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Pulmonary Hypertension

By

Mark T. Gladwin

, MD, University of Pittsburgh School of Medicine;


Andrea R. Levine

, MD, University of Maryland School of Medicine

Medically Reviewed Sep 2022
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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 may become constricted, pruned, lost, 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.

There are three distinct hemodynamic profiles of pulmonary hypertension (see also table Hemodynamic Profiles of Pulmonary Hypertension Hemodynamic Profiles of Pulmonary Hypertension Hemodynamic Profiles of Pulmonary Hypertension ):

  • Pre-capillary pulmonary hypertension

  • Post-capillary pulmonary hypertension

  • Combined pre- and post-capillary pulmonary hypertension

Table

Etiology of Pulmonary Hypertension

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 Classification of Pulmonary Hypertension Classification of Pulmonary Hypertension ) based on a number of pathologic, physiologic, and clinical factors. In the first group (pulmonary arterial hypertension [PAH]), the primary disorder affects the small pulmonary arterioles.

A small number of cases of AH occur sporadically, unrelated to any identifiable disorder; these cases are termed idiopathic PAH.

Hereditary forms of PAH (autosomal dominant with incomplete penetrance) have been identified; mutations of the following genes have been found:

  • Activin-like kinase type 1 receptor (ALK-1)

  • Bone morphogenetic protein receptor type 2 (BMPR2)

  • Caveolin 1 (CAV1)

  • Endoglin (ENG)

  • Growth differentiation factor 2 (GDF2)

  • Potassium channel subfamily K member 3 (KCNK3)

  • Mothers against decapentaplegic homologue 9 (SMAD9)

  • T-box transcription factor 4 (TBX4)

Mutations in BMPR2 cause 75% of cases. The other mutations are much less common, occurring in about 1% of cases.

In about 20% of cases of hereditary PAH, the causative mutations are unidentified.

A mutation in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) has been linked to pulmonary veno-occlusive disease, a form of PAH Group 1' (1, 2 Etiology references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Certain drugs and toxins are risk factors for PAH. Those definitely associated with PAH are appetite suppressants (fenfluramine, dexfenfluramine, aminorex), toxic rapeseed oil, benfluorex, amphetamines, methamphetamines, and dasatinib. Similarly, other protein kinase inhibitors have also been linked to drug-induced pulmonary hypertension (3 Etiology references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). Selective serotonin reuptake inhibitors taken by pregnant women are a risk for development of persistent pulmonary hypertension of the newborn Persistent Pulmonary Hypertension of the Newborn Persistent pulmonary hypertension of the newborn is the persistence of or reversion to pulmonary arteriolar constriction, causing a severe reduction in pulmonary blood flow and right-to-left... read more . Drugs that are likely or possibly associated with PAH are amphetamine-like drugs, cocaine, phenylpropanolamine, St. John's wort, interferon-alpha, interferon-beta, alkylating agents, bosutinib (only possibly linked to PAH), direct-acting antiviral agents against hepatitis C virus, leflunomide, indirubin, and L-tryptophan (4 Etiology references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Patients with hereditary causes of hemolytic anemia Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more Overview of Hemolytic Anemia , such as sickle cell disease Sickle Cell Disease Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in people with African ancestry. It is caused by homozygous inheritance of genes for hemoglobin... read more 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 hemoglobin 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 Overview of Iron Overload Typical adults lose about 1 mg iron (Fe) per day in shed epidermal and gastrointestinal cells; menstruating females lose on average an additional 0.5 to 1 mg/day from menses. This iron loss... read more , liver dysfunction, thrombotic disorders Overview of Thrombotic Disorders In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more , and chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more Chronic Kidney Disease .

Table

Etiology references

Pathophysiology of Pulmonary Hypertension

Pathophysiologic mechanisms that cause pulmonary hypertension include

  • Increased pulmonary vascular resistance

  • Increased pulmonary venous pressure

  • Increased pulmonary venous flow due to congenital heart diseases

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. Mutations in the BMPR2 gene account for most cases of hereditary PAH and also occurs in idiopathic PAH. Aberrant BMPR2 signaling disturbs the TGF-β/BMP balance, favoring a pro-proliferative and anti-apoptotic response in pulmonary artery smooth muscle and endothelial cells. BMPR2 signaling, therefore, has become an increasingly studied drug target for pulmonary hypertension.

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 LV failure Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more LV failure with preserved ejection fraction (HFpEF), typically in older women who have hypertension and metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal fat), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia. Causes... read more .

In pulmonary hypertension secondary to HFpEF, certain hemodynamic parameters predict an increased risk of death. These parameters include

  • Transpulmonary gradient (TPG, defined as the mean pulmonary artery pressure to pulmonary artery occlusion pressure gradient) > 12 mm Hg

  • Pulmonary vascular resistance (PVR, defined as the TPG divided by the cardiac output) ≥ 3 Woods units

  • Diastolic pulmonary gradient (DPG, defined as the pulmonary artery diastolic pressure to pulmonary artery occlusion pressure gradient) ≥ 7 mm Hg

In most patients, pulmonary hypertension eventually leads to right ventricular hypertrophy followed by dilation and right ventricular failure RV failure Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more RV failure . Right ventricular failure limits cardiac output during exertion.

Symptoms and Signs of Pulmonary Hypertension

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 Raynaud Syndrome Raynaud syndrome is vasospasm of parts of the hand in response to cold or emotional stress, causing reversible discomfort and color changes (pallor, cyanosis, erythema, or a combination) in... read more Raynaud Syndrome occurs in about 10% of patients with idiopathic pulmonary arterial hypertension; the majority are women. Hemoptysis Hemoptysis Hemoptysis is coughing up of blood from the respiratory tract. Massive hemoptysis is production of ≥ 600 mL of blood (about a full kidney basin’s worth) within 24 hours. Most of the lung’s blood... read more 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, possibly with v-waves. 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 of Pulmonary Hypertension

  • Exertional dyspnea

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

  • Identification of underlying disorder: Spirometry, ventilation/perfusion scanning or CT angiography, high-resolution CT (HRCT) of the chest, pulmonary function testing, polysomnography, HIV testing, complete blood count, liver tests, and autoantibody testing

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

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

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 show mild restriction, and diffusing capacity for carbon monoxide (DLCO) is usually reduced. Other ECG findings include right axis deviation, R > S in V1, S1Q3T3 (suggesting right ventricular hypertrophy), and peaked P waves (suggesting right atrial dilation) in lead II.

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 in patients in whom CT angiography is not done

  • 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), anti-ribonucleoprotein [anti-RNP], and anticentromere antibodies) to gather evidence for or against associated autoimmune disorders

Chronic thromboembolic pulmonary hypertension is suggested by CT angiography 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 tests, and polysomnography, are done in the appropriate clinical context.

  • Right atrial pressure

  • Right ventricular pressure

  • Pulmonary artery pressure

  • Pulmonary artery occlusion pressure

  • Cardiac output

  • Left ventricular diastolic pressure

Right-sided oxygen saturation should be measured to exclude left-to-right shunt through atrial septal defect Atrial Septal Defect (ASD) An atrial septal defect (ASD) is an opening in the interatrial septum, causing a left-to-right shunt and volume overload of the right atrium and right ventricle. Children are rarely symptomatic... read more . Although finding a mean pulmonary arterial pressure of > 20 mm Hg and a pulmonary artery occlusion pressure ≤ 15 mm Hg in the absence of an underlying disorder identifies pulmonary arterial hypertension (PAH), most patients with PAH present with substantially higher pressure (eg, mean of 60 mm Hg).

Drugs that acutely dilate the pulmonary vessels, 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 Echocardiography This photo shows a patient having echocardiography. This image shows all 4 cardiac chambers and the tricupsid and mitral valves. Echocardiography uses ultrasound waves to produce an image of... read more Echocardiography findings of right heart systolic dysfunction (eg, tricuspid annular plane systolic excursion) and certain right heart catheterization results (eg, low cardiac output, very 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-minute walk Six-minute walk test The two most common forms of exercise testing used to evaluate pulmonary disorders are the 6-minute walk test Cardiopulmonary exercise testing This simple test measures the maximal distance... read more 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 PAH, 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 PAH can help identify family members at risk. If patients are negative for BMPR2, gene testing for SMAD9, KCN3, and CAV1 can further help identify family members at risk.

Prognosis for Pulmonary Hypertension

Five-year survival for treated patients is about 50%. However, some patient registries suggest lower mortality (eg, 20 to 30% at 3 to 5 years in the French registry and 10 to 30% at 1 to 3 years 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-minute walk distance

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

  • Echocardiographic indicators of right heart systolic dysfunction (eg, a tricuspid annular plane systolic excursion of < 1.6 cm, dilated right ventricle, flattened interventricular septum with paradoxical septal motion, and pericardial effusion)

  • Right heart catheterization showing low cardiac output, very 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 (PAH) have a worse prognosis than those without PAH. For example, patients with sickle cell disease and PAH have a 40% 4-year mortality rate.

Treatment of Pulmonary Hypertension

  • 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, subcutaneous, or IV prostacyclin analogs; oral endothelin-receptor antagonists; oral phosphodiesterase 5 inhibitors, oral soluble guanylate cyclase stimulators; oral prostacyclin (IP2) receptor agonists

  • 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 of pulmonary arterial hypertension (PAH) is rapidly evolving. Drugs target 4 aberrant pathways implicated in the development of PAH:

  • Endothelin pathway

  • Nitric oxide pathway

  • Prostacyclin pathway

  • BMPR2 pathway

The endothelin pathway is targeted by bosentan, ambrisentan, and macitentan, which are oral endothelin-receptor antagonists (ERAs).

The nitric oxide pathway is targeted by sildenafil, tadalafil, and vardenafil, which are oral phosphodiesterase 5 (PDE5) inhibitors. Riociguat, a soluble guanylate cyclase stimulator, also acts via the nitric oxide pathway.

The prostacyclin pathway is targeted by IV epoprostenol, a prostacyclin analog, which improves function and lengthens survival even in patients who are unresponsive to a vasodilator during catheterization (1 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). Disadvantages are the need for continuous central catheter infusion and frequent, troubling adverse effects, including flushing, diarrhea, and bacteremia due to the indwelling central catheter. Prostacyclin analogs that are inhaled, taken orally, or given subcutaneously or IV (iloprost and treprostinil) are available. Selexipag is an orally bioavailable small molecule that activates the prostaglandin I2 receptor and lowers mortality and morbidity rates (2 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

The BMPR2 (bone morphogenic receptor type 2) pathway is targeted by sotatercept, a novel drug. BMPR2 is the most common gene mutation in patients with inheritable PAH and in idiopathic PAH. Sotatercept helps restore the balance between anti-proliferation and pro-proliferation signaling pathways that is dysregulated in patients with PAH related to BMP signaling. When added to background therapy for pulmonary hypertension, sotatercept reduced pulmonary vascular resistance in a dose-dependent manner. This change was driven by a reduction in mean pulmonary artery pressures rather than pulmonary artery wedge pressure or cardiac output. This finding was consistent among all background therapy (including prostacyclin infusion therapy) subgroups (3 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Combination therapy is generally preferred. For example, 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 (4 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). 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-minute walk distances and the percentage of satisfactory clinical responses. This example supports targeting multiple pathways by beginning treatment of PAH 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 recommended rather than initial combination therapy. Studies confirm that morbidity and mortality decreased with macitentan, whether used alone or when combined with other drugs to treat PAH. Riociguat increased 6-minute walk distance, decreased pulmonary vascular resistance, and improved functional class as sequential combination therapy in patients receiving an endothelin-receptor antagonist or prostacyclin analog (as well as when used as monotherapy) (5 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). The FREEDOM-EV study found that adding oral treprostinil to baseline monotherapy with an ERA or PDE5 inhibitor was more effective than placebo in reducing clinical worsening, reducing NT-proBNP, improving functional class, and improving 6-minute walk distance (6 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Morbidity and mortality are lower with selexipag than with placebo when selexipag is combined with a PDE 5 inhibitor, an ERA, or both (7, 8 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). However, studies suggest that initial triple-therapy combining macitentan, tadalafil, and selexipag does not improve pulmonary vascular resistance or hemodynamics more than initial double therapy with macitentan and tadalafil alone (9 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). In certain clinical scenarios in patients with idiopathic, heritable, drug- or toxin-induced, or connective tissue disease associated PAH, adding selexipag is recommended for patients receiving dual oral ERA/PDE5 inhibitor therapy (10 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Guidelines for sequence of therapies may be evolving. The current recommendation is to do vasoactive testing in the catheterization laboratory. If patients are vasoreactive, they should be treated with a calcium channel blocker. Patients who are not vasoreactive should be treated based on their New York Heart Association class New York Heart Association (NYHA) Classification of Heart Failure New York Heart Association (NYHA) Classification of Heart Failure (NYHA). Patients who are NYHA class II to III should be started on an ERA plus a PDE5 inhibitor. Clinicians can consider adding selexipag to the ERA/PDE5 inhibitor combination. Patients who are NYHA class IV at the time of therapy initiation should be started on parenteral epoprostenol plus an ERA/PDE5 inhibitor, and early consideration should be given to referral to a transplant center (11 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Selected subgroups are sometimes treated differently. 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 Portopulmonary Hypertension Portopulmonary hypertension is pulmonary arterial hypertension associated with portal hypertension without other secondary causes. Pulmonary hypertension occurs in patients with various conditions... read more . Vasodilators should be avoided in patients with PAH due to pulmonary veno-occlusive disease due to the risk of catastrophic pulmonary edema (12 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Lung transplantation Lung and Heart-Lung Transplantation Lung or heart-lung transplantation is an option for patients who have respiratory insufficiency or failure and who remain at risk of death despite optimal medical treatment. (See also Overview... read more offers the only hope of cure but has high morbidity because of rejection (bronchiolitis obliterans syndrome) and infection. The 5-year survival rate is 50%. Lung transplantation is reserved for patients with NYHA 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.

Adjunctive therapies to treat heart failure, including diuretics, are necessary for many patients. Most patients should receive warfarin unless contraindicated.

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. No multi-center trials have demonstrated benefit from using PAH-specific therapies for pulmonary hypertension secondary to left-heart disease. Therefore, the use of these drugs is not recommended for group 2 patients. The inhaled prostacyclin analog treprostinil has been shown to improve exercise capacity.

Patients with lung disorders and hypoxia benefit from supplemental oxygen as well as treatment of the primary disorder. There is no conclusive evidence to support the use of pulmonary vasodilators in COPD (chronic obstructive pulmonary disease). Inhaled treprostinil has been shown to improve exercise capacity in patients with pulmonary hypertension secondary to interstitial lung disease (13 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). The use of riociguat and the ERAs is generally contraindicated in pulmonary hypertension secondary to interstitial lung disease due to an increase in adverse events in clinical trials (14, 15 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

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. Balloon pulmonary angioplasty is another interventional option. This procedure should be done only at expert centers for symptomatic patients who are not eligible for pulmonary endarterectomy. 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 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). Macitentan has also demonstrated improvements in pulmonary vascular resistance, 6-minute walk test, and NT-proBNP levels in inoperable patients with chronic thromboembolic pulmonary hypertension (16 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ). Macitentan has also demonstrated safety when used combination with other PAH therapies, including riociguat (17 Treatment references Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more ).

Patients with sickle cell disease who have pulmonary hypertension are aggressively treated using hydroxyurea, iron chelation, and supplemental oxygen as indicated. In symptomatic patients with elevated pulmonary vascular resistance with normal pulmonary artery wedge pressure confirmed by right heart catheterization (similar to PAH pathophysiology), 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. Barst RJ, Rubin LJ, Long WA, et al: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334(5):296–301, 1996. doi: 10.1056/NEJM199602013340504

  • 2. 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

  • 3. Humbert M, McLaughlin V, Gibbs JSR, et al: Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med 384(13):1204–1215, 2021. doi: 10.1056/NEJMoa2024277

  • 4. 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

  • 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. White RJ, Jerjes-Sanchez C, Bohns Meyer GM, et al: Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial. Am J Respir Crit Care Med 201(6):707–717, 2020. doi: 10.1164/rccm.201908-1640OC

  • 7. 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

  • 8. 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.

  • 9. Chin KM, Sitbon O, Doelberg M, et al: Three- versus two-drug therapy for patients with newly diagnosed pulmonary arterial hypertension. J Am Coll Cardiol 78(14):1393–1403, 2021. doi: 10.1016/j.jacc.2021.07.057

  • 10. McLaughlin VV, Channick R, De Marco T, et al: Results of an expert consensus survey on the treatment of pulmonary arterial hypertension with oral prostacyclin pathway agents. Chest 157(4):955–965, 2020. doi: 10.1016/j.chest.2019.10.043

  • 11. Condon DF, Nickel NP, Anderson R, et al: The 6th World Symposium on Pulmonary Hypertension: what's old is new. F1000Research 8:F1000 Faculty Rev-888, 2019. doi: 10.12688/f1000research.18811.1

  • 12. 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

  • 13. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al: Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 384(4):325–334, 2021. doi: 10.1056/NEJMoa2008470

  • 14. Nathan SD, Behr J, Collard HR, et al: Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study. Lancet Respir Med 7(9):780–790, 2019. doi: 10.1016/S2213-2600(19)30250-4

  • 15. Sahay S, Channick R, Chin K, et al: Macitentan in pulmonary hypertension (PH) due to chronic lung disease: Real-world evidence from OPUS/OrPHeUS. J Heart Lung Trans 40 (4) [Suppl]: S105-S106, 2021.

  • 16. Ghofrani HA, Simonneau G, D'Armini AM, et al: Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med 5(10):785–794, 2017. doi:10.1016/S2213-2600(17)30305-3

  • 17. Channick R, McLaughlin V, Chin K, et al: Treatment of chronic thromboembolic pulmonary hypertension (CTEPH): Real-world experience with macitentan. J Heart Lung Trans 38(4) [suppl]: S483, 2019. doi: https://www.jhltonline.org/article/S1053-2498(19)31231-8/fulltext

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 combination therapy with vasodilators and, if these are ineffective, consider lung transplantation.

  • Consider treating group 3 with inhaled treprostinil.

  • Treat group 4 with pulmonary thromboendarterectomy unless the patient is not a candidate for surgery.

  • Treat groups 2, 3, and 5 by managing the underlying disorder, treating symptoms, and sometimes using other measures.

Drugs Mentioned In This Article

Drug Name Select Trade
Fintepla
Sprycel
Adzenys, Adzenys XR, Dyanavel XR, Evekeo
GOPRELTO, NUMBRINO
No brand name available
BOSULIF
Arava
5-HTP, 5-HTP Maximum Strength
RYPLAZIM
Flolan, Veletri
Tracleer
LETAIRIS
Opsumit
Revatio, Viagra
Adcirca, ALYQ, Cialis, Tadliq
Levitra, Staxyn
Adempas
Ventavis
Orenitram, Remodulin, Tyvaso , TYVASO DPI, Tyvaso Refill Kit, Tyvaso Starter Kit
UPTRAVI, Uptravi Powder
Coumadin, Jantoven
DROXIA, Hydrea, Mylocel, Siklos
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