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Pulmonary hypertension

Pulmonary hypertension in adults, from hemodynamic definition and clinical classification through diagnosis, risk assessment, treatment of each group, chronic thromboembolic disease, pregnancy, surgery, and acute right ventricular failure.

Hemodynamic definition of pulmonary hypertension

Pulmonary hypertension is a hemodynamic state, not a single disease. The 7th World Symposium on Pulmonary Hypertension (WSPH, 2024) kept the definition adopted in 2018: a mean pulmonary artery pressure (mPAP) above 20 mm Hg at rest. The 2022 European Society of Cardiology and European Respiratory Society (ESC/ERS) guideline endorsed the same definition. There is no current ACC/AHA pulmonary hypertension guideline, so US practice follows the WSPH documents, the ESC/ERS guideline, and the 2019 CHEST guideline on drug therapy.

The threshold was lowered from 25 mm Hg because normal mPAP is about 14 mm Hg with an upper limit near 20 mm Hg, and because mortality rises in large referral cohorts from values above 20 mm Hg. The upper limit of normal for pulmonary vascular resistance (PVR) was lowered from 3 to 2 Wood units (WU) on the same reasoning. The drugs approved for pulmonary arterial hypertension (PAH) were tested in patients who met the older definition, and no therapy is approved specifically for an mPAP of 21 to 24 mm Hg.

Hemodynamic definitions from the 7th WSPH (2024), unchanged from the 2022 ESC/ERS guideline. PVR = (mPAP − PAWP) ÷ cardiac output. mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; WU, Wood units.

The three measurements locate the disease. A normal wedge pressure with a high resistance places it in the pulmonary arterioles. A high wedge pressure with a normal resistance indicates passive back-transmission from the left heart. A high wedge pressure with a high resistance indicates left heart disease that has remodeled the pulmonary vessels. The hemodynamic phenotype is not the clinical diagnosis: pre-capillary hemodynamics occur in PAH, in lung disease, and in chronic thromboembolic disease, and the label "pre-capillary pulmonary hypertension" is used until the cause is established.

Wedge pressure at the boundary. The upper limit of normal wedge pressure is 13 mm Hg, but PAH trials enrolled patients with values up to 15 mm Hg and showed benefit in those with 13 to 15 mm Hg. The 7th WSPH therefore kept 15 mm Hg as the cutoff and described 12 to 18 mm Hg as a zone of uncertainty. In that zone the phenotype is assigned from the whole patient: age, obesity, hypertension, diabetes, atrial fibrillation, left atrial size, diastolic indices, and any history of pulmonary edema. Occult left heart disease is unmasked by a wedge pressure above 18 mm Hg after a rapid infusion of 500 mL of saline (or 7 mL/kg over 5 to 10 minutes). A wedge pressure above 25 mm Hg during exercise or a PAWP/cardiac output slope above 2 mm Hg/L/min has the same significance. Catheterization technique, waveform interpretation at end-expiration, and the formulas behind these values are covered on the right heart catheterization and hemodynamics page.

Severity thresholds outside group 1. In left heart disease, a PVR above 5 WU indicates a severe pre-capillary component. In chronic lung disease, the 2022 ESC/ERS guideline defines severe pulmonary hypertension as a PVR above 5 WU, the value with the strongest association with mortality in chronic obstructive pulmonary disease (COPD). In sarcoidosis, an mPAP of 40 mm Hg or more and a PVR of 5 WU or more predict reduced transplant-free survival.

Classifying a hemodynamic study: pre-capillary, post-capillary, and combined

The phenotype follows from three catheter measurements: mean pulmonary artery pressure, wedge pressure, and cardiac output by thermodilution or direct Fick. The diastolic pulmonary gradient is derived when the pulmonary artery diastolic pressure is available.

PVR = (mPAP − PAWP) ÷ cardiac output; transpulmonary gradient = mPAP − PAWP; diastolic pulmonary gradient = PA diastolic pressure − PAWP. The example (mPAP 52 mm Hg, PAWP 9 mm Hg, cardiac output 3.9 L/min) gives a PVR of 11.0 WU, pre-capillary pulmonary hypertension with a markedly raised resistance. Values of mPAP 40 mm Hg, PAWP 20 mm Hg, and cardiac output 3.5 L/min give a PVR of 5.7 WU, combined post- and pre-capillary disease with a severe pre-capillary component.

The five clinical groups of pulmonary hypertension

The clinical classification groups conditions that share mechanism, hemodynamics, and treatment. The 7th WSPH kept the five groups and made four changes: long-term responders to calcium channel blockers returned as a subgroup of idiopathic PAH; group 2 was subdivided into heart failure, valvular disease, and other cardiovascular conditions; group 3 was organized by lung disease instead of by functional abnormality; and mitomycin C and carfilzomib joined the drugs with a definite association with PAH.

Clinical classification of pulmonary hypertension, after the 7th WSPH (Kovacs et al., 2024). Heritable and drug-associated PAH can also include long-term calcium channel blocker responders.

The groups differ in treatment more than in hemodynamics. PAH-targeted drugs are effective in group 1, have defined roles in CTEPH and in pulmonary hypertension with interstitial lung disease, and are not used routinely in groups 2 and 3, where some have caused harm. Patients often have more than one mechanism; the dominant one determines the group, and a group 3 or group 2 label is favored when significant lung or left heart disease is present.

Epidemiology, natural history, and survival

Pulmonary hypertension of any cause affects about 1% of the world's population and up to 10% of people older than 65 years. Groups 2 and 3 account for 90% to 95% of cases, most with mild to moderate disease and limited pulmonary vascular involvement; about 1% to 10% of patients with left heart or lung disease develop severe pulmonary hypertension out of proportion to the underlying condition. In a global systematic review, the prevalence of catheter-confirmed PAH averaged 3.7 cases per 100,000. CTEPH has an estimated incidence of 5 to 6 cases per million per year, rising to about 13 per million where patients are followed systematically after pulmonary embolism.

The demographics of PAH have changed. Early registries described young women with idiopathic disease. Contemporary European registries describe a mean age at diagnosis in the mid-60s, with more men and more cardiopulmonary comorbidity, and a phenotype that overlaps with heart failure with preserved ejection fraction (HFpEF) and mild lung disease. Women still predominate in idiopathic, heritable, and connective tissue disease-associated PAH.

Untreated idiopathic PAH is fatal, and death results from progressive right ventricular failure or sudden death. Modern therapy has lengthened survival, which falls steeply with functional class at enrollment. Survival is shortest in PAH associated with systemic sclerosis and in pulmonary veno-occlusive disease, and longest in long-term calcium channel blocker responders and in repaired congenital shunts.

Survival in pulmonary arterial hypertension before and after modern therapy (D'Alonzo et al., 1991; Farber et al., 2015; Sitbon et al., 2005). Survival after pulmonary endarterectomy and angioplasty is given in the section on chronic thromboembolic pulmonary hypertension.

Pulmonary hypertension worsens prognosis in every group. In left heart disease, combined post- and pre-capillary hemodynamics carry higher mortality than isolated post-capillary disease. In COPD and interstitial lung disease, severe pulmonary hypertension predicts death independent of spirometry.

Pathobiology of pulmonary arterial hypertension

PAH is a proliferative vasculopathy of the small muscular pulmonary arteries and arterioles. Medial hypertrophy, intimal proliferation and fibrosis, adventitial thickening, in situ thrombosis, and plexiform lesions (disorganized channels of proliferating endothelial cells at arterial branch points) narrow and obliterate the vessels. Vasoconstriction contributes early and in a minority of patients; in most patients, fixed remodeling dominates, which explains why acute vasodilator responses are uncommon and modest.

Four signaling pathways are deranged, and each is the target of a drug class:

• Endothelin. Endothelin-1 is overexpressed in the lung vasculature and acts on endothelin A and B receptors on smooth muscle cells to cause vasoconstriction and proliferation. Endothelin receptor antagonists block it.
• Nitric oxide. Endothelial nitric oxide synthase activity is reduced. Nitric oxide normally activates soluble guanylate cyclase to generate cyclic guanosine monophosphate (cGMP), which relaxes smooth muscle. Phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP breakdown, and riociguat stimulates soluble guanylate cyclase directly.
• Prostacyclin. Prostacyclin synthase is reduced and thromboxane increased. Prostacyclin analogs and the prostacyclin receptor agonist selexipag raise cyclic adenosine monophosphate, causing vasodilation and inhibiting proliferation and platelet aggregation.
• Bone morphogenetic protein and activin. Loss of signaling through bone morphogenetic protein receptor type 2 (BMPR2) and excess activin and growth differentiation factor signaling through the activin receptor type IIA shift the balance toward proliferation. Sotatercept, which sequesters activins and related growth factors, rebalances this pathway.

Inflammation, altered mitochondrial metabolism with a glycolytic shift, DNA damage, and estrogen signaling contribute, and several are targets of drugs in development.

Genetics. Heterozygous loss-of-function variants in BMPR2 are present in most families with heritable PAH and in about 10% to 20% of patients with apparently idiopathic disease. Penetrance is incomplete and higher in women, and carriers present younger with more severe hemodynamics. An international panel classified 12 genes as having definitive evidence for PAH (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4). Variants in ACVRL1 and ENG link PAH with hereditary hemorrhagic telangiectasia, and biallelic EIF2AK4 variants cause heritable pulmonary veno-occlusive disease. The 2022 ESC/ERS guideline recommends genetic counseling and testing in idiopathic, heritable, and anorexigen-associated PAH and in pulmonary veno-occlusive disease. A pathogenic variant confirms heritable disease, informs relatives, and identifies carriers for annual screening.

Causes and associated forms of pulmonary arterial hypertension

Idiopathic PAH is a diagnosis of exclusion after left heart disease, lung disease, chronic thromboembolism, drugs and toxins, connective tissue disease, HIV, portal hypertension, congenital shunts, and schistosomiasis have been sought.

Drugs and toxins. The anorexigens aminorex, fenfluramine, dexfenfluramine, and benfluramine established the association. Methamphetamine-associated PAH is increasingly recognized in the United States. Dasatinib causes PAH that is often partly reversible after withdrawal, and a switch to another tyrosine kinase inhibitor is usual. Carfilzomib and mitomycin C (which causes a veno-occlusive phenotype) were added as definite associations in 2024.

Drugs and toxins associated with PAH, after the 7th WSPH (2024). *Associated with a veno-occlusive or capillary phenotype.

The other associated forms differ in how they are recognized, which mechanisms coexist, and how standard PAH therapy is modified.

Associated forms of PAH (group 1.4 and 1.5), after the 7th WSPH (2024) and the 2022 ESC/ERS guideline. mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; WU, Wood units.

The resistance thresholds that decide whether a congenital shunt can be closed are covered on the atrial septal defect and patent foramen ovale page.

The right ventricle under pressure load

The right ventricle is a thin-walled chamber built to pump into a low-resistance, high-compliance circuit. It tolerates volume load well and acute pressure load poorly: a previously normal right ventricle cannot generate a mean pressure much above 40 mm Hg, which is why acute pulmonary embolism produces shock at pressures that chronic disease reaches with little symptom.

Chronic pressure load is met first by homeometric adaptation: hypertrophy and increased contractility that preserve coupling between ventricular contractility and arterial load (end-systolic elastance relative to arterial elastance). Stroke volume is maintained at a normal ventricular size. When contractility can no longer match afterload, the ventricle dilates (heterometric adaptation), and coupling is lost. Dilation stretches the tricuspid annulus and adds functional regurgitation, raises wall stress and oxygen demand, and displaces the septum into the left ventricle. Septal shift and pericardial constraint reduce left ventricular filling, so a failing right ventricle lowers left ventricular stroke volume through ventricular interdependence. The septum is flattened in systole by pressure overload and in diastole by volume overload, producing the D-shaped left ventricle in short axis.

Right ventricular coronary flow normally continues through systole. As right ventricular pressure approaches systemic pressure, systolic flow ceases, and systemic hypotension then reduces right ventricular perfusion when wall stress is highest. Ischemia lowers contractility, output falls further, and the spiral of acute right heart failure follows. This mechanism is why systemic pressure is defended in acute decompensation and why every PAH therapy is judged by its effect on the right ventricle. Right atrial pressure, cardiac index, stroke volume index, mixed venous saturation, right atrial area, and pericardial effusion are among the strongest predictors of survival in PAH, and all describe right ventricular adaptation. The pulmonary artery pulsatility index (pulmonary artery pulse pressure divided by right atrial pressure) quantifies how much flow the right ventricle still generates against its load.

Symptoms, examination, ECG, and chest radiograph

Symptoms are nonspecific and appear late. Exertional dyspnea and fatigue come first, from the inability to raise cardiac output with exercise. Exertional chest pain reflects right ventricular ischemia or, less often, compression of the left main coronary artery by a dilated pulmonary artery. Exertional presyncope and syncope indicate a fixed output and a poor prognosis. Bendopnea, abdominal distension, edema, and early satiety reflect right heart failure. Hemoptysis occurs in CTEPH, Eisenmenger syndrome, and veno-occlusive disease, and hoarseness from compression of the left recurrent laryngeal nerve (Ortner syndrome) occurs with a dilated pulmonary artery. Diagnosis is often delayed by years, and asthma, deconditioning, and anxiety are frequent misdiagnoses.

The pulmonary component of the second heart sound is loud and often palpable. Right ventricular hypertrophy produces a left parasternal lift and a right-sided fourth sound. Tricuspid regurgitation produces a holosystolic murmur at the left lower sternal border that increases with inspiration (Carvallo sign), and pulmonary regurgitation produces a high-pitched early diastolic murmur (Graham Steell murmur). The jugular venous pulse shows a prominent a wave from a stiff right ventricle and, with significant tricuspid regurgitation, a large v wave. Hepatomegaly, a pulsatile liver, ascites, and edema follow. Examination also identifies associated conditions: sclerodactyly, telangiectasia, and digital ulcers in systemic sclerosis; spider angiomas and splenomegaly in liver disease; clubbing in congenital heart disease, veno-occlusive disease, and interstitial lung disease; and fine crackles in pulmonary fibrosis. Clubbing is not a feature of idiopathic PAH.

The electrocardiogram shows right axis deviation, right ventricular hypertrophy with repolarization changes in the right precordial leads, right atrial enlargement (P pulmonale), and right bundle branch block. In an adult with dyspnea, right axis deviation has a high positive predictive value for pulmonary hypertension; a normal electrocardiogram with a normal natriuretic peptide and normal gas exchange makes it unlikely. Atrial flutter and atrial fibrillation are poorly tolerated and frequently precipitate decompensation.

The chest radiograph shows enlarged central pulmonary arteries, attenuated peripheral vessels, and filling of the retrosternal space by an enlarged right ventricle. It also identifies emphysema, fibrosis, pulmonary venous congestion, and the septal lines of veno-occlusive disease. A normal radiograph does not exclude pulmonary hypertension.

Natriuretic peptides. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) rise with right ventricular wall stress. They are not specific, are lowered by obesity, and are raised by kidney dysfunction and atrial fibrillation, but serial values are central to risk assessment and response to therapy.

Echocardiographic probability of pulmonary hypertension

Transthoracic echocardiography is the first test in suspected pulmonary hypertension. It estimates the probability of pulmonary hypertension, identifies left heart disease, valve disease, and shunts, and measures how the right heart has adapted. It cannot establish the diagnosis or the hemodynamic type, because both pressure and resistance estimates are imprecise in individual patients.

Pulmonary artery systolic pressure is estimated as 4 × (peak tricuspid regurgitant velocity)² plus right atrial pressure in the absence of pulmonic or outflow obstruction. Right atrial pressure is estimated from the inferior vena cava: a diameter of 2.1 cm or less with more than 50% inspiratory collapse indicates about 3 mm Hg, a diameter above 2.1 cm with less than 50% collapse indicates about 15 mm Hg, and other combinations indicate about 8 mm Hg. Because errors in right atrial pressure and in the velocity both propagate, current guidelines grade probability from the velocity itself and from supporting signs, not from the calculated pressure. A velocity error of 10% produces a pressure-gradient error of about 21%.

Signs from the 2022 ESC/ERS guideline, reproduced in the 7th WSPH. Signs from at least two categories modify the probability assigned by tricuspid regurgitant velocity. TAPSE, tricuspid annular plane systolic excursion; PASP, pulmonary artery systolic pressure.

The ESC/ERS scheme assigns low probability to a velocity of 2.8 m/s or less (or no measurable jet) without signs from two categories. Intermediate probability is assigned to a velocity of 2.8 m/s or less with signs from two categories, or to 2.9 to 3.4 m/s without them. High probability is assigned to 2.9 to 3.4 m/s with signs from two categories, or to any velocity above 3.4 m/s. The 2025 American Society of Echocardiography (ASE) right heart guideline uses a related rule. A peak velocity of 2.9 m/s or more suggests pulmonary hypertension. A velocity of 2.8 m/s suggests it when at least two supporting signs are present (right ventricular basal diameter greater than left ventricular basal diameter, eccentricity index above 1.1, mid-systolic notching of the outflow tract Doppler signal, end-diastolic pulmonary regurgitant velocity above 2.2 m/s, or an inferior vena cava above 2.1 cm or right atrial area above 18 cm²).

The pulmonary regurgitant velocity is end-diastolic in the ASE document and early diastolic in the ESC/ERS list, and an enlarged inferior vena cava or right atrium counts once toward the ASE criterion. The example (velocity 3.1 m/s, eccentricity index above 1.1, dilated inferior vena cava with reduced collapse) has signs in two categories and a high ESC/ERS probability.

Right ventricular size and function. A right ventricular basal diameter of 4.1 cm or more is enlarged by ASE 2025 criteria, and right ventricular wall thickness of 0.5 cm or more indicates hypertrophy. Systolic function is reported with at least one quantitative index: TAPSE of 1.7 cm or less, tissue Doppler S′ of 9.5 cm/s or less, fractional area change of 35% or less, three-dimensional ejection fraction of 45% or less, and free-wall longitudinal strain of 20% or less in absolute value are abnormal. TAPSE overestimates function when severe tricuspid regurgitation distorts the annulus. The TAPSE/PASP ratio expresses ventricular-arterial coupling; values below 0.19 mm/mm Hg identify patients with PAH at high risk. A pericardial effusion indicates high right atrial pressure and is an adverse sign.

Sources of discordance. A low velocity does not exclude severe disease. In torrential tricuspid regurgitation, right ventricular and right atrial pressures equalize early in systole, and the dense, triangular, early-peaking envelope underestimates the gradient. A failing right ventricle generates less pressure, so a falling estimated pressure with a falling outflow tract velocity-time integral and a lower TAPSE/PASP ratio indicates deterioration, not response. Pulmonic stenosis or outflow obstruction makes the tricuspid gradient report right ventricular pressure, not pulmonary artery pressure. High-flow states raise the gradient without raising resistance; the ratio of tricuspid velocity to outflow tract velocity-time integral helps separate flow from resistance but does not replace catheter PVR.

Pre-capillary or post-capillary. The left heart findings shift the probability toward one phenotype before catheterization. In established pulmonary hypertension, tricuspid velocity reflects pulmonary vascular disease and is not used as a marker of left atrial pressure. Agitated saline contrast identifies intracardiac shunts, and transesophageal echocardiography or cardiac MRI defines sinus venosus defects and anomalous venous return.

Echocardiographic findings that favor post-capillary or pre-capillary pulmonary hypertension, after the 2022 ESC/ERS guideline and the 7th WSPH. The findings modify probability; right heart catheterization establishes the phenotype.

Diagnostic pathway and the decision to catheterize

The 7th WSPH proposes a stepwise evaluation whose purpose is to identify patients who need referral to a pulmonary hypertension center and invasive hemodynamics. Patients with a high probability of PAH or CTEPH, especially with signs of right heart failure, rapid progression, syncope, or a low cardiac output, are referred directly at any step.

1. Clinical assessment: symptoms, examination, and risk factors (connective tissue disease, portal hypertension, HIV, congenital heart disease, prior venous thromboembolism, left heart disease, lung disease, family history, and drug or stimulant exposure).
2. Basic tests: electrocardiogram, chest radiograph, pulse oximetry, blood count, electrolytes, kidney and liver function, and BNP or NT-proBNP.
3. Heart and lung assessment: echocardiography, pulmonary function tests with diffusing capacity, and arterial blood gases.
4. Further evaluation by suspected cause: ventilation-perfusion scintigraphy, chest CT, cardiac MRI, cardiopulmonary exercise testing, serologies, and abdominal ultrasound.
5. Right heart catheterization at a pulmonary hypertension center, with vasoreactivity testing, exercise, or fluid challenge as the phenotype requires.

Ventilation-perfusion scintigraphy. Every patient with newly diagnosed or unexplained pulmonary hypertension is screened for CTEPH, because it is the potentially curable form. A normal perfusion scan essentially excludes CTEPH. In a referral series, planar scintigraphy had a sensitivity above 96% for chronic thromboembolic disease, whereas multidetector CT pulmonary angiography had a sensitivity of 51%. Mismatched segmental defects lead to CT pulmonary angiography and referral to a CTEPH center. Perfusion defects also occur in veno-occlusive disease, pulmonary artery sarcoma, vasculitis, and fibrosing mediastinitis.

Chest CT. High-resolution CT identifies emphysema, interstitial lung disease, and the septal lines, ground-glass nodules, and lymph nodes of veno-occlusive disease; it is recommended particularly in current or former smokers with a diffusing capacity below 45% of predicted. Contrast CT shows an enlarged main pulmonary artery (a ratio of pulmonary artery to ascending aorta diameter above 1 suggests pulmonary hypertension), right ventricular enlargement, mosaic perfusion, bronchial artery collaterals, webs and bands in CTEPH, and anomalous pulmonary venous return. Dual-energy CT perfusion is an alternative to scintigraphy in experienced centers.

Cardiac MRI is the reference standard for right ventricular volumes, mass, and ejection fraction and is used for diagnosis when echocardiography is inconclusive and for risk assessment. MRI also identifies shunts, anomalous veins, and myocardial disease that suggest group 2.

Pulmonary function, gas exchange, and sleep. In PAH, spirometry and lung volumes are normal or mildly reduced, and the diffusing capacity is mildly to moderately reduced. A severely reduced diffusing capacity with near-normal spirometry suggests veno-occlusive disease, systemic sclerosis, or a lung-vascular phenotype associated with smoking. Arterial blood gases show hypocapnia in PAH; hypercapnia suggests hypoventilation. Overnight oximetry or polysomnography is performed when sleep-disordered breathing or hypoventilation is suspected; obstructive sleep apnea alone rarely causes more than mild pulmonary hypertension.

Cardiopulmonary exercise testing. PAH produces a reduced peak oxygen consumption, a high ventilatory equivalent for carbon dioxide, and a low end-tidal carbon dioxide that falls during exercise.

Laboratory tests. Antinuclear antibodies, anticentromere, anti-topoisomerase I (Scl-70), and anti-RNA polymerase III antibodies screen for systemic sclerosis, with other serologies as indicated; HIV and hepatitis serologies, thyroid function, and liver tests are standard. Abdominal ultrasound with Doppler identifies portal hypertension. Testing for antiphospholipid antibodies is part of the CTEPH evaluation.

Who undergoes right heart catheterization. Catheterization is performed when it will change management: when echocardiographic probability is high, or intermediate in a patient with risk factors for PAH or CTEPH, or when symptoms remain unexplained after noninvasive testing. In patients with left heart or lung disease, it is reserved for suspected severe pulmonary hypertension, a suspected second cause, or evaluation for transplantation or valve intervention. Diagnostic catheterization establishes mPAP, wedge pressure, cardiac output, PVR, right atrial pressure, and mixed venous saturation, and includes an oxygen saturation run when a shunt is possible. It is performed at a pulmonary hypertension center because classification depends on precise measurements.

Screening of asymptomatic high-risk groups. Annual screening with echocardiography, electrocardiography, and natriuretic peptide measurement is applied to BMPR2 carriers, first-degree relatives of patients with heritable PAH, patients being evaluated for liver transplantation or a transjugular intrahepatic portosystemic shunt, and patients with systemic sclerosis spectrum disorders. In systemic sclerosis of more than 3 years' duration with a diffusing capacity below 60% of predicted, the two-step DETECT algorithm (serologies, biomarkers, electrocardiogram, and pulmonary function, followed by echocardiography) selects patients for catheterization. Patients with other connective tissue diseases, HIV, or portal hypertension without transplant evaluation undergo testing when symptoms appear.

Acute vasoreactivity testing and calcium channel blockers

Acute vasoreactivity testing identifies the small group of patients whose PAH responds to high-dose calcium channel blockers. It is performed only in the forms in which a positive response predicts long-term benefit. In other forms of PAH and in groups 2 through 5, responses are misleading and calcium channel blockers can cause harm. Empirical calcium channel blockers without a positive test cause hypotension, right ventricular failure, and death.

Acute vasoreactivity testing and definitions of response, after the 2022 ESC/ERS guideline and the 7th WSPH (2024). mPAP, mean pulmonary artery pressure.

In the largest idiopathic series, 70 of 557 patients (12.6%) were acute responders, and only 38 (6.8%) remained in functional class I or II with sustained hemodynamic improvement after at least 1 year on calcium channel blockers alone. Long-term responders have excellent survival; acute responders who do not meet the long-term criteria are treated with the standard PAH algorithm.

Calcium channel blockers for vasoreactive PAH, with target doses from the 2022 ESC/ERS guideline and the choice of drug by baseline heart rate from the 2015 ESC/ERS guideline. Doses are started low and titrated to the target.

Risk assessment in pulmonary arterial hypertension

Treatment in PAH is driven by estimated 1-year mortality. At diagnosis, the 2022 ESC/ERS guideline uses a three-strata model that integrates clinical, exercise, biomarker, imaging, and hemodynamic variables. For initial treatment, the 7th WSPH separates patients only into high risk and not high risk.

Three-strata risk assessment at diagnosis, after the 2022 ESC/ERS guideline. Percentages are estimated 1-year mortality. At diagnosis, the stratum is assigned from as many variables as possible, with emphasis on disease type, functional class, walk distance, natriuretic peptide, and hemodynamics. RA, right atrium; RAP, right atrial pressure; CI, cardiac index; SVI, stroke volume index; SvO₂, mixed venous oxygen saturation; RVEF, right ventricular ejection fraction; RVESVI, right ventricular end-systolic volume index; WHO, World Health Organization; VO₂, oxygen consumption; VE/VCO₂, ventilatory equivalent for carbon dioxide.

At follow-up, most patients fall in the intermediate stratum of the three-strata model, which therefore separates them poorly. The four-strata model, derived from the COMPERA registry and adopted by the 2022 ESC/ERS guideline and the 7th WSPH, uses functional class, 6-minute walk distance, and BNP or NT-proBNP with refined cutoffs. It splits the intermediate group into intermediate-low and intermediate-high. The US alternative is REVEAL Lite 2, which scores functional class, systolic blood pressure, heart rate, walk distance, natriuretic peptide, and kidney function. A score of 5 or less indicates low risk, and a score of 9 or more defined the high-risk population of the ZENITH trial. Both perform similarly. Neither is validated outside group 1, and in older patients with comorbidities the variables reflect more than PAH.

Grades: functional class I or II, 1; III, 3; IV, 4. Walk distance >440 m, 1; 320–440 m, 2; 165–319 m, 3; <165 m, 4. NT-proBNP <300 ng/L, 1; 300–649, 2; 650–1,100, 3; >1,100, 4 (BNP <50, 50–199, 200–800, >800 ng/L). The mean of available grades is rounded to the nearest integer: 1, low; 2, intermediate-low; 3, intermediate-high; 4, high. The example (class III, 380 m, NT-proBNP 900 ng/L) grades 3, 2, and 3, a mean of 2.67, intermediate-high risk.

Low risk is the treatment goal, yet in a pooled analysis of AMBITION, GRIPHON, and SERAPHIN more than 20% of patients classified as low risk had a clinical worsening event within 3 years. Additional goals proposed by the 7th WSPH include a PVR below 5 WU, a fall in PVR of more than 50%, a normal stroke volume index, and normal or near-normal right ventricular size and function on imaging. Risk is reassessed 3 to 4 months after each change in therapy and every 3 to 6 months in stable patients.

Supportive care in pulmonary arterial hypertension

• Exercise training. Supervised exercise training improves walk distance, peak oxygen consumption, and quality of life in stable patients on medical therapy. Strenuous isometric exertion and exercise to the point of presyncope are avoided.
• Diuretics and fluid balance. Loop diuretics treat congestion, often with a mineralocorticoid receptor antagonist. Sodium and fluid restriction support them. Overdiuresis lowers preload and cardiac output in a preload-dependent right ventricle.
• Oxygen. Long-term oxygen is prescribed when arterial oxygen tension is consistently below 60 mm Hg (8 kPa). In-flight oxygen is advised for patients on oxygen or with a resting arterial oxygen tension below 60 mm Hg at sea level.
• Iron. Iron deficiency is common, impairs exercise capacity, and predicts worse outcome. Iron-deficiency anemia is corrected, preferably with intravenous iron because oral absorption is impaired.
• Vaccination. Immunization against influenza, Streptococcus pneumoniae, and SARS-CoV-2 is recommended, and a single dose of respiratory syncytial virus vaccine is recommended for adults with pulmonary hypertension aged 50 years or older.
• Anticoagulation. Randomized data are lacking, and observational data conflict. Anticoagulation is not generally recommended in idiopathic, heritable, or drug-associated PAH and is not recommended in connective tissue disease-associated PAH, where registry data suggest no benefit and possible harm. It is used when another indication exists, such as atrial fibrillation or a central venous catheter for prostacyclin infusion in selected patients.
• Contraception and pregnancy. Pregnancy is advised against, and clear contraceptive advice is given at diagnosis (see the section on pregnancy).
• Psychosocial support and transplant preparation. Depression and anxiety are common. Weight optimization, tobacco and drug abstinence, and treatment of comorbidities keep transplantation available.
• Arrhythmias. Atrial flutter and fibrillation are treated with early restoration of sinus rhythm; flutter ablation is highly effective. Beta-blockers and nondihydropyridine calcium channel blockers are used cautiously because they lower cardiac output.

PAH drug classes: endothelin, nitric oxide, and prostacyclin pathways

Drugs approved for PAH in the United States, after the 7th WSPH treatment algorithm (Table 2). Doses are the usual adult regimens from US labeling; individual titration follows tolerance and blood pressure. In April 2025, the US Food and Drug Administration removed the pregnancy-related Risk Evaluation and Mitigation Strategy (REMS) requirements for ambrisentan and macitentan; bosentan remains under a REMS for hepatotoxicity, and all endothelin receptor antagonists keep a boxed warning for embryo-fetal toxicity.

Endothelin receptor antagonists. SERAPHIN was the first event-driven PAH trial. Bosentan was the first oral PAH drug and is now used less because of hepatotoxicity and drug interactions. Ambrisentan is contraindicated in idiopathic pulmonary fibrosis because it increased disease progression in ARTEMIS-IPF.

Nitric oxide pathway. Sildenafil and tadalafil improve exercise capacity and hemodynamics. Riociguat stimulates soluble guanylate cyclase directly and does not require nitric oxide for its effect. Riociguat and PDE5 inhibitors are never combined, because the combination caused hypotension without added benefit. In REPLACE, patients at intermediate risk on a PDE5 inhibitor improved more often after switching to riociguat than after continuing the PDE5 inhibitor.

Prostacyclin pathway. Intravenous epoprostenol improved survival in a 12-week randomized trial in severe idiopathic PAH and remains the most potent therapy. Patients carry a backup pump, and a lost line is an emergency. Subcutaneous treprostinil avoids a central line at the cost of site pain.

Pivotal randomized trials of oral PAH therapy. Rates are active treatment versus comparator. PVR, pulmonary vascular resistance; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PDE5, phosphodiesterase type 5.

Sotatercept and the activin pathway

Sotatercept is a fusion protein of the extracellular domain of the activin receptor type IIA and the Fc portion of human immunoglobulin G1. By sequestering activins and growth differentiation factors, it restores the balance between proliferative and antiproliferative signaling that loss of BMPR2 signaling disturbs. Unlike every earlier PAH drug, it has little acute vasodilator effect, and its hemodynamic benefit comes from reversal of remodeling. In the phase 2 PULSAR trial, sotatercept 0.7 mg/kg lowered PVR by about 240 dyn·s·cm⁻⁵ relative to placebo. The US Food and Drug Administration approved it in 2024 for adults with PAH.

Phase 3 trials of add-on sotatercept in PAH. Rates are sotatercept versus placebo.

Hemoglobin and platelet count are measured before each of the first 5 doses and periodically after; a significant rise in hemoglobin or fall in platelets leads to dose delay or reduction, and treatment is not started with a platelet count below 50,000/µL. Telangiectasia developed in about 10% of patients in STELLAR, and epistaxis and gingival bleeding are frequent, so bleeding risk and concurrent anticoagulation or prostacyclin therapy are reviewed before treatment. The drug is self-administered subcutaneously every 3 weeks after training. Its place in therapy is as add-on treatment to established oral or parenteral combination therapy; it has not been tested as initial therapy or in groups 2 through 5.

Initial combination therapy, escalation, and treatment goals

Therapy for confirmed group 1 PAH is directed by risk, delivered in or with a pulmonary hypertension center, and escalated until the goals are met. Vasoreactive patients are treated with calcium channel blockers as above. The 7th WSPH algorithm applies to patients with idiopathic, heritable, drug-associated, and connective tissue disease-associated PAH without major cardiopulmonary comorbidity.

Treatment algorithm for PAH, after Chin et al. (7th WSPH). Maximal medical therapy is four drugs acting on four pathways. Clinical deterioration leads to escalation without waiting for the scheduled reassessment.

Evidence for upfront combination. Initial dual oral therapy rests on AMBITION, in which combination therapy halved the risk of clinical failure compared with monotherapy. Initial triple oral therapy with selexipag did not lower PVR further in TRITON and is not recommended. Observational data support initial triple therapy with a parenteral prostacyclin in high-risk patients, with better survival than less intensive regimens.

Patients with comorbidities. Patients with PAH and three or more risk factors for left heart disease (obesity, hypertension, diabetes, coronary disease) or with mild lung disease tolerate combination therapy less well and respond less. The 2022 ESC/ERS guideline recommends initial monotherapy in these patients, with a decision about escalation made individually. In the US, the CHEST guideline's recommendation of initial ambrisentan plus tadalafil for treatment-naive patients in functional class II or III is consistent with the WSPH algorithm.

Mild disease. No therapy is approved for an mPAP of 21 to 24 mm Hg or a PVR of 2 to 3 WU, and these patients are followed closely or enrolled in trials.

Lung transplantation, atrial septostomy, and palliative care

Referral for lung transplant evaluation is made when disease progresses or leads to hospitalization despite therapy, when parenteral prostacyclin is needed, when veno-occlusive disease is known or suspected, or when liver or kidney dysfunction develops from right heart failure. Evaluation is considered at diagnosis in high-risk patients and recommended at follow-up when intermediate-high or high risk persists. Bilateral lung transplantation is the usual operation; the right ventricle recovers after the afterload is removed. Heart-lung transplantation is reserved for complex congenital disease or irreversible left heart disease. Patients with PAH have higher waiting-list mortality than those with parenchymal lung disease, so referral is early. Venoarterial extracorporeal membrane oxygenation, often in an ambulatory configuration, bridges selected patients to transplantation.

Balloon atrial septostomy creates a right-to-left shunt that decompresses the right ventricle and raises left ventricular filling and systemic output at the cost of oxygen saturation. It is used as palliation or as a bridge to transplantation, most often where drug therapy is unavailable, and is avoided when right atrial pressure is very high or baseline saturation is low because of high procedural mortality. Palliative care, with attention to dyspnea, edema, anxiety, and goals of care, is integrated early in advanced disease.

Pulmonary hypertension from left heart disease (group 2)

Left heart disease is the most common cause of pulmonary hypertension. It is common in heart failure with reduced or preserved ejection fraction and in severe mitral disease, and in a community series 53% of patients with aortic stenosis had at least moderately elevated pulmonary pressure. Raised left atrial pressure is transmitted backward (isolated post-capillary disease). With time and in susceptible patients, venous and arterial remodeling add a pre-capillary component (combined disease), which carries a worse prognosis and a higher risk of right ventricular failure. The 7th WSPH proposed a staging of pulmonary hypertension in left heart disease from A (at risk) through D (advanced), parallel to the heart failure stages.

The central diagnostic task is separation from PAH in older patients with cardiometabolic risk factors. A wedge pressure of 12 to 18 mm Hg in a patient with obesity, hypertension, diabetes, atrial fibrillation, left atrial enlargement, or abnormal diastolic indices is resolved with fluid or exercise challenge and the full clinical picture before a group 1 label is assigned; scores such as H2FPEF estimate the probability of HFpEF. The HFpEF and diastolic function page covers this evaluation.

Treatment. The left heart disease is treated: guideline-directed therapy for heart failure with reduced ejection fraction, sodium-glucose cotransporter 2 inhibitors, diuretics, blood pressure and rhythm control, weight loss in obesity, and timely valve intervention. Pulmonary vasodilators are not recommended. In SIOVAC, sildenafil given for persistent pulmonary hypertension after successful valve surgery worsened clinical outcomes. Macitentan in MELODY-1 caused fluid retention without hemodynamic benefit, and trials of endothelin antagonists, prostacyclin, and riociguat in heart failure have been neutral or harmful. Increasing pulmonary flow into a left heart that cannot accept it raises wedge pressure and can cause pulmonary edema. Patients with combined disease and a severe pre-capillary component (PVR above 5 WU) are referred to a pulmonary hypertension center, and trial enrollment is preferred.

Valve disease. In mitral stenosis, pulmonary pressure falls after balloon commissurotomy or surgery, although a severe pre-capillary component may regress only partly. Pulmonary hypertension predicts higher risk after aortic and mitral valve procedures but does not by itself exclude them. In heart transplant candidates, a high PVR that does not fall with vasodilator challenge or mechanical unloading raises the risk of donor right ventricular failure.

Pulmonary hypertension from lung disease and hypoxia (group 3)

Pulmonary hypertension complicates COPD, interstitial lung disease, combined pulmonary fibrosis and emphysema, sarcoidosis, and hypoventilation disorders. Hypoxic vasoconstriction, loss of the capillary bed, inflammation, and vascular remodeling contribute. Most patients have mild or moderate disease with a PVR below 5 WU, in whom pulmonary hypertension marks advanced lung disease; a minority have severe disease (PVR above 5 WU) that limits exercise more than the lung disease explains. A reduced diffusing capacity, desaturation with exercise, and a cardiovascular pattern of exercise limitation (preserved breathing reserve) point to a dominant vascular component. In smokers with a severely reduced diffusing capacity and mild emphysema or fibrosis on CT, the boundary between group 1 and group 3 is uncertain, and these patients are classified at a pulmonary hypertension center.

Treatment. The lung disease is optimized, hypoxemia is corrected with long-term oxygen, sleep-disordered breathing and hypoventilation are treated, pulmonary rehabilitation is offered, and eligible patients are referred for lung transplantation.

• Interstitial lung disease. Inhaled treprostinil is the one drug with randomized benefit (INCREASE) and is approved in the United States for this indication. A PDE5 inhibitor may be considered in severe pulmonary hypertension with interstitial lung disease in an expert center. Ambrisentan and riociguat are contraindicated in fibrotic lung disease.
• COPD. No PAH drug has shown benefit. Pulmonary vasodilators can worsen ventilation-perfusion matching and hypoxemia. Patients with severe pulmonary hypertension and a vascular phenotype are managed individually in expert centers.

Randomized trials of pulmonary vasodilators in pulmonary hypertension from left heart disease and lung disease. Rates are active treatment versus placebo. mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; WU, Wood units; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

High altitude. Chronic hypoxia at high altitude causes pulmonary vasoconstriction and remodeling. Chronic mountain sickness combines excessive erythrocytosis, hypoxemia, and pulmonary hypertension and improves with descent. In patients with established pulmonary hypertension, travel to altitude and air travel without supplemental oxygen can worsen hypoxemia and right ventricular load.

Chronic thromboembolic pulmonary hypertension

CTEPH is the main group 4 condition. It results from failure of thrombus to resolve after pulmonary embolism, with organized fibrotic obstruction of proximal and segmental arteries and a secondary small-vessel arteriopathy in unobstructed territories. Chronic thromboembolic pulmonary disease (CTEPD) is the umbrella term for symptomatic patients with persistent mismatched perfusion defects and chronic organized obstruction after at least 3 months of anticoagulation, with or without pulmonary hypertension at rest. CTEPH is CTEPD with pulmonary hypertension by the current hemodynamic definition. A quarter or more of patients have no recognized prior embolism. Risk factors include unprovoked or recurrent embolism, large perfusion defects, antiphospholipid syndrome (about 10% of patients), splenectomy, ventriculoatrial shunts, infected intravenous lines, inflammatory bowel disease, and cancer. Persistent dyspnea or exercise limitation 3 to 6 months after acute embolism leads to echocardiography and, when the probability of pulmonary hypertension is intermediate or high, ventilation-perfusion scintigraphy. Management of acute embolism is covered on the pulmonary embolism page.

Diagnosis requires mismatched perfusion defects on scintigraphy or CT perfusion, characteristic findings on CT pulmonary angiography or invasive pulmonary angiography (webs, bands, pouch defects, abrupt tapering, and chronic total occlusions), and catheter-confirmed pulmonary hypertension after at least 3 months of therapeutic anticoagulation. Every patient is reviewed by a multidisciplinary CTEPH team with a pulmonary endarterectomy surgeon, a balloon angioplasty interventionalist, a pulmonary hypertension specialist, and a radiologist.

Anticoagulation. Lifelong therapeutic anticoagulation is recommended. Vitamin K antagonists are the established standard and are required in antiphospholipid syndrome; direct oral anticoagulants are widely used in patients without it, although observational data suggest a higher recurrence rate in some series.

Pulmonary endarterectomy. Surgery is the treatment of choice for operable disease. The operation removes a cast of the organized material to the subsegmental level. Operability depends on lesion accessibility, the match between the obstruction and the PVR, comorbidity, and above all surgical experience; disease judged inoperable at one center can be operable at another.

Balloon pulmonary angioplasty and medical therapy. Inoperable disease and persistent or recurrent pulmonary hypertension after endarterectomy are treated with staged angioplasty, drugs, or both. Riociguat is the only drug approved for CTEPH in the United States. Macitentan lowered PVR in MERIT-1, and subcutaneous treprostinil improved walk distance in CTREPH. Many centers give medical therapy before angioplasty, and many patients receive surgery, angioplasty, and drugs in sequence. Five-year survival in inoperable patients treated with angioplasty and medical therapy now approaches 90%.

Treatment options in CTEPH, after the 7th WSPH (Kim et al., 2024), CHEST-1 (2013), and RACE (2022). mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; WU, Wood units.

Pulmonary hypertension with unclear or multifactorial mechanisms (group 5)

Group 5 gathers conditions in which several mechanisms combine. In sarcoidosis, pulmonary hypertension arises from fibrosis, granulomatous vasculitis, extrinsic compression of pulmonary arteries or veins by nodes, and left ventricular involvement; it carries a poor prognosis, and lung transplantation outcomes are similar to those for other indications. In chronic hemolytic anemias, including sickle cell disease, pulmonary hypertension can be pre-capillary or post-capillary and is associated with high mortality; PDE5 inhibitors increased painful crises in sickle cell disease. Myeloproliferative neoplasms cause pulmonary hypertension through thrombosis, extramedullary hematopoiesis, and drug effects. In chronic kidney failure, arteriovenous fistula flow, volume overload, and left heart disease contribute. Fibrosing mediastinitis, usually from histoplasmosis, compresses central pulmonary arteries and veins and is treated with stenting in selected patients. Pulmonary tumor thrombotic microangiopathy, most often from gastric or breast adenocarcinoma, causes rapidly progressive pulmonary hypertension and hypoxemia. Treatment in every group 5 condition is directed at the underlying disorder; PAH drugs are used only in selected patients at expert centers.

Pregnancy and contraception in pulmonary hypertension

Pregnancy imposes a 30% to 50% rise in cardiac output and plasma volume, a fall in systemic vascular resistance, a hypercoagulable state, and abrupt shifts in preload at delivery. A right ventricle facing a fixed high resistance cannot accommodate these changes. In a systematic review of cohorts from 2008 to 2018, maternal mortality in PAH was 12% overall and 20% in idiopathic PAH, down from 30% to 56% in older series but still prohibitive. Most deaths occur late in pregnancy, at delivery, or in the first weeks after delivery, from right ventricular failure, pulmonary hypertensive crisis, arrhythmia, or thromboembolism. Pulmonary hypertension of any cause with significant elevation of PVR carries a similar risk, and pulmonary arterial hypertension is in the highest category (modified World Health Organization class IV) of maternal cardiovascular risk.

Contraception. Pregnancy is advised against at diagnosis, and contraception is discussed with every woman of childbearing potential. Endothelin receptor antagonists and riociguat are teratogenic, and sotatercept is avoided in pregnancy; pregnancy is excluded before treatment, highly reliable contraception is used throughout, and pregnancy-testing requirements follow each drug's current labeling. Women considering pregnancy receive genetic counseling when heritable disease is present.

Contraception in women with pulmonary hypertension, after the 2022 ESC/ERS guideline.

Pregnancy in a woman with PAH. A woman who becomes pregnant is informed of the risk and offered termination, which is safest early. A woman who continues pregnancy is managed in a center with pulmonary hypertension, obstetric, anesthetic, and intensive care expertise. Teratogenic drugs are stopped, and PDE5 inhibitors and inhaled or parenteral prostacyclins are continued or started; women who are untreated often begin parenteral prostacyclin. Delivery is planned, usually by cesarean section with carefully titrated neuraxial anesthesia, and general anesthesia is avoided when possible. Monitoring continues for several weeks after delivery, the period of highest risk. Prophylactic anticoagulation is often used in the peripartum period.

Noncardiac surgery and anesthesia in pulmonary hypertension

Pulmonary hypertension increases perioperative mortality, heart failure, arrhythmia, and respiratory failure after noncardiac surgery. Risk rises with severity of pulmonary hypertension, right ventricular dysfunction, right atrial pressure, low walk distance, functional class III or IV, emergency surgery, and high-risk procedures. The 2023 AHA scientific statement on pulmonary hypertension in noncardiac surgery recommends preoperative assessment of the pulmonary hypertension group, severity, and right ventricular function; optimization of therapy before elective surgery; and surgery at a center with pulmonary hypertension expertise for patients with PAH or CTEPH.

PAH therapy is continued without interruption; parenteral prostacyclin is never stopped, and oral PDE5 inhibitors can be replaced by intravenous sildenafil when patients cannot take oral drugs. Anesthetic management maintains systemic vascular resistance and right ventricular perfusion pressure, avoids hypoxemia, hypercapnia, acidosis, hypothermia, and high airway pressures, all of which raise PVR, and avoids abrupt falls in preload. Induction of general anesthesia and the start of positive-pressure ventilation are the moments of highest risk, and vasopressors and inhaled pulmonary vasodilators are prepared before induction. Laparoscopic insufflation raises PVR through hypercapnia and impaired venous return. Monitoring continues after surgery, when fluid shifts and pain raise the risk of decompensation.

Acute right ventricular failure in pulmonary hypertension

Acute decompensated right heart failure in a patient with pulmonary hypertension carries high in-hospital mortality and is managed in an intensive care unit with pulmonary hypertension expertise. The usual triggers are infection, arrhythmia (especially atrial flutter or fibrillation), interruption of PAH therapy, pulmonary embolism, anemia, pregnancy, surgery, and nonadherence to diuretics or sodium restriction.

Management addresses preload, systemic pressure, contractility, and right ventricular afterload together.

Management of acute right ventricular failure in pulmonary hypertension, after the 2022 ESC/ERS guideline and the 2018 AHA scientific statement on right-sided heart failure. PVR, pulmonary vascular resistance.

Monitoring includes lactate, urine output, central venous saturation, and, in selected patients, a pulmonary artery catheter. Rising right atrial pressure, falling cardiac index, worsening kidney or liver function, and refractory hypotension identify patients who need escalation, transplant evaluation, or a transition to palliative care. Shock from other causes is covered on the cardiogenic shock page.

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