**7. Diagnostic approach**

Patients with CTEPH have a higher mortality rate that may reach up to 10% to 20% among untreated patients [58, 59]. Thus, the most important step is the early detection of a population at risk, patients with a CTEPH and the accurate diagnosis of this pathology in order to adopt the best therapeutic strategy. Patients who experience acute symptomatic pulmonary embo‐ lism, persistent symptoms of dyspnea and chest pain may guide further diagnostic studies. Moreover, the persistence of pulmonary vascular perfusion defects are also common, 30% within 12 months after acute pulmonary embolism, and are associated with a higher preva‐ lence of persistent symptoms, worse exercise capacity and pulmonary hypertension [60]. Thus, clinical and radiologic monitoring may detect patients with pulmonary embolism who have an increased risk of developing CTEPH.

It is important to acknowledge a history of deep vein thrombosis as an element that can guide the diagnosis, but it lacks sensitivity. Indeed, many patients with CTEPH have not had a documented DVT or PE [61, 62]. Patients monitored for pulmonary hypertension of another cause may exhibit symptoms similar to those of CTEPH [63]. V/Q scanning is an important tool for evaluation of all patients with pulmonary hypertension. It is essen‐ tial because of the fact that CTEPH requires different therapies and may be amenable to surgical intervention. Thus, the objectives of the diagnostic processes are first to identify CTEPH, and then to define the stage of the disease and distribution of pulmonary arteri‐ al occlusion, with an assessment of the severity of pulmonary hypertension and other concomitant diseases, and finally determine eligibility for pulmonary endarterectomy (PEA) or medical treatment.

After a thorough history and physical exam, patients with suspicious symptoms or signs of pulmonary hypertension and a history of pulmonary embolism or pulmonary hypertension of unknown cause should be investigated to confirm or exclude the diagnosis of CTEPH [64]. Imaging is central to making the diagnosis and management of CTEPH, but which test do you use, and when? The imaging algorithm used at Papworth Hospital for CTEPH diagnosis is shown in Figure 1. Echocardiography is used in the initial assessment of suspected pulmonary hypertension. V/Q lung scanning may be used to differentiate chronic thromboembolic pulmonary hypertension from other causes of pulmonary hypertension.

**Figure 1.** Diagnostic imaging algorithm for chronic thromboembolic pulmonary hypertension (CTEPH). CT: computed tomography; MR: magnetic resonance.: pulmonary angiography is usually performed in conjunction with right heart catheterisation and should be performed at centres experienced with CTEPH and pulmonary endarterectomy [20].

#### **7.1. Echocardiography**

in the diagnosis. It identifies clinical events that could be compatible with an unidentified acute venous thromboembolism [52, 53]. Symptoms of CTEPH are very similar to many other etiologies of pulmonary arterial hypertension. The majority of patients who displayed CTEPH were past the age of 60. The symptoms often occurred insidiously and were often attributed to other cardiac comorbidities, obesity or an underlying lung disease [54]. Dyspnea and fatigue were the symptoms most frequently encountered. Patients may present with exertional angina, presyncope, syncope and lower extremity edema. Chest pain may be caused by right ventric‐ ular ischemia. Syncope is an alarming symptom that raises concerns of advanced heart failure

Physical signs vary depending on the severity of the pulmonary hypertension and associated right heart failure. Cardiac auscultation may be notable for accentuated pulmonic valve closure, tricuspid regurgitant murmur, or possibly bruit over the lung fields caused by turbulent blood flow through partially occluded pulmonary arteries [55, 56]. At a late stage, clinical signs of right ventricular failure may be present (jugular venous distension, hepatoju‐

Patients with CTEPH have a higher mortality rate that may reach up to 10% to 20% among untreated patients [58, 59]. Thus, the most important step is the early detection of a population at risk, patients with a CTEPH and the accurate diagnosis of this pathology in order to adopt the best therapeutic strategy. Patients who experience acute symptomatic pulmonary embo‐ lism, persistent symptoms of dyspnea and chest pain may guide further diagnostic studies. Moreover, the persistence of pulmonary vascular perfusion defects are also common, 30% within 12 months after acute pulmonary embolism, and are associated with a higher preva‐ lence of persistent symptoms, worse exercise capacity and pulmonary hypertension [60]. Thus, clinical and radiologic monitoring may detect patients with pulmonary embolism who have

It is important to acknowledge a history of deep vein thrombosis as an element that can guide the diagnosis, but it lacks sensitivity. Indeed, many patients with CTEPH have not had a documented DVT or PE [61, 62]. Patients monitored for pulmonary hypertension of another cause may exhibit symptoms similar to those of CTEPH [63]. V/Q scanning is an important tool for evaluation of all patients with pulmonary hypertension. It is essen‐ tial because of the fact that CTEPH requires different therapies and may be amenable to surgical intervention. Thus, the objectives of the diagnostic processes are first to identify CTEPH, and then to define the stage of the disease and distribution of pulmonary arteri‐ al occlusion, with an assessment of the severity of pulmonary hypertension and other

gular reflux, lower limb edema, enlarged liver, and ascites). [56, 57].

and should prompt urgent examination.

**6. Physical examination**

148 Pulmonary Hypertension

**7. Diagnostic approach**

an increased risk of developing CTEPH.

Transthoracic echocardiography with Doppler imaging is a sensitive exam for the detection of pulmonary hypertension and right ventricular dysfunction, but it is not specific for the diagnosis of chronic thromboembolic pulmonary hypertension. [65] Common echocardio‐ graphic findings include right ventricular dilatation, hypertrophy, and hypokinesis; right atrial enlargement; right ventricular pressure overload as suggested by interventricular septal deviation toward the left ventricle during systole; and tricuspid regurgitation. The tricuspid regurgitant jet gradient provides an estimate of the pulmonary artery systolic pressure. In rare cases, transthoracic echocardiography shows proximal pulmonary artery thrombus. However, echocardiography cannot be used to reliably differentiate among acute, subacute, and chronic pulmonary embolism. Thus, all patients with pulmonary hypertension should be evaluated with a V/Q scan [66, 67] in addition to angiography.

analysis does not distinguish between acute and chronic embolism. However, several studies have shown that acute pulmonary embolism disappears within 4 to 6 weeks in 90% of patients and within 6 months in all patients [75]. Therefore, symptomatic patients in whom perfusion defects persist despite adequate anticoagulation after 3 to 6 months should be referred to a specialist center for further evaluation, especially if there is direct or indirect evidence of pulmonary hypertension in the echocardiography. Sometimes, patients show symptoms at a later stage after the appearance of the signs of severe right ventricular dysfunction which might require urgent surgery or semi-urgent surgery, even if they have not yet completed 3 to 6 months of anticoagulation. Right heart catheterization and pulmonary angiography are generally required for definitive diagnosis of CTEPH. The spiral lung CT is also increasingly used to assess the extent of chronic thromboembolic disease. However, the spiral CT lung can

Chronic Thromboembolic Pulmonary Hypertension

http://dx.doi.org/10.5772/54749

151

This test is also useful for defining the anatomy and extent of obstruction in CTEPH. Currently, it is not routinely used in patients who can undergo conventional angiography, but in comparison with spiral CT, it seems to be equivalent for the identification of signs of CTEPH [77]. Both techniques provide a wealth of additional anatomical information, allowing the detection of other diagnoses that may be associated with pulmonary hypertension such as

Preoperative evaluation of patients with CTEPH requires a battery of complementary exami‐ nations, starting with right heart catheterization and pulmonary angiography [78]. Right heart catheterization is necessary to confirm the diagnosis and severity of pulmonary hypertension and provide prognostic information. It allows precise measurement of pulmonary artery pressure and right atrial pressure, pulmonary artery occlusion pressure, and cardiac output. In patients with chronic thromboembolic obstruction, PH usually occurs with increased cardiac output; pulmonary artery pressure will rise in a nearly linear fashion and normal pulmonary vascular resistance will not occur [79]. In patients with CTEPH and risk factors for coronary artery disease, left heart catheterization with coronary angiography is performed

Pulmonary angiography may confirm the diagnosis of chronic pulmonary thromboembolic disease. The angiographic appearance of CTEPH is distinct from that seen in acute pulmonary embolism, although the two processes can be seen simultaneously [80]. By defining the character of the proximal or distal lesions, pulmonary angiography is a determining factor in the use of PEA. The angiographic abnormalities related to CTEPH include intraluminal filling defects. A recently developed classification system for the anatomical location of thrombi is

sometimes fail to identify the presence of chronic thromboembolic disease.

**7.5. Right heart catheterization and pulmonary angiography and angioscopy**

**7.4. Magnetic resonance imaging**

*7.5.1. Right heart catheterization*

*7.5.2. Pulmonary angiography*

before PEA.

pulmonary vein stenosis and fibrosing mediastinitis.

#### **7.2. Lung scan ventilation-perfusion**

The V/Q lung scan should be performed in patients with PH to look for potentially treatable CTEPH. The V/Q scan remains the screening method of choice for CTEPH because of its higher sensitivity relative to CT scans. A normal- or low-probability V/Q scan effectively excludes CTEPH with a sensitivity of 90–100% and a specificity of 94–100% [68, 69, 76]. A recent study has shown that lung scintigraphy V/Q had a negative predictive value of 98.5% to exclude CTEPH, while CT pulmonary angiography had a negative predictive value of 79.7% compared with pulmonary angiography gold standard. Therefore, a negative pulmonary CT angiogra‐ phy does not formally exclude CTEPH [76].

In PAH the V/Q lung scan may be normal; it may also show small peripheral unmatched and nonsegmental perfusion defects. Contrast-enhanced CT may be used as a comple‐ mentary investigation but does not replace the ventilation/perfusion (henceforth V/Q) scan or traditional pulmonary angiogram. One caveat is that unmatched perfusion defects are also seen in pulmonary veno-occlusive disease (PVOD). The V/Q scan in CTEPH typi‐ cally shows multiple segmental or larger perfusion defects in areas of normal ventilation. Since there is often only partial vascular obstruction in CTEPH, there may be grey zones, and the lung perfusion scan can underestimate the degree of vascular obstruction. On the other hand, a normal or low probability V/Q scan virtually excludes the possibility of sur‐ gical intervention of CTEPH [70, 71].

#### **7.3. Computed tomography**

The spiral CT has the advantage of being non-invasive, with a spatial resolution close to pulmonary angiography. In patients with CTEPH, the spiral CT lung may reveal the presence of an organized thrombus lining the proximal pulmonary vessels and may better visualize thickening of the pulmonary arterial wall to identify a cleavage plane for endarterectomy. Conversely, it allows for the identification of atherosclerotic calcification of the arterial wall lung, which will increase the complexity of PEA. It also evokes rare differential diagnoses such as fibrous mediastinitis, arteritis, pulmonary emboli tumors or/and sarcomas [72]. The spiral CT lung is now considered the benchmark in acute pulmonary embolism and can accurately define the nature and extent of disease in CTEPH, and provide multi-planar reconstruction to produce a three-dimensional vascular tree [73]. The recent development of this method allows imaging to differentiate perfusion defects distal to those of proximal infusion [74]. The V/Q analysis does not distinguish between acute and chronic embolism. However, several studies have shown that acute pulmonary embolism disappears within 4 to 6 weeks in 90% of patients and within 6 months in all patients [75]. Therefore, symptomatic patients in whom perfusion defects persist despite adequate anticoagulation after 3 to 6 months should be referred to a specialist center for further evaluation, especially if there is direct or indirect evidence of pulmonary hypertension in the echocardiography. Sometimes, patients show symptoms at a later stage after the appearance of the signs of severe right ventricular dysfunction which might require urgent surgery or semi-urgent surgery, even if they have not yet completed 3 to 6 months of anticoagulation. Right heart catheterization and pulmonary angiography are generally required for definitive diagnosis of CTEPH. The spiral lung CT is also increasingly used to assess the extent of chronic thromboembolic disease. However, the spiral CT lung can sometimes fail to identify the presence of chronic thromboembolic disease.

#### **7.4. Magnetic resonance imaging**

diagnosis of chronic thromboembolic pulmonary hypertension. [65] Common echocardio‐ graphic findings include right ventricular dilatation, hypertrophy, and hypokinesis; right atrial enlargement; right ventricular pressure overload as suggested by interventricular septal deviation toward the left ventricle during systole; and tricuspid regurgitation. The tricuspid regurgitant jet gradient provides an estimate of the pulmonary artery systolic pressure. In rare cases, transthoracic echocardiography shows proximal pulmonary artery thrombus. However, echocardiography cannot be used to reliably differentiate among acute, subacute, and chronic pulmonary embolism. Thus, all patients with pulmonary hypertension should be evaluated

The V/Q lung scan should be performed in patients with PH to look for potentially treatable CTEPH. The V/Q scan remains the screening method of choice for CTEPH because of its higher sensitivity relative to CT scans. A normal- or low-probability V/Q scan effectively excludes CTEPH with a sensitivity of 90–100% and a specificity of 94–100% [68, 69, 76]. A recent study has shown that lung scintigraphy V/Q had a negative predictive value of 98.5% to exclude CTEPH, while CT pulmonary angiography had a negative predictive value of 79.7% compared with pulmonary angiography gold standard. Therefore, a negative pulmonary CT angiogra‐

In PAH the V/Q lung scan may be normal; it may also show small peripheral unmatched and nonsegmental perfusion defects. Contrast-enhanced CT may be used as a comple‐ mentary investigation but does not replace the ventilation/perfusion (henceforth V/Q) scan or traditional pulmonary angiogram. One caveat is that unmatched perfusion defects are also seen in pulmonary veno-occlusive disease (PVOD). The V/Q scan in CTEPH typi‐ cally shows multiple segmental or larger perfusion defects in areas of normal ventilation. Since there is often only partial vascular obstruction in CTEPH, there may be grey zones, and the lung perfusion scan can underestimate the degree of vascular obstruction. On the other hand, a normal or low probability V/Q scan virtually excludes the possibility of sur‐

The spiral CT has the advantage of being non-invasive, with a spatial resolution close to pulmonary angiography. In patients with CTEPH, the spiral CT lung may reveal the presence of an organized thrombus lining the proximal pulmonary vessels and may better visualize thickening of the pulmonary arterial wall to identify a cleavage plane for endarterectomy. Conversely, it allows for the identification of atherosclerotic calcification of the arterial wall lung, which will increase the complexity of PEA. It also evokes rare differential diagnoses such as fibrous mediastinitis, arteritis, pulmonary emboli tumors or/and sarcomas [72]. The spiral CT lung is now considered the benchmark in acute pulmonary embolism and can accurately define the nature and extent of disease in CTEPH, and provide multi-planar reconstruction to produce a three-dimensional vascular tree [73]. The recent development of this method allows imaging to differentiate perfusion defects distal to those of proximal infusion [74]. The V/Q

with a V/Q scan [66, 67] in addition to angiography.

**7.2. Lung scan ventilation-perfusion**

150 Pulmonary Hypertension

phy does not formally exclude CTEPH [76].

gical intervention of CTEPH [70, 71].

**7.3. Computed tomography**

This test is also useful for defining the anatomy and extent of obstruction in CTEPH. Currently, it is not routinely used in patients who can undergo conventional angiography, but in comparison with spiral CT, it seems to be equivalent for the identification of signs of CTEPH [77]. Both techniques provide a wealth of additional anatomical information, allowing the detection of other diagnoses that may be associated with pulmonary hypertension such as pulmonary vein stenosis and fibrosing mediastinitis.

#### **7.5. Right heart catheterization and pulmonary angiography and angioscopy**

#### *7.5.1. Right heart catheterization*

Preoperative evaluation of patients with CTEPH requires a battery of complementary exami‐ nations, starting with right heart catheterization and pulmonary angiography [78]. Right heart catheterization is necessary to confirm the diagnosis and severity of pulmonary hypertension and provide prognostic information. It allows precise measurement of pulmonary artery pressure and right atrial pressure, pulmonary artery occlusion pressure, and cardiac output. In patients with chronic thromboembolic obstruction, PH usually occurs with increased cardiac output; pulmonary artery pressure will rise in a nearly linear fashion and normal pulmonary vascular resistance will not occur [79]. In patients with CTEPH and risk factors for coronary artery disease, left heart catheterization with coronary angiography is performed before PEA.

#### *7.5.2. Pulmonary angiography*

Pulmonary angiography may confirm the diagnosis of chronic pulmonary thromboembolic disease. The angiographic appearance of CTEPH is distinct from that seen in acute pulmonary embolism, although the two processes can be seen simultaneously [80]. By defining the character of the proximal or distal lesions, pulmonary angiography is a determining factor in the use of PEA. The angiographic abnormalities related to CTEPH include intraluminal filling defects. A recently developed classification system for the anatomical location of thrombi is helpful in the selection of patients for PEA. Type I disease is characterised by a clear central thrombus; type II consists of the thickening of the intima and fibrous reticulum in a main or segmental bronchus, without thrombus in a main vessel; type III is limited to segmental or sub-segmental regions and type IV involves only peripheral vessels and is not an operable disease.[80, 81]. In addition, pulmonary angiography is not free of significant risk in the context of severe pulmonary hypertension. Therefore, some security measures should be taken [82, 83]. The biplane acquisition technique should be used whenever possible. The systematic use of the side view is extremely useful in determining the location and extent of anatomical proximal embolic obstruction and, therefore, surgical accessibility.

evaluating the presence of associated left heart disease with echocardiography to assess LV size and function as well as coronary angiography to exclude coronary artery disease in the appropriate patient [87]. Patients are also evaluated for significant concurrent disorders such as malignancy, using age-appropriate targeted screening, based on careful consideration of the symptoms presented. Patients are usually maintained on systemic anticoagulation immediately before surgery, although the actual protocol depends on local experience and preference of the expert center. Supplemental oxygen and diuretics are often administered to optimize the patient's oxygen and volume status. Thromboendarerectomy is the treatment of choice for symptomatic patients with CTEPH when surgically feasible. In some of these patients, particularly those with severe pulmonary hypertension and right ventricular failure, medical treatment pre-PEA with parenteral prostanoids (eg epoprostenol) may be initiated as

Chronic Thromboembolic Pulmonary Hypertension

http://dx.doi.org/10.5772/54749

153

Pulmonary endarterectomy is the preferred treatment for patients with CTEPH because of the potential for cure and complete resolution of PH and its complications. PEA has the potential to restore near normal cardiopulmonary function. Patient selection for surgery depends on the extent and location of the organized thrombus in relation to the degree of pulmonary hyper‐ tension. When the thrombus is situated in a proximal location, it represents the ideal condition for surgery, but if the thrombus is more distal, the intervention becomes more difficult.

PEA is performed during total circulatory arrest under conditions of profound hypothermia. This is required to enable visibility in the distal pulmonary arterial branches, which would otherwise be subject to back-bleeding during the endarterectomy due to the development of a systemic-to-pulmonary artery circulation at the precapillary level. A relatively recent technical advance is the introduction of video-assisted pulmonary endarterectomy, which uses a video camera connected to a rigid angioscope [90, 91]. Video technology is beneficial because it provides a source of light, allows visualization of the distal pulmonary vascular tree, and

After a median sternotomy, followed by a vertical pericardiotomy, the patient is placed on cardiopulmonary bypass with hypothermia at 18 to 20 ° C. Before the cardiopulmonary bypass the patient's head is wrapped in a blanket with circulating cold water at 4° C. [90, 91]. This blanket has a thermometer and a device for regulating the water circulation. After the cardiopulmonary bypass has been started vents are placed in the pulmonary artery and the right superior pulmonary vein. The right pulmonary artery is dissected between the aorta and the superior vena cava and is mobilised within the pericardial reflection. During a first period of circulatory arrest, the plane is circumferentially followed down to the segmental and sometimes subsegmental branches of each lobe using special suction dissectors, until a complete endartectomy is achieved. Once the field has been prepared, the endarterectomy

facilitates a close view of the surgery by the assistant surgeons.

a bridge to endarterectomy [87, 88, 89].

*8.1.2. Pulmonary Endarterectomy (PEA)*

*8.1.2.1. Surgical strategy*

*8.1.2.2. Surgical procedure*

#### *7.5.3. Pulmonary angioscopy*

Pulmonary angioscopy is used as an adjunct to pulmonary angiography. In the early years of endarterectomy, pulmonary angioscopy was used more frequently. More recent‐ ly, it has been replaced by other, less invasive imaging techniques [84]. The technique in‐ volves the introduction of the angioscope through an introducer, preferably in the right internal jugular vein, then through the right atrium and right ventricle and the right and left pulmonary arteries, where it can be guided in each lobe of the arteries. The distal bal‐ loon is inflated with carbon dioxide, which obstructs blood flow transiently and allows visualization of the vascular bed [84].
