Group 4 Pulmonary Hypertension Workup

Updated: Mar 16, 2020
  • Author: Paresh Chandra Giri, MD, FCCP; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Approach Considerations

Any patient with unexplained pulmonary hypertension should be evaluated for chronic thromboembolic pulmonary hypertension (CTEPH). The diagnostic evaluation is geared toward (1) confirmation of obstructing thromboembolic disease and (2) determining the surgical accessibility of the disease. [30] Based on current evidence, routine screening for CTEPH is not recommended in survivors of an acute pulmonary embolism (PE). [31] Initial evaluation for CTEPH typically begins with chest radiography, echocardiography, and pulmonary function testing to evaluate dyspnea. [32] Once pulmonary vascular disease is suspected, the evaluation becomes more focused.


Chest Radiography

In early stages of the disease, radiography findings may be normal. As disease progresses, right ventricular enlargement with obliteration of the retrosternal space and prominence of the right-side heart border can be seen. The lung fields may be clear, have areas of hypoperfusion called the Westermark sign, or have evidence of previous infarction, called the Hampton hump. Central pulmonary artery enlargement often occurs with advanced disease.



Echocardiography should be performed in every patient being evaluated for pulmonary hypertension. It is used to evaluate right ventricular systolic pressure (sometimes expressed as pulmonary artery systolic pressure, [PASP]), chamber size, right and left ventricular systolic and diastolic function, valvular function, and for the presence of pericardial effusion. PASP is estimated using the tricuspid regurgitant jet velocity and right atrial pressure (RAP) using the modified Bernoulli equation, PASP = 4v2 + RAP, where “v” is the maximum velocity of the tricuspid regurgitant jet. Intravenous bubbles can be administered to detect intracardiac shunts. In the setting of right ventricular overload, systolic flattening of the intraventricular septum (called the “D” sign) and thickening of the right ventricular free wall may be observed.

Echocardiography is also useful for excluding left ventricular dysfunction, valvular heart disease, and congenital heart disease as causes of pulmonary hypertension. In addition, although Doppler-derived pressure estimations in general correlate with invasive measurements of right ventricular pressures, they may be inaccurate in an individual patient. PASP may be underestimated in severe tricuspid regurgitation, and overestimations by greater than 10 mm Hg for PASP may also occur. [33] Right-sided heart catheterization is required to confirm the diagnosis and to define the hemodynamic profile in greater detail and accuracy. [34]


Ventilation-Perfusion Scanning

A ventilation-perfusion (V/Q) scan is the recommended initial imaging test of choice for CTEPH, followed by a high-quality pulmonary angiogram to confirm and define the pulmonary vascular involvement [2] ; and all patients undergoing evaluation for pulmonary hypertension should undergo a V/Q scan. [2] A normal V/Q scan effectively excludes CTEPH with a sensitivity of 90-100% and a specificity of 94-100%. [35] In one study of confirmed CTEPH cases, the V/Q scan was found to be superior to CT pulmonary angiography (CTPA) with a sensitivity of 97.4% versus 51%. [36] However, other studies show improved sensitivity and specificity with CTPA. Advantages to obtaining CT imaging include concomitant assessment of collateral vasculature, pulmonary parenchyma, and mediastinum, which can aid in planning for surgical procedures.

Patients with CTEPH show one or more segmental or larger unmatched perfusion defects, as shown in the image below.

Ventilation perfusion scan showing bilateral large Ventilation perfusion scan showing bilateral large wedge-shaped mismatched perfusion defects and areas of gray indicating decreased perfusion. Right-sided heart catheterization for this patient showed combined precapillary and postcapillary pulmonary hypertension and the following: right atrial pressure 10 mm Hg, right ventricular pressure 82/8 mm Hg, pulmonary artery wedge pressure 22 mm Hg, and pulmonary artery pressure 83/27 mm Hg with a mean of 49 mm Hg. He was referred to an expert center for pulmonary endarterectomy evaluation, where he underwent pulmonary angiography. Findings from the right side showed an occluded upper lobe anterior segment, a proximal web in the upper lobe, and disease in all lower segments. Findings from the left side showed an occluded superior segment of the lower lobe with disease in basal segments, proximal web in lingula, and intact upper lobe vessels. He underwent pulmonary endarterectomy with intraoperative University of California San Diego classification of thrombus as right 1 and left 2. Postoperatively, he has had dramatic improvement in his symptoms and is off all pulmonary arterial hypertension therapy.

In contrast, patients with pulmonary hypertension caused by small-vessel disease such as pulmonary arterial hypertension (PAH) have normal or mottled perfusion scans with subsegmental perfusion defects. [37] The magnitude of perfusion defects often underestimates the degree of vascular obstruction in CTEPH. This is because of organization and recanalization of clot resulting in partial rather than complete obstruction of pulmonary arteries, which allows limited passage of radiolabeled aggregated albumin, resulting in gray zones in areas of hypoperfused lung on the perfusion scan. Because of this, further evaluation for chronic thromboembolic disease (CTED) should be conducted even when the V/Q scan shows a limited number of mismatched perfusion defects.

Despite the value of lung scintigraphy, V/Q scanning is underused and data from the PAH-QuERI (Pulmonary Arterial Hypertension Quality Enhancement Research Initiative) registry demonstrate that only 57% of PAH patients undergo V/Q imaging to exclude CTEPH during their evaluation. [38]


Pulmonary Vasculature Imaging

CT pulmonary angiography

CTPA is a commonly used method in the diagnosis of acute PE, but the sensitivity of CTPA to detect CTEPH has been considered lower than that of conventional angiography, especially for distal vessel disease. However, with technological advances and increased experience, the accuracy of CTPA in the detection of CTED has improved. Chronic thromboemboli may appear as complete vascular obstruction or partial vascular obstruction, with organized lining thrombus mimicking thickening of the vascular wall, eccentric filling defects, intraluminal webs or bands, or abrupt vessel narrowing (see the first image below). Other findings suggesting CTEPH include enlarged bronchial arteries and collateral arteries from the systemic circulation to the lung (see the second image below). These dilated bronchial arteries are seen in roughly half the patients with CTEPH and are helpful in distinguishing CTEPH from patients with acute PE or PAH, in whom dilated bronchial arteries are rarely present. Lymph node enlargement was seen in 36% of patients in one study specifically analyzing adenopathy in patients with CTEPH, probably due to slowing of lymph flow because of increased central venous pressure. [39] Lung parenchymal changes include mosaic attenuation caused by areas of relative hypoperfusion or hyperperfusion (see the third image below) and peripheral irregular, wedge-shaped, or linear opacities caused by pulmonary infarction. CT imaging also allows for preoperative surgical assessment, which can sometimes be important in patients with previous mediastinal surgery or massive right-side heart chamber enlargement. Pulmonary vascular imaging also helps differentiate other vascular disorders that may mimic CTEPH, such as pulmonary artery sarcoma, fibrosing mediastinitis, and pulmonary venoocclusive disease.

The heart is enlarged, with right atrial and ventr The heart is enlarged, with right atrial and ventricular enlargement in addition to reflux of contrast into the intrahepatic inferior vena cava. The main pulmonary artery itself measures approximately 3 cm. There was mosaic attenuation of both lungs, most pronounced related to the right-middle and upper lobes (not shown).
Extensive pulmonary emboli are seen in both lungs, Extensive pulmonary emboli are seen in both lungs, with a dominant, eccentric thrombus related to the left main pulmonary artery. More distal emboli were noted in the subsegmental pulmonary arteries (not shown). This is a 42-year-old woman with a history of multiple pulmonary emboli and protein S deficiency who initially presented with severe dyspnea (New York Heart Association functional class IV) and was initiated on multiple pulmonary arterial hypertension medications, including intravenous prostacyclin. She underwent pulmonary endarterectomy, and the images of the clots that were removed intraoperatively are shown in another image.
Mosaic pattern seen on expiratory images of a ches Mosaic pattern seen on expiratory images of a chest CT scan in a patient with chronic thromboembolic pulmonary hypertension. The same patient’s ventilation/perfusion scan is also shown. The areas of hypovascularity in blood vessels with clots cause areas of relative hypoperfusion, which appear darker than normal lung and give rise to the differential opacities seen on this image.

Although CTPA can play a valuable role in the evaluation of patients with CTEPH, two caveats must be kept in mind. The first is that CTPA alone is not sensitive enough to rule out CTED, and the second is that the presence of chronic clots on CT does not confirm the diagnosis of CTEPH. Although not widely available, cone-beam CT has the advantage of evaluating organized thrombi in segmental and subsegmental pulmonary arteries in greater detail. [40]

MRI of pulmonary vessels

Magnetic resonance angiography has been shown to accurately show findings of CTEPH (intraluminal webs/bands, vessel cutoffs, and organized central thromboemboli) up to the segmental level. In addition, three-dimensional contrast-enhanced lung perfusion MRI tracks the dynamic passage of a contrast bolus, allowing imaging of regional pulmonary perfusion. Cardiac MRI has been proved useful in the evaluation of right-side heart function and detection of anatomic abnormalities, and it can be used to assess right ventricular volumes, left ventricular septal bowing, and muscle mass, as well as calculation of stroke volume. MRI is particularly advantageous in patients with suboptimal echocardiographic imaging, and it also allows pulmonary angiographic imaging without exposure to radiation or iodinated contrast. [41] However, it is used infrequently because it is time consuming, not as readily available, and requires interpretive expertise.

Conventional pulmonary angiography

Pulmonary angiography (either conventional or digital subtraction) is the criterion standard in the evaluation of CTEPH. The angiographic appearance of CTED is different from that of acute PE because of the organization and recanalization that takes place during partial embolic resolution. Characteristic angiographic findings in CTEPH include vascular webs or bandlike narrowings, intimal irregularities, pouch defects, abrupt narrowing of vessels, and proximal obstruction of pulmonary arteries (see the image below).

Extensive pulmonary emboli are seen in both lungs, Extensive pulmonary emboli are seen in both lungs, with a dominant, eccentric thrombus related to the left main pulmonary artery. More distal emboli were noted in the subsegmental pulmonary arteries (not shown). This is a 42-year-old woman with a history of multiple pulmonary emboli and protein S deficiency who initially presented with severe dyspnea (New York Heart Association functional class IV) and was initiated on multiple pulmonary arterial hypertension medications, including intravenous prostacyclin. She underwent pulmonary endarterectomy, and the images of the clots that were removed intraoperatively are shown in another image.

Biplane angiography is optimal because lateral images provide better detail of lobar and segmental vessels that overlap on anteroposterior images. Angiography should be performed at an experienced center that works closely with a surgical team in order to guide optimal therapy. Other modalities of imaging include dynamic contrast-enhanced lung perfusion MRI and single-photon emission CT scanning, but prospective data for these tests are lacking. While angiography has been considered the criterion standard for characterizing vessel morphology in CTEPH, it is being challenged by new advances in noninvasive modalities, including dual-energy CT, ECG-gated area detector CT, cone-beam CT, and contrast-enhanced magnetic resonance pulmonary angiography.

As imaging modalities improve, the ability to predict the level of disease preoperatively has improved; however, invariably more disease is encountered at the time of surgery than predicted on routine imaging preoperatively.


Right-Sided Heart Catheterization

Right-sided heart catheterization is used to confirm the diagnosis of pulmonary hypertension and can be used to differentiate group 4 pulmonary hypertension from other underlying etiologies. Measurements obtained from this procedure include pulmonary artery wedge pressure (PAWP), mean pulmonary arterial pressure (mPAP), cardiac output, pulmonary vascular resistance (PVR), transpulmonary gradient (TPG = mPAP - PAWP), and diastolic pressure gradient (DPG = dPAP - PAWP, where dPAP is diastolic pulmonary artery pressure). This assessment defines the severity of the pulmonary hypertension and degree of cardiac dysfunction, which are helpful in assessing the risk of surgical intervention. Measurement of left ventricular end-diastolic pressure may be necessary since determining accurate PAWP can be difficult. Preoperative and postoperative PVR are known long-term predictors of prognosis. [42]

Exercise hemodynamic measurements can be obtained in symptomatic patients without pulmonary hypertension at rest. A significant increase in PVR is an abnormal physiologic response to exercise. Historically accepted indications for pulmonary thromboendarterectomy (PTE) were a mPAP greater than 30 mm Hg, PVR greater than 300 dyn·s·cm−5, and New York Heart Association functional classification of III-IV. However, it is also presently indicated for patients with symptomatic CTED who are dyspneic or develop pulmonary hypertension only with exercise.


Other Tests


Electrocardiography findings in pulmonary hypertension are nonspecific but may suggest right-side ventricular disease. Signs of right-side ventricular hypertrophy include right axis deviation, incomplete and complete right bundle-branch block, and an R-wave-to-S-wave ratio greater than 1 in lead V1. Additionally, increased P-wave amplitude in lead II is indicative of right atrial enlargement.

Pulmonary function testing

Although there are no specific findings that suggest CTEPH, pulmonary function testing is helpful for excluding significant coexistent airway or parenchymal lung disease. In the absence of other lung disease, patients with CTEPH typically have normal spirometry and lung volumes. Up to 20% may show a mild restrictive defect related to parenchymal scarring from previous lung infarction. Diffusing capacity of the lungs for carbon dioxide (DLCO) may be normal or mildly to moderately reduced. Severe reductions in DLCO should prompt further lung parenchymal evaluation. [30]

Other etiologies of pulmonary hypertension should be evaluated with a polysomnography (to assess for obstructive sleep apnea).


Laboratory Studies

Baseline complete blood cell count, basic metabolic panel, and liver function tests should be obtained in all patients. Serologic evaluation for other etiologies of WHO groups 1, 2, 3, and 5 pulmonary hypertension should be obtained in order to identify concomitant etiologies.

Assessment for thrombophilic states should be performed. Obtaining a brain natriuretic peptide level and troponin level can be helpful in establishing baseline values and as a means to monitor the degree of chamber stretch and myocardial injury.