Group 4 Pulmonary Hypertension

Pulmonary hypertension is divided into five distinct World Health Organization (WHO) groups, which are categorized according to similar pathophysiologic changes, clinical presentation, and available therapies. WHO group 4 is classified as pulmonary hypertension due to pulmonary artery obstructions, of which there are two subdivisions: (1) chronic thromboembolic pulmonary hypertension (CTEPH) and (2) other pulmonary artery obstructions.[1] CTEPH is defined by mean pulmonary arterial pressure (mPAP) greater than 20 mm Hg in the presence of organized, nonacute, thromboembolic material and altered vascular remodeling in the pulmonary vasculature.[2] It is a rare but life-threatening complication of acute pulmonary embolism (PE) and differs from other forms of pulmonary hypertension in terms of pathophysiology and treatment.

The 6th World Symposium on Pulmonary Hypertension Task Force on pulmonary hypertension diagnosis and classification has defined precapillary pulmonary hypertension by a mPAP greater than 20 mm Hg, a pulmonary artery wedge pressure (PAWP) less than 15 mm Hg, and a pulmonary vascular resistance (PVR) greater than 3 Wood units. These hemodynamic thresholds may be applied to CTEPH. Residual pulmonary vasculopathy without evidence of pulmonary hypertension is termed chronic thromboembolic disease (CTED). Despite clear criteria, CTEPH and CTED can be difficult to diagnose and appropriate evaluation is often delayed. There is, however, an increasing interest in CTEPH as the only surgically curable form of pulmonary hypertension.[3]

Pathological specimens in CTEPH look very different than in acute PE. The acute PE thrombus consists of a mesh of fibrin with red blood cells. Clots in CTEPH are yellow; contain collagen, fibroblasts, elastin, recanalization vessels, and inflammatory cells; and are firmly adhered to the vascular wall.[4] CTEPH presents with bands and webs, stenosis, and occlusion developing in the area of the former PE, primarily in large and median arteries. These changes cause a redistribution of blood flow to unobstructed vessels, thereby increasing the pressures and shear stress experienced by the vessels.[5] These vessels then show tendencies toward vasoconstriction, hypertrophy, and microvascular thrombi, and ultimately lead to vascular remodeling that lends itself to much higher pressures than originally expected, with eventual disease progression.[6] Alongside this, a pulmonary arteriopathy similar to the one developed in WHO group 1 pulmonary arterial hypertension (PAH) occurs in small, low-resistance vessels.[7] In patients with CTEPH, a reduction in the production of nitric oxide contributes to platelet dysfunction, vascular remodeling, and reduction of antiproliferative stimuli.[8] As the disease progresses, connections between the bronchial artery branches and precapillary pulmonary arterioles or veins can be formed, triggering further remodeling.[9]

The combination of small-vessel arteriopathy with in situ thrombosis, dysfunction of the pulmonary vascular endothelium, secretory abnormalities in the vascular active substances and cytokines, vascular remodeling, and macrovascular formation of bands and webs with obstruction and vasoconstriction results in pulmonary hypertension and right ventricular pressure overload and failure.[6] There is also an increase in PVR, which results in elevated pulmonary artery systolic pressure (PASP) that is usually greater than those observed in acute PE.[10]

Multiple clinical conditions may predispose to CTEPH (see below).[11] It is well known, for example, that patients with cancer have an increased risk of developing thromboembolic events resulting from activation of fibrinolytic and coagulation systems, acute-phase reactions, inflammation, and cytokine production.[12] CTEPH is also most common in patients with non-O blood groups; 77% of patients with CTEPH have this blood group, compared with 58% in patients with PAH.[13] Patients with CTEPH have a higher prevalence of abnormal fibrinogen molecule (Aα-Thr312A1a mutation), and levels of thrombin-activatable fibrinolysis inhibitor, an enzyme that inhibits fibrinolysis, are higher in CTEPH patients.[14] Certain platelet-activating conditions (eg, thyroid hormone therapy) and splenectomy are associated with increased CTEPH risk, which suggests a role for platelets in this disease.[15] Levels of C-reactive protein are elevated in patients with CTEPH, and they decrease after pulmonary thromboendarterectomy (PTE), which suggests there may be an inflammatory component to CTEPH development.[16] Other inflammatory markers (eg, interleukin 10, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and matrix metalloproteinase 9) are also elevated in CTEPH. Chronic Staphylococcus aureus infection has also been identified in CTEPH patients, and some postulate that thrombus infection is a trigger for the development of this entity.[17] Impaired angiogenesis, biological factors, and genetic factors have also been associated with CTEPH.

Risk factors for the development of CTEPH

Acute PE-related risk factors are as follows:

• Recurrent pulmonary embolic events
• Large perfusion defect
• Higher pulmonary artery pressure at the time of initial PE diagnosis
• Idiopathic (unprovoked) PE

Hemostatic risk factors are as follows:

• Elevated factor VIII, von Willebrand factor, or type 1 plasminogen activator inhibitor
• Abnormal fibrinogen structure
• Antiphospholipid antibodies and lupus anticoagulant
• Non–type-O blood groups
• Elevated lipoprotein(a)

Associated medical conditions are as follows:

• Splenectomy
• Ventriculoatrial shunt
• Infected intravenous catheters/devices
• Chronic inflammatory disorders
• Hypothyroidism
• Malignancy

According to registry data, there are no sex differences in the prevalence of CTEPH. The average age onset is usually in the 60s. Nonresolution of PE is the most common cause of CTEPH.[7] In a European registry, 75% of patients with CTEPH reported previous PE.[15]

The incidence of CTEPH after acute PE is not clear. A review estimates that the full incidence of CTEPH in the United States is 4,886 cases per year,[18] based on an incidence of CTEPH after PE of 0.57% reported by Klok et al.[19] Possibly the most quoted study related to PE incidence was published in the New England Journal of Medicine in 2004.[20] In this study, 223 patients with acute PE and without a previous venous thromboembolic event were followed for 10 years. Seven (3.8%) of 223 patients developed symptomatic CTEPH 2 years after the initial thromboembolic event. Other studies corroborated the fact that the majority of CTEPH cases developed 2 years after the initial event of acute PE.[21] Historically, between 0.1% and 0.5% of patients with PE were thought to develop CTEPH.[3] In 2006, another study showed that CTEPH developed in 1% of patients with acute PE, but this study excluded patients with known venous thromboembolic risk development. Since then, other studies have revealed a prevalence of 0.4-4.8%.[22] These rate differences are likely due to the different populations studied, different methods of screening, and follow-up duration. In summary, irrespective of the rate of CTEPH from PE used in estimates, it is clear that a large proportion of CTEPH cases are underdiagnosed each year. Factors contributing to this underdiagnosis and treatment include poor specificity of initial signs and symptoms and unknown PE history at presentation.[7]

The epidemiological analysis suggests that the full incidence of CTEPH in the United States and Europe ranges from 3-5 cases per 100,000 population per year. The average diagnosis rate was 14.2% for the United States and Europe in 2013, which equates to a diagnosed incidence of 4-7 cases per million. Although the incidence of PE in Japan is substantially lower than the incidence observed in United States and Europe, the rate of CTEPH is much higher. This disparity might be related to genetics, population demographics, or lifestyle, among other factors. An alternative explanation is that only severe cases of PE might be diagnosed, while mild cases might not be recognized or reported.[23]

Not only diagnosis, but also proper referral to an expert center, seem to be delayed in CTEPH. In one study, the mean delay from symptom onset to diagnosis of CTEPH was 18 ±26 months. This also transpires in the severity of disease, since most of the patients present with WHO functional class III and IV.[24] Late diagnosis can negatively impact treatment options and overall quality of life.

Epidemiological projections in seven countries indicate that the incidence of CTEPH, especially late-stage disease, will increase over time from 32,636 cases (16%) diagnosed in 2015 to 37,009 cases (28%) in 2025.[25]

In a 3-year span, outcomes comparing PTE versus medical therapy for the diagnosis of CTEPH revealed a survival rate of 89% versus 70%, respectively. Factors that influence these outcomes include old age (>70 years), residual postoperative pulmonary hypertension, intraoperative complications or additional cardiac surgeries, patient comorbidities (eg, coronary artery disease, chronic obstructive pulmonary disease, heart failure, history of cancer or dialysis), and factors related to the extent of the disease, including elevated right atrial pressure (RAP), WHO functional class IV, and PVR greater than 15 Wood units.[26, 27] Of patients undergoing PTE, 17-30% had residual pulmonary hypertension and postoperative PVR is an independent risk factor for in-hospital and 1-year mortality.[28]

Patients should be educated about the symptoms of CTEPH. If the patient is a surgical candidate, detailed information about the procedure itself, risks, benefits, and prognosis should also be discussed at an expert center. If the patient is not a surgical candidate, education about the importance of strict medication and diet adherence to avoid progression of symptoms should be emphasized. Symptoms that require prompt medical evaluation and treatment should also be communicated to patients. Patients also should be encouraged to comply with weight and fluid monitoring.

The following further patient resources from medical societies are also available:

• American Thoracic Society: Chronic Thromboembolic Pulmonary Hypertension
• CHEST Foundation: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
• CTEPH.com

Patients usually present with exercise intolerance, fatigue, and progressive dyspnea. Because these symptoms are nonspecific, they are typically attributed to more common diseases such as obstructive lung disease, cardiac abnormalities, obesity, and deconditioning. When pulmonary pressures continue to increase and right ventricular failure develops, chest discomfort, syncope, hemoptysis, light-headedness, and peripheral edema can occur.[29]

The symptoms arise from limitations in cardiac output caused by an increased pulmonary vascular resistance (PVR) and increased minute ventilation requirements secondary to increased dead space ventilation. It is essential that clinicians take a careful history in order to recognize previous events consistent with venous thromboembolism and other risk factors (see Risk Factors). Although most patients with chronic thromboembolic pulmonary hypertension (CTEPH) have a history of at least one previous acute thromboembolic event, approximately 30-40% have no such history, thereby making the diagnosis of CTEPH more challenging.[13]

Findings of CTEPH on physical examination may include a diminished or fixed splitting of the second heart sound (S2), accentuation of the pulmonic closure sound (P2), a palpable right ventricular heave, jugular venous distention, a right-side third heart sound (S3), tricuspid regurgitation, hepatomegaly, ascites, and peripheral edema. Bruits may be heard on auscultation over the peripheral lung fields; they rise from turbulent flow through partially obstructed pulmonary arteries. Cyanosis may be a sign of right-to-left shunting through a patent foramen ovale.

If not appropriately diagnosed and treated, CTEPH results in right ventricular failure, severe hypoxemic respiratory failure with need for mechanical ventilation, cardiogenic shock, and death. If CTEPH is diagnosed in a timely manner, treatment options can also carry potential complications. Different medical and surgical therapies for CTEPH and complications thereof are discussed in Complications in the Treatment section.

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.

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]

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 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]

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 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, 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 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, 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 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.

Electrocardiography

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).

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.

Treatment in chronic thromboembolic pulmonary hypertension (CTEPH) is unique in that surgery is able to provide definitive and curative outcomes without having to proceed to transplantation. Thus, the goal of treatment is to assess for surgical candidacy (see the image and patient history caption below). Medical therapy is offered to nonoperative candidates or patients with residual pulmonary hypertension postsurgery.

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.

Preoperative assessment

With the diagnosis confirmed or suspected, assessment of surgical candidacy for pulmonary thromboendarterectomy (PTE) should be performed at centers with expertise in the management of CTEPH. Proximal organized thrombi represent the ideal surgical circumstance, but patients with more distal obstruction (isolated segmental disease) often also derive hemodynamic benefit.[43] Because the increase in pulmonary vascular resistance (PVR) arises not only from central surgically accessible lesions but also from distal, small-vessel arteriopathy, patients with a significant component of small-vessel arteriopathy may not experience a significant decrease in PVR following PTE. Determining the presence and extent of small-vessel arteriopathy before surgery remains challenging. Poor subpleural perfusion on pulmonary angiography may suggest distal vessel disease but remains to be explored.[44]

Comorbid diseases must also be assessed as part of the preoperative evaluation. Coronary artery disease and valvular heart disease can be corrected at the time of PTE. Severe underlying parenchymal disease, particularly involving regions of the lung anticipated to be reperfused with an endarterectomy, is a contraindication to surgery, which has the potential to increase ventilation-perfusion (V/Q) mismatch and worsen hypoxemia and postoperative respiratory failure.

Pulmonary thromboendarterectomy

PTE should be offered to all eligible patients with CTEPH (see the image below and patient history caption). The international registry of incident cases of CTEPH reported 3-year survival of 90% in those operated and 70% in those not having surgery.[27] Characteristics that favor good long-term outcomes for PTE include the following:

• History of deep venous thrombosis/pulmonary embolism (PE)
• Absence of right-side heart failure and other comorbidities
• Clear concordance on all images
• Bilateral lower-lobe disease
• PVR less than 1,000 dyn·s·cm−5, in proportion to site and number of obstructions on imaging
• Higher pulmonary artery pulse pressure
• Good functional capacity (New York Heart Association functional class II or III)

The most important surgical advance has been in redefining the distal limits of endarterectomy,[45] as well as perioperative and postoperative care, which have resulted in a reduction of perioperative mortality from almost 20% in the early years to less than 2% at University of California San Diego.[43]

Intraoperative clot during pulmonary endarterectomy. 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. Preoperative right-sided heart catheterization showed right atrial pressure of 16 mm Hg, pulmonary artery pressure of 124/29 mm Hg with a mean of 67 mm Hg, cardiac output of 4.53, and pulmonary vascular resistance of 12 Wood units. Immediate postoperative right-sided heart catheterization showed right atrial pressure of 9 mm Hg, pulmonary artery pressure of 40/15 mm Hg with a mean of 25 mm Hg, cardiac output of 5.15, and pulmonary vascular resistance of 2.9 Wood units. She came off all her pulmonary arterial hypertension therapy immediately postoperatively and continues to do well.

In expert centers, surgery can be performed successfully in patients with distal chronic thromboembolism.[46] The advances in diagnostics and growing surgical experience have contributed to this success and have led to an intraoperative classification of the specimens retrieved during pulmonary endarterectomy.[11]

University of California San Diego surgical classification is as follows:

• Surgical level 0: No evidence of thromboembolic disease in either lung
• Surgical level I: Chronic thromboembolism starting in the main pulmonary arteries (Level IC: Complete occlusion of one main pulmonary artery with chronic thromboembolism)
• Surgical level II: Chronic thromboembolism starting at the level of the lobar arteries or in the main descending pulmonary arteries
• Surgical level III: Chronic thromboembolism starting at the level of the segmental arteries
• Surgical level IV: Chronic thromboembolism starting at the level of the subsegmental arteries

A median sternotomy with use of cardiopulmonary bypass with periods of hypothermic circulatory arrest is the crucial element of the surgical procedure. Deep hypothermia provides for tissue protection, whereas intermittent circulatory arrest periods avoid back-bleeding from the bronchial artery to pulmonary artery anastomoses and provides the necessary bloodless field to allow the optimal dissection of chronic thromboembolic material from the pulmonary vessels.

Immediately following surgery, a reduction in mean pulmonary arterial pressure (mPAP) with augmentation in cardiac output has been a consistent observation. Some patients do not achieve normal pulmonary pressures and right-side heart function following PTE surgery, although the definition of residual pulmonary hypertension varies among reporting centers. Occurrence estimates vary between 5% and 35%. Possible explanations for this postoperative outcome include (1) chronic thromboembolic disease (CTED) that could not be surgically resected and (2) a significant amount of coexisting distal vasculopathy. Mortality rates reported from centers performing PTE surgery have steadily declined over the years, currently in the range of 2.2-11.4%, with the lower perioperative mortality figures at centers with more extensive experience.[28] Intraoperative and postoperative extracorporeal membrane oxygenation is often done at CTEPH centers to help avoid reperfusion injuries and to assist with right ventricular pump failure.[47]

Balloon pulmonary angioplasty

Balloon pulmonary angioplasty (BPA) should be considered for symptomatic CTEPH patients ineligible for PTE due to distal chronic thromboembolism or persistent/recurrent pulmonary hypertension after surgery.[2] BPA has evolved into an important component of the CTEPH treatment algorithm since the 2012 reports from Japan[48] and is part of the European Society of Cardiology/European Respiratory Society recommended guidelines.[31] This involves treatment of vascular CTEPH lesions with semicompliant balloons at relatively low pressures (about 6-10 atm), over several sessions. BPA has been reported to improve hemodynamics, symptoms, exercise capacity, and right ventricular function, with significantly lower rates of major complications compared with the report from 2001.[2] BPA patient selection is important and requires a multidisciplinary review of all available and pertinent data, with anatomical and functional assessment of pulmonary arteries and lung perfusion to identify the target vessels, and, possibly, a selective pulmonary angiogram or other intravascular imaging and pressure gradient analysis to aid in lesion assessment and balloon sizing of the target vessels.[49] In experienced hands, BPA has emerged as a promising and established treatment for inoperable CTEPH.

Pulmonary hypertension - targeted medical therapy

While PTE remains the treatment of choice for most patients with CTEPH, around 40% of the patients in the international CTEPH registry were considered inoperable because of concerns over inaccessible vascular obstruction, pulmonary artery pressure out of proportion to morphological lesions, and significant prohibitive comorbidities.[15] A large number of small studies and three large randomized controlled trials (BENEFIT, CHEST, MERIT-1) have demonstrated varying improvements with targeted medical therapy in technically inoperable patients. Riociguat is the currently approved medical therapy in the United States for inoperable CTEPH based on the CHEST trials.[50] In 2017, the MERIT-1 trial of macitentan in the treatment of inoperable CTEPH showed improvements of the primary endpoint, PVR, and of other endpoints (eg, 6-minute walk distance, N-terminal pro-brain natriuretic peptide).[51] This study provided the first evidence on combination drug therapy in inoperable CTEPH. Of the included patients, 61% were already treated with phosphodiesterase type 5 inhibitors and/or oral/inhaled prostanoids at inclusion, and the addition of macitentan showed similar efficacy compared with the drug-naïve patients. Accordingly, macitentan is being considered for potential CTEPH registration. Patients with persistent/residual postoperative pulmonary hypertension were also included in the BENEFIT and CHEST-1 trials, representing around 30% of the study population.[50, 52]

Using medical therapy as a bridge to PTE is more controversial and is believed to delay timely surgical referral and, therefore, definitive treatment. In the international registry and in a University of California San Diego cohort, 28% and up to 37%, respectively, of the patients were on some form of pulmonary hypertension–targeted drug(s) at the time of surgical referral.[15] In both cohorts, the delay between diagnosis and surgery was doubled in the pretreated patients, without demonstrable clinical benefit. In the international registry, pretreatment even independently predicted worse outcome (hazard ratio 2.62; P = .0072).[27] Key limitations of these reports are the inherent referral bias and the possibility of medical therapy potentially stabilizing otherwise deteriorating cases (unknown and not tested). Event-driven morbidity/mortality studies have not been performed in CTEPH, and the role of medical treatment prior to and following PTE and BPA is still being investigated.

The use of intravenous epoprostenol, a prostacyclin derivative, in patients with inoperable CTEPH has also been examined, with limited studies showing improvement in hemodynamics, 6-minute walk distance, WHO functional class,[53] and, in some instances, survival.[42]

Diuretics

Diuretics (eg, furosemide, bumetanide) should be used in patients who develop right-side heart failure and those who have systemic congestion manifested by hepatomegaly, ascites, and marked lower extremity edema. Severe right-side heart failure may also compromise function of the left ventricle (ventricular interdependence, reverse Bernheim effect), leading to pulmonary congestion. Therefore, judicious use of diuretics helps reduce systemic congestion and edema. However, excessive hypovolemia may lower cardiac output further and interfere with tissue oxygenation and worsen renal dysfunction. Thus, a careful balance with close clinical follow up is required.

Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule.

Bumetanide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis.

Anticoagulation

Lifelong anticoagulation is recommended for patients with CTEPH, and vitamin K antagonists have been studied the most and are the therapy of choice.[31]

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders.

Patients who undergo PTE may develop complications that are common to other types of cardiothoracic surgery (eg, arrhythmias, atelectasis, wound infection, pericardial effusions, delirium). They may also experience two very unique complications that impair gas exchange resulting in profound hypoxic respiratory failure. The first is pulmonary artery steal, where redistribution of pulmonary arterial blood flow to the newly endarterectomized areas causes a severe V/Q mismatch. The second is reperfusion pulmonary edema, where high-permeability shift of fluids develops in the areas where the thromboendarterectomy occurred. Usually, the treatment is supportive (oxygen supplementation, mechanical ventilation) and inhaled nitric oxide.[54]

If the patient is not a surgical candidate, pharmacologic regimens are also a possible source of adverse effects and possible complications. The guanylate cyclase stimulant, riociguat, can trigger hypotension, bleeding, and numerous gastrointestinal complaints. If endothelin receptor antagonists such are bosentan are used, possible hypotension, edema, headaches, respiratory tract infections, and transaminitis can develop. If phosphodiesterase type 5 inhibitors are used, flushing, headaches, and hypotension can result. If prostanoids are used, in severe inoperable disease, multiple adverse effects can occur, including flushing, hypotension, chest pain, headaches, anxiety, jaw pain, and catheter-associated sepsis.

While no specific guidelines exist, patients with CTEPH, especially with right-side heart failure, should generally follow a low-sodium diet to minimize excessive fluid retention.

Guidelines recommend that patients with pulmonary arterial hypertension (PAH) remain active, although they should avoid excessive activity that precipitates symptoms. Supervised exercise rehabilitation should also be recommended to deconditioned patients, as this has been shown to increase functional capacity and quality of life.[55]

The majority of cases of PAH are not preventable. Patients should avoid using anorexigen drugs, as well as illicit stimulant drugs such as amphetamine-derivatives and cocaine, which can increase risk of group 1 PAH. To minimize potential contributions from WHO group 3 disease, patients should not smoke. Those with obstructive sleep apnea or other lung disease should be optimally treated for these diseases to avoid further insults from hypoxemia/chronic pulmonary disease.

Once a diagnosis of CTEPH has been made, patients should be evaluated by a center specializing in CTEPH. Medical assessment including 6-minute walk distance testing should be performed at least twice a year to assess for a decline in functional status. Transthoracic echocardiography is often performed on at least an annual basis as well, with right-sided heart catheterization undertaken for patients who have a change in clinical status.

The following guidelines are available:

• Chronic thromboembolic pulmonary hypertension, from the Proceedings of the 6th World Symposium on Pulmonary Hypertension ^[2]
• 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension, from the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society and endorsed by the Association for European Paediatric and Congenital Cardiology and the International Society for Heart and Lung Transplantation ^[31]

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

These agents facilitate the pathways that play a role in vasodilation.

Riociguat (Adempas)

Riociguat stimulates vasodilation by increasing generation of cyclic guanosine monophosphate (cGMP) as it stimulates the soluble guanylate cyclase-cGMP pathway.

Class Summary

Endothelin-receptor antagonists competitively bind to the endothelin-1 receptors EtA and EtB, causing reductions in pulmonary arterial pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP).

Bosentan (Tracleer)

Bosentan inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in PAP, PVR, and mean RAP.

Macitentan (Opsumit)

Macitentan blocks the binding of endothelin-1 to endothelin receptor subtypes ETa and ETb on smooth muscle and vascular endothelium. The stimulation of these receptors is associated with fibrosis, inflammation, hypertrophy, and vasoconstriction.

Ambrisentan (Letairis)

Ambrisentan improves exercise ability and slows the progression of clinical symptoms. It inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in PAP, PVR, and mean RAP.

Class Summary

The antiproliferative effects of the phosphodiesterase type 5 (PDE5) pathway, which regulates cGMP hydrolysis, may be significant in the long-term treatment of pulmonary arterial hypertension (PAH) with PDE5 inhibitors.

Sildenafil (Revatio)

Sildenafil promotes selective smooth-muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.

Tadalafil (Adcirca)

Tadalafil is a PDE5 inhibitor indicated for improving exercise capacity in patients with WHO class 1 PAH. It increases cGMP, the final mediator in the nitric oxide pathway.

Class Summary

Prostacyclin is a strong vasodilator of all vascular beds and a potent endogenous inhibitor of platelet aggregation. Platelet effects result from activation of intracellular adenylate cyclase and from increased cyclic adenosine monophosphate (cAMP) concentrations within platelets. Prostacyclin may decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation.

Iloprost (Ventavis)

Iloprost is a synthetic analogue of prostacyclin that dilates systemic and pulmonary arterial vascular beds. It is indicated in patients with New York Heart Association class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.

Class Summary

Judicious use of diuretics helps reduce systemic congestion and edema. Conversely, excessive hypovolemia may interfere with tissue oxygenation by lowering cardiac output.

Furosemide (Lasix)

Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, thereby, in turn, inhibiting sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. The dosage must be individualized to the patient. Depending on the response, administer furosemide in increments of 20-40 mg, no sooner than 6-8 hours after the previous dose, until the desired diuresis occurs. When treating infants, titrate with increments of 1 mg/kg until a satisfactory effect is achieved.

Bumetanide (Bumex, Burinex)

Bumetanide increases excretion of water by interfering with the chloride-binding cotransport system; this, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle. Bumetanide does not appear to act in the distal renal tubule.

Class Summary

Long-term anticoagulation with warfarin should be considered in selected patients with secondary PAH. These include patients with chronic pulmonary embolism (PE), pulmonary veno-occlusive disease, and atrial fibrillation induced by left- or right-side heart failure who are at high risk for developing venous thromboembolism (eg, those with cor pulmonale or immobility secondary to severe dyspnea).

Warfarin (Coumadin, Jantoven)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of deep venous thrombosis, PE, and thromboembolic disorders.

Tailor the dose to maintain an international normalized ratio (INR) in the range of 2-3. Recurrence of deep venous thrombosis and PE increases dramatically when the INR drops below 2 and decreases when it is kept between 2 and 3. Serious bleeding risk (including hemorrhagic stroke) is approximately constant when the INR is between 2.5 and 4.5 but rises dramatically when it exceeds 5.