease

Sleep-disordered breathing

Other pulmonary disorders with a mixed restrictive and obstructive pattern

4

Pulmonary hypertension due to chronic thrombotic or embolic disorders

Nonthrombotic pulmonary embolism (eg, due to tumors, parasites, or foreign materials)

Thromboembolic obstruction of distal or proximal pulmonary arteries

5

Miscellaneous (unclear or multifactorial mechanisms)

Hematologic disorders:

  • Chronic hemolytic anemia

  • Myeloproliferative disorders

  • Splenectomy

Systemic disorders:

  • Sarcoidosis

  • Pulmonary Langerhans cell histiocytosis

  • Lymphangioleiomyomatosis

Metabolic disorders:

  • Glycogen storage disease

  • Gaucher disease

  • Thyroid disorders

Other disorders:

  • Fibrosing mediastinitis

  • Tumor, causing obstruction

  • Chronic kidney disease

  • Segmental pulmonary hypertension

Adapted from the Fifth World Symposium on PAH, Nice, 2013; Simonneau G, Gatzoulis MA, AdatiaI, et al: Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 62 (supplement D):D34–D41, 2013.

Etiology references

  • 1. Eyries M, Montani D, Girerd B, et al: EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 46(1):65-9, 2014. doi: 10.1038/ng.2844.

  • 2. Simonneau G, Gatzoulis MA, AdatiaI, et al: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62 (25 Suppl): D34-41, 2013. doi: 10.1038/ng.2844. Erratum in J Am Coll Cardiol. 63(7): 746, 2014.

Pathophysiology

Pathophysiologic mechanisms that cause pulmonary hypertension include

  • Increased pulmonary vascular resistance

  • Increased pulmonary venous pressure

Increased pulmonary vascular resistance is caused by obliteration of the pulmonary vascular bed and/or by pathologic vasoconstriction. Pulmonary hypertension is characterized by variable and sometimes pathologic vasoconstriction and by endothelial and smooth muscle proliferation, hypertrophy, and chronic inflammation, resulting in vascular wall remodeling. Vasoconstriction is thought to be due in part to enhanced activity of thromboxane and endothelin-1 (both vasoconstrictors) and reduced activity of prostacyclin and nitric oxide (both vasodilators). The increased pulmonary vascular pressure that results from vascular obstruction further injures the endothelium. Injury activates coagulation at the intimal surface, which may worsen the hypertension. Thrombotic coagulopathy due to platelet dysfunction, increased activity of plasminogen activator inhibitor type 1 and fibrinopeptide A, and decreased tissue plasminogen activator activity may also contribute. Platelets, when stimulated, may also play a key role by secreting substances that increase proliferation of fibroblasts and smooth muscle cells such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β). Focal coagulation at the endothelial surface should not be confused with chronic thromboembolic pulmonary hypertension, in which pulmonary hypertension is caused by organized pulmonary emboli.

Increased pulmonary venous pressure is typically caused by disorders that affect the left side of the heart and raise left chamber pressures, which ultimately lead to elevated pressure in the pulmonary veins. Elevated pulmonary venous pressures can cause acute damage to the alveolar-capillary wall and subsequent edema. Persistently high pressures may eventually lead to irreversible thickening of the walls of the alveolar-capillary membrane, decreasing lung diffusion capacity. The most common setting for pulmonary venous hypertension is in left heart failure with preserved ejection fraction (HF-PEF), typically in older women who have hypertension and metabolic syndrome. When the transpulmonary gradient (mean pulmonary artery pressure to pulmonary artery occlusion pressure gradient) is > 12 mm Hg or the pulmonary artery diastolic pressure to pulmonary artery occlusion pressure gradient is > 6 mm Hg, prognosis is poor.

In most patients, pulmonary hypertension eventually leads to right ventricular hypertrophy followed by dilation and right ventricular failure. Right ventricular failure limits cardiac output during exertion.

Symptoms and Signs

Progressive exertional dyspnea and easy fatigability occur in almost all patients. Atypical chest discomfort and exertional light-headedness or presyncope may accompany dyspnea and indicate more severe disease. These symptoms are due primarily to insufficient cardiac output caused by right heart failure. Raynaud syndrome occurs in about 10% of patients with idiopathic pulmonary arterial hypertension; the majority are women. Hemoptysis is rare but may be fatal. Hoarseness due to recurrent laryngeal nerve compression by an enlarged pulmonary artery (ie, Ortner syndrome) also occurs rarely.

In advanced disease, signs of right heart failure may include right ventricular heave, widely split 2nd heart sound (S2), an accentuated pulmonic component (P2) of S2, a pulmonary ejection click, a right ventricular 3rd heart sound (S3), tricuspid regurgitation murmur, and jugular vein distention. Liver congestion and peripheral edema are common late manifestations. Pulmonary auscultation is usually normal. Patients also may have manifestations of causative or associated disorders.

Diagnosis

  • Exertional dyspnea

  • Initial confirmation: Chest x-ray, spirometry, ECG, echocardiography, and CBC

  • Identification of underlying disorder: Ventilation/perfusion scan or CT angiography, high-resolution CT (HRCT) of the chest, pulmonary function testing, polysomnography, HIV testing, liver function testing, and autoantibody testing

  • Confirmation of the diagnosis and gauging severity: Pulmonary artery (right heart) catheterization

  • Additional studies to determine severity: 6-min walk distance and plasma levels of N-terminal brain natriuretic peptide (BNP) or pro-BNP

Pulmonary hypertension is suspected in patients with significant exertional dyspnea who are otherwise relatively healthy and have no history or signs of other disorders known to cause pulmonary symptoms.

Patients initially undergo chest x-ray, spirometry, and ECG to identify more common causes of dyspnea, followed by transthoracic Doppler echocardiography to assess right ventricular function and pulmonary artery systolic pressures as well as to detect structural left heart disease that might be causing pulmonary hypertension. CBC is obtained to document the presence or absence of erythrocytosis, anemia, and thrombocytopenia.

The most common x-ray finding in pulmonary hypertension is enlarged hilar vessels that rapidly prune into the periphery and a right ventricle that fills the anterior airspace on lateral view. Spirometry and lung volumes may be normal or detect mild restriction, and diffusing capacity for carbon monoxide (DLco) is usually reduced. Common ECG findings include right axis deviation, R > S in V1, S1Q3T3 (suggesting right ventricular hypertrophy), and peaked P waves (suggesting right atrial dilation).

Additional tests are obtained as indicated to diagnose secondary causes that are not apparent clinically. These tests can include

  • Ventilation/perfusion scanning or CT angiography to detect thromboembolic disease

  • HRCT for detailed information about lung parenchymal disorders

  • Pulmonary function tests to identify obstructive or restrictive lung disease

  • Serum autoantibody tests (eg, antinuclear antibodies [ANA], rheumatoid factor [RF], Scl-70 [topoisomerase I], anti-Ro (anti-SSA), antiribonucleoprotein [anti-RNP], and anticentromere antibodies) to gather evidence for or against associated autoimmune disorders

Chronic thromboembolic pulmonary hypertension is suggested by CT or ventilation/perfusion (VQ) scan findings and is confirmed by arteriography. CT angiography is useful to evaluate proximal clot and fibrotic encroachment of the vascular lumen. Other tests, such as HIV testing, liver function tests, and polysomnography, are done in the appropriate clinical context.

When the initial evaluation suggests a diagnosis of pulmonary hypertension, pulmonary artery catheterization is necessary to measure right atrial, right ventricular, pulmonary artery, and pulmonary artery occlusion pressures; cardiac output; and left ventricular diastolic pressure. Right-sided oxygen saturation should be measured to exclude atrial septal defect. Although finding a mean pulmonary arterial pressure of > 25 mm Hg and a pulmonary artery occlusion pressure ≤ 15 mm Hg in the absence of an underlying disorder identifies pulmonary arterial hypertension, most patients with pulmonary arterial hypertension present with substantially higher pressure (eg, mean of 60 mm Hg). Vasodilating drugs, such as inhaled nitric oxide, IV epoprostenol, or adenosine, are often given during catheterization. Decreasing right-sided pressures in response to these drugs may help in the choice of drugs for treatment. Lung biopsy, once widely done, is neither needed nor recommended because of its associated high morbidity and mortality.

Echocardiography findings of right heart systolic dysfunction (eg, tricuspid annular plane systolic excursion) and certain right heart catheterization results (eg, low cardiac output, high mean pulmonary artery pressures, and high right atrial pressures) indicate that pulmonary hypertension is severe. Other indicators of severity in pulmonary hypertension are assessed to evaluate prognosis and to help monitor responses to therapy. They include a low 6-min walk distance and high plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) or brain natriuretic peptide (BNP).

Once pulmonary hypertension is diagnosed, the patient's family history should be reviewed to detect possible genetic transmission (eg, premature deaths in otherwise healthy members of the extended family). In familial pulmonary arterial hypertension, genetic counseling is needed to advise mutation carriers of the risk of disease (about 20%) and to advocate serial screening with echocardiography. Testing for mutations in the BMPR2 gene in idiopathic pulmonary arterial hypertension can help identify family members at risk.

Prognosis

Five-year survival for treated patients is about 50%. However, some patient registries suggest lower mortality (eg, 20 to 30% at 3 to 5 yr in the French registry and 10 to 30% at 1 to 3 yr in the REVEAL registry), presumably because currently available treatments are superior. Indicators of a poorer prognosis include

  • Lack of response to vasodilators

  • Hypoxemia

  • Reduced overall physical functioning

  • Low 6-min walk distance

  • High plasma levels of NT-pro-BNP or BNP

  • Echocardiographic indicators of right heart systolic dysfunction (eg, tricuspid annular plane systolic excursion)

  • Right heart catheterization showing low cardiac output, high mean pulmonary artery pressures, and/or high right atrial pressures

Patients with systemic sclerosis, sickle cell disease, or HIV infection with pulmonary arterial hypertension have a worse prognosis than those without pulmonary arterial hypertension. For example, patients with sickle cell disease and pulmonary hypertension have a 40% 4-yr mortality rate.

Treatment

  • Avoidance of activities that may exacerbate the condition (eg, cigarette smoking, high altitude, pregnancy, use of sympathomimetics)

  • Idiopathic and familial pulmonary arterial hypertension: IV epoprostenol; inhaled, oral, sc, or IV prostacyclin analogs; oral endothelin-receptor antagonists; oral phosphodiesterase 5 inhibitors, and/or soluble guanylate cyclase stimulators

  • Secondary pulmonary arterial hypertension: Treatment of the underlying disorder

  • Lung transplantation

  • Adjunctive therapy: Supplemental oxygen, diuretics, and/or anticoagulants

Pulmonary arterial hypertension, group 1

Treatment is rapidly evolving.

IV epoprostenol, a prostacyclin analog, improves function and lengthens survival even in patients who are unresponsive to a vasodilator during catheterization. Epoprostenol is currently the most effective therapy for pulmonary arterial hypertension. Disadvantages are the need for continuous central catheter infusion and frequent, troubling adverse effects, including flushing, diarrhea, and bacteremia associated with the indwelling central catheter. Prostacyclin analogs that are inhaled, taken orally, or given sc or IV (iloprost and treprostinil), are available. Selexipag became available in 2015 and is an orally bioavailable small molecule that activates the prostaglandin I2 receptor and lowers mortality and morbidity rates (1).

Three oral endothelin-receptor antagonists, bosentan, ambrisentan, and macitentan, are now available. Sildenafil, tadalafil, and vardenafil, which are oral phosphodiesterase 5 inhibitors, can also be used. Riociguat is the first available soluble guanylate cyclase stimulator. A 2015 study compared the efficacy of monotherapy with oral ambrisentan 10 mg and oral tadalafil 40 mg to combination therapy of these same 2 drugs all taken once daily (2). Adverse clinical outcomes (death, hospitalization, disease progression, or poor long-term outcome) were fewer with combination therapy than with monotherapy. Combination therapy also significantly reduced NT-proBNP levels and increased 6-min walk distances and the percentage of satisfactory clinical responses. This study supports targeting multiple pathways by beginning treatment of pulmonary arterial hypertension with combination therapy. However, phosphodiesterase 5 inhibitors cannot be combined with riociguat because both drug classes increase cyclic guanosine monophosphate (cGMP) levels, and the combination can lead to dangerous hypotension. Patients with severe right heart failure who are at high risk of sudden death may benefit from early therapy with an intravenous or subcutaneous prostacyclin analog.

Sequential combination therapy is an alternative to initial combination therapy. Studies confirm that morbidity and mortality decreased with macitentan, whether used alone or when combined with other drugs to treat PAH. Morbidity and mortality are lower with selexipag than with placebo, whether selexipag is used alone or combined with a phosphodiesterase 5 inhibitor, an endothelin-receptor antagonist, or both (3, 4). Finally, riociguat increased 6-min walk distance, decreased pulmonary vascular resistance, and improved functional class, whether used as monotherapy or as sequential combination therapy in patients receiving an endothelin-receptor antagonist or prostanoid (5).

Prostacyclin analogs, endothelin-receptor antagonists, and guanylate cyclase stimulators have been studied primarily in idiopathic PAH; however, these drugs can be used cautiously (attending to drug metabolism and drug-drug interactions) in patients with PAH due to connective tissue disease, HIV, or portopulmonary hypertension. Vasodilators should be avoided in patients with PAH due to pulmonary veno-occlusive disease due to the risk of catastrophic pulmonary edema (6).

Lung transplantation offers the only hope of cure but has high morbidity because of rejection (bronchiolitis obliterans syndrome) and infection. The 5-yr survival rate is 50%. Lung transplantation is reserved for patients with New York Heart Association class IV disease (defined as dyspnea associated with minimal activity, leading to bed to chair limitations) or complex congenital heart disease in whom all therapies have failed and who meet other health criteria to be a transplant candidate.

Many patients require adjunctive therapies to treat heart failure, including diuretics, and most should receive warfarin unless there is a contraindication.

Pulmonary hypertension, groups 2 to 5

Primary treatment involves management of the underlying disorder. Patients with left-sided heart disease may need surgery for valvular disease. Patients with lung disorders and hypoxia benefit from supplemental oxygen as well as treatment of the primary disorder. Traditional PAH therapies should be used cautiously because they may contribute to V/Q mismatch by reversing underlying hypoxic vasoconstriction. The first-line treatment for patients with severe pulmonary hypertension secondary to chronic thromboembolic disease includes surgical intervention with pulmonary thromboendarterectomy. During cardiopulmonary bypass, an organized endothelialized thrombus is dissected along the pulmonary vasculature in a procedure more complex than acute surgical embolectomy. This procedure cures pulmonary hypertension in a substantial percentage of patients and restores cardiopulmonary function; operative mortality is < 10% in centers that have extensive experience. Riociguat has improved exercise capacity and pulmonary vascular resistance in patients who are not surgical candidates or for whom the risk to benefit ratio is too high (5).

Patients with sickle cell disease who have pulmonary hypertension are aggressively treated using hydroxyurea, iron chelation, and supplemental oxygen as indicated. In patients with pulmonary arterial hypertension and elevated pulmonary vascular resistance confirmed by right heart catheterization, selective pulmonary vasodilator therapy (with epoprostenol or an endothelin-receptor antagonist) can be considered. Sildenafil increases incidence of painful crises in patients with sickle cell disease and so should be used only if patients have limited vaso-occlusive crises and are being treated with hydroxyurea or transfusion therapy.

Treatment references

  • 1. Sitbon O, Channick R, Chin KM, et al: Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 373: 2522-33, 2015. doi: 10.1056/NEJMoa1503184.

  • 2. Galie N, Barbera JA, Frost AE, et al: Initial use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 373: 834-44, 2015. doi: 10.1056/NEJMoa1413687.

  • 3. Tamura Y, Channick RN: New paradigm for pulmonary arterial hypertension treatment. Curr Opin Pulm Med 22(5): 429-33, 2016. doi: 10.1097/MCP.0000000000000308.

  • 4. McLaughlin VV, Channick R, Chin K, et al: Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: Results of the GRIPHON study. J Am Coll Cardiol 65 (suppl): A1538 , 2015.

  • 5. Ghofrani HA, Galiè N, Grimminger F, et al: Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369(4): 330-40, 2013. doi: 10.1056/NEJMoa1209655.

  • 6. Galiè N, Humbert M, Vachiery JL, et al: 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1): 67-119, 2016. doi: 10.1093/eurheartj/ehv317.

Key Points

  • Pulmonary hypertension is classified into 5 groups.

  • Suspect pulmonary hypertension if patients have dyspnea unexplained by another clinically evident cardiac or pulmonary disorder.

  • Begin diagnostic testing with chest x-ray, spirometry, ECG, and transthoracic Doppler echocardiography.

  • Confirm the diagnosis by right heart catheterization.

  • Treat group 1 by giving pulmonary vasodilators and, if these are ineffective, considering lung transplantation.

  • Treat groups 2 to 5 by managing the underlying disorder, treating symptoms, and sometimes other measures.

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