Pulmonary Arterial Hypertension (PAH)

Patients with pulmonary arterial hypertension (PAH) are required to undergo a series of initial diagnostic evaluations before the diagnosis is established. Initial diagnostic evaluations include a complete family history; a detailed physical examination for the presence of PAH-related signs and symptoms;¹ and screening for the presence of risk factors such as connective tissue disease (CTD), liver disease, human immunodeficiency virus (HIV), or exposure to drugs or toxins (eg, methamphetamine).²

Based on the initial evaluation, patients suspected to have PAH are recommended to be referred to a specialty pulmonary hypertension (PH) center for a comprehensive set of diagnostic evaluations including electrocardiography, transthoracic echocardiography, several laboratory tests, ventilation/perfusion scan, and pulmonary function studies.

A diagnosis is considered in patients with mean PAP ≥ 20 mm Hg, pulmonary artery wedge pressure (PAWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) > 3.0 Wood Units.²

Diagnosis of PAH also requires exclusion of other diseases that lead to abnormal cardiopulmonary hemodynamics such as cardiac diseases (eg, left ventricular dysfunction, congenital heart disease, valvular disease, and cardiomyopathy), or parenchymal lung disease. Patients who are at risk for heritable PAH (HPAH) are recommended genetic testing to screen for mutations in BMPR2 or other selected genes.¹

Finally, all patients suspected to have PAH after the preliminary tests are required to undergo cardiac catheterization at rest to confirm PAH diagnosis.¹ It is recommended to perform an acute vasodilator test (using vasodilators such as nitric oxide) or fluid loading test (using saline infusion) during catheterization to evaluate physiological responses and guide therapeutic options.¹

Preliminary Tests

Blood-Based Biomarkers

Several laboratory tests are performed for PAH screening such as complete blood count, complete metabolic panel, thyroid function, antinuclear antibody, Rh factor, coagulation studies, and biomarker testing for CTD or HIV.¹

The blood biomarkers currently used for screening PAH patients are brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), and serum urate. NT-pro-BNP, an inactive precursor of BNP, is released by cardiomyocytes in response to increased myocardial wall stress caused by PAH. However, elevated levels of NT-pro-BNP can also be found in patients with other conditions such as left ventricular dysfunction. Elevated serum urate levels suggest impairment of oxidative metabolism due to tissue ischemia and have been found to be predictive of PAH.³

Chest Radiograph

Chest radiograph reveals abnormalities in about 90% of patients with idiopathic PAH. Abnormalities include central pulmonary arterial dilatation, which contrasts with loss of the peripheral blood vessels. It can also reveal enlargement of the right ventricle (RV) or right atrium (RA), particularly in advanced cases. It may assist in differential diagnosis by revealing changes suggestive of lung disease or left heart disease. However, PAH cannot be excluded if the chest radiograph is normal.⁴

Electrocardiography (ECG)

Electrocardiography measures the electrical impulses of the heart using electrodes attached to the patient’s skin and provides an early clue to the presence of PAH. ECG may reveal abnormalities indicative of right atrial or ventricular dilatation like right bundle branch block (RBB), right axis deviation (RAD), RV hypertrophy, RV strain, P pulmonale, and QTc prolongation. RV strain is more sensitive for screening than RV hypertrophy.⁴

Transthoracic Echocardiography

Doppler transthoracic echocardiography involves taking a sonogram of the heart using an ultrasound probe placed on the patient’s chest. It is used to assess normal functioning of the heart and estimate the pressures in the right heart. One of the most important parameters of echocardiography is the tricuspid regurgitation velocity (TRV) that allows an estimate of the systolic pulmonary artery pressure (PAP), which was found to be associated with poor outcome if elevated by even mild levels.

It can be used to determine the size and thickness of the right ventricle, which may get enlarged in patients with PAH. Other echocardiographic parameters associated with PAH include measurements from the pulmonary artery (eg reduced RV outflow tract acceleration time), ventricles (eg,  RV/left ventricle basal diameter ratio > 1.0, flattening of the interventricular septum), or increases in inferior vena cava diameter or right atrium area.⁴

Pulmonary Function Tests

Pulmonary function tests in PAH patients assess the amount of air the lungs can hold, the amount of air moving in and out, and the lungs’ ability to exchange oxygen. They use spirometry measurements of total lung capacity (TLC), forced expiratory volume (FEV), forced vital capacity (FVC), and lung diffusion capacity for carbon monoxide (DL_CO).²

Most patients with PAH, particularly patients with PAH associated with systemic sclerosis, have decreased DL_CO. Abnormally low values of DL_CO (defined as 45% of predicted) are associated with a poor outcome. However, a normal DL_CO does not exclude PAH, particularly in patients with very early disease or those with HPAH, when DL_CO can be preserved.

Another parameter is the ratio of FVC to DL_CO, whose high value (a ratio of ≥ 1.8) in patients with systemic sclerosis (SSc) suggests significant reduction in gas transfer compared with lung volume and a higher likelihood of developing PAH.^3,5

Cardiopulmonary Exercise Testing (CPET)

CPET provides information about exercise capacity as well as gas exchange and cardiac function during exercise. It can help to distinguish between the metabolic, cardiovascular, and pulmonary components of exercise intolerance if performed by experts at PH specialist centers. The typical CPET findings in PAH patients include reductions in peak rate of oxygen uptake (VO₂), ratio of oxygen uptake to heart rate (O₂ pulse), work rate, and anaerobic threshold; and an increase in the ratio of minute ventilation to CO₂ production (V_E/V_CO2 slope) and the ratio of dead space to tidal volume (V_D/V_T).³

Ventilation/Perfusion Scan

Ventilation/perfusion scan (V/Q scan) is performed using radioactive material that is inhaled as well as injected (via a blood vessel) into the lungs. This produces a picture of air and blood flow in the lungs that may reveal the presence of blood clots within the lungs. The doctor will review the images that are produced to evaluate the health of the lungs.

The V/Q scan is useful for differential diagnosis for excluding chronic thromboembolic pulmonary hypertension (CTEPH) that can be cured by surgical pulmonary thromboendarterectomy.²

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging (MRI) is an accurate and reliable method that helps assess multiple cardiac parameters including RV size and function, cardiac output (CO), stroke volume, and pulmonary artery distensibility.⁴

Confirmatory Test

Right Heart Catheterization

Under current guidelines, right heart catheterization (RHC) is a gold standard test for confirming the diagnosis of PAH before any PAH treatment is initiated. RHC is used to measure PAP, left ventricular filling pressure, and CO. It can also evaluate pulmonary hypertension due to left heart disease, assess the severity of pulmonary hypertension, and identify the subset of patients who respond favorably to acute vasodilators such as nitric oxide (these patients respond favorably to treatment with high-dose calcium channel blockers/CCBs).⁴  The patients who respond favorably to acute vasodilator testing and are treated with CCBs should be followed closely for safety and efficacy with a complete reassessment including RHC after 3 to 4 months of therapy.

References

1. Austin ED, Phillips JA III, Loyd JE. Heritable pulmonary arterial hypertension overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews^®. University of Washington, Seattle; 2002. Updated Dec. 3, 2020. Accessed July 29, 2021.
2. Sahay S. Evaluation and classification of pulmonary arterial hypertension. J Thorac Dis. 2019;11(Suppl 14):S1789-S1799. doi:10.21037/jtd.2019.08.54
3. Kiely DG, Lawrie A, Humbert M. Screening strategies for pulmonary arterial hypertension. Eur Heart J Suppl. 2019;21(Suppl K):K9-K20. doi:10.1093/eurheartj/suz204
4. Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119. doi:10.1093/eurheartj/ehv317
5. Thakkar V, Stevens W, Prior D, et al. The inclusion of n-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study. Arthritis Res Ther. 2013;15(6):R193. doi:10.1186/ar4383

Article reviewed by Debjyoti Talukdar, MD, on July 1, 2021.

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Erum Naqvi, PhD

Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.