**1. Introduction**

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by organizing throm‐ botic obstructions in the pulmonary arteries by nonresolving thromboemboli, formation of fibrosis and remodeling of pulmonary blood vessels. It is defined as precapillary PH as assessed by right heart catheterization (mean pulmonary arterial pressure, mPAP ≥ 25 mmHg with a pulmonary arterial occlusion pressure, (PAOP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) > 3 wood units, in the presence of one or more mismatched segmental or larger perfusion defects by ventilation-perfusion lung scintigraphy, computerized tomogra‐ phy, and/or pulmonary angiography after at least 3 months of effective anticoagulation (Lang, 2010) (Table 1).

Although the incidence and prevalence of CTEPH have been a matter of debate, it represents one of the most prevalent forms of PH. Current data derived from registries suggest that CTEPH occurs at an incidence of 3-30 cases per million in the general population. Classical estimates of disease frequency refer to the number of CTEPH cases per survived pulmonary thromboembolic events and report cumulative incidences between 0.1% and 9.1% after a single episode of pulmonary embolism (median follow-up of 4-8 years) and 13.4% after recurrent venous thromboembolism. However, 25 to 40% of patients with CTEPH do not have a documented antecedent venous thromboembolic event (depending on prospective versus retrospective reports, respectively) (Pengo et al., 2004; Bonderman et al., 2009; Pepke-Zaba et al., 2011). Finally, CTEPH can be diagnosed if organized thrombi in main, lobar, segmental or

© 2013 Grignola et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Grignola et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

subsegmental pulmonary arteries can be visualized in a patient with precapillary pulmonary hypertension.

**2. Pathogenesis of CTEPH**

arteries.

Kim & Lang, 2012).

The pathogenesis of CTEPH is complex and is not fully understood. The most important pathobiological process is non-resolution of acute embolic thrombi which later undergo endothelialization and fibrosis, thus leading to narrowed or even obstructed pulmonary

Assessment of Diagnostic Testing to Guide the Surgical Management of Chronic Thromboembolic…

http://dx.doi.org/10.5772/55687

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Incomplete resolution occurs in a significant proportion of patients despite appropriate treatment, placing them at risk of developing CTEPH. Several studies have evaluated the resolution rate of acute PE and report divergent data. A meta-analysis of four prospective imaging studies found that more than 50% of patients with PE still have pulmonary perfusion defects 6 months after the primary diagnosis. A history of acute thromboembolism is not present in approximately 30% of patients presenting with CTEPH. Factors that appear to predispose to the development of CTEPH include recurrent embolic events, estimated systolic pulmonary pressure > 50 mmHg (on echocardiogram) at presentation of an acute pulmona‐ ry embolic event, and greater than 50% occlusion of the pulmonary vascular bed after a "single" embolic occurrence. Although CTEPH is commonly conceptualized as a thromboem‐ bolic disorder, neither coagulation cascade risk factors for venous thromboembolism nor defects in the fibrinolytic system have been identified in affected patients (Bonderman & Lang, 2012). For example, a deficiency of protein C, protein S, or antithrombin III, or the presence of factor V Leiden and factor II mutations, do not appear to be associated with a higher risk of CTEPH. Only the presence of a lupus anticoagulant (10%), elevated levels of antiphospholipid antibodies (20%), and elevated levels of factor VIII (39%), all well-known prothrombotic risk factors for venous thromboembolism, have been found in a significant proportion of CTEPH patients in a majority of studies (Wong et al., 2010). Other factors such as immunologic, inflammatory, or infectious mechanisms trigger pathological remodeling of major and small pulmonary vessels as a response to deranged thrombus resolution. Cer‐ tain conditions are associated with an increased risk for CTEPH, including previous splenec‐ tomy, ventriculo-atrial shunt or pacemakers recipients with a history of device infection, and individuals with inflammatory bowel disease, myeloproliferative disorders, cancer, hypo‐ thyroidism treated with thyroid hormone replacement, non-0 blood types, and carriers of the fibrinogen Aα Thr312Ala polymorphism (Bonderman et al., 2009; Bonderman & Lang, 2012;

There are two main hypotheses explaining the pathologic process in CTEPH. In the classical *embolic hypothesis*, acute (single or recurrent) pulmonary emboli arising from sites of venous thrombosis are the initial event in developing CTEPH, but disease progression probably results from progressive vascular remodeling of the small vessels (Salisbury et al., 2011). The alter‐ native *thrombotic hypothesis,* states that pulmonary vascular occlusions are caused by a primary arteriopathy and endothelial dysfunction and secondary *in situ* (local) thrombosis. Once vessel obliteration is sufficient to cause an increase in the pulmonary arterial pressure, self-perpetu‐ ated pulmonary vascular remodeling occurs and culminates in the development of PH (Jenkins et al., 2012b). This is supported by the fact that 1) unlike acute PE, there is no linear correlation between a compromised hemodynamic state and the mechanical obstruction of pulmonary


**Table 1.** Diagnostic criteria in CTEPH.

Hemodynamic failure and death occur in 20% of patients within 1 hour of acute pulmonary embolism (massive pulmonary embolism). Among the survivors, the natural evolution, in most cases, is the reabsorption of blood clots by local fibrinolysis with complete restoration of the pulmonary arterial bed. In some patients, reabsorption does not occur and the emboli evolves from an organized clot into fibrous tissue inside the pulmonary artery (PA). A latency period ("honeymoon") between the acute pulmonary embolus and the occurrence of symptoms of PH is common. The occurrence of dyspnoea after a symptom-free interval of several years is not due to recurrent emboli, but to development of local thrombosis and small vessels arteriopathy (Dartevelle et al., 2004).

Management decisions for patients with CTEPH should be made at an expert center based upon interdisciplinary discussion among internists, subspecialists, radiologists, and expert surgeons. Surgical pulmonary endarterectomy (PEA) is the therapy of choice for patients with CTEPH as it is a potentially curative treatment option, leading to a profound improvement in hemodynamics, functional class and survival (Wilkens et al., 2011; Pepke-Zaba, 2010). Selecting the candidates who will benefit from surgery is still a challenging task. Detailed preoperative patient evaluation and selection, surgical technique and experience, and meticulous post-operative management are essential prerequisites for success after this intervention (Pepke-Zaba et al., 2011). Criteria for surgical suitability have been described but the decision to proceed with surgical intervention remains subjective (Jamieson et al., 2003; Condliffe et al., 2009; Skoro-Sajer et al., 2009; Freed et al., 2011). This is in agreement with a recent prospective CTEPH international registry, which showed a wide variation in non operability amongst participating countries (from 12 to 61%) (Mayer et al., 2011).

The aims of the present chapter are to evaluate the different preoperative diagnostic tools to assess the relative contribution of the extent of mechanical obstructions by organized thrombi and the distal small vessel disease. In addition, we analyze these tools to predict the hemody‐ namic improvement and early mortality after PEA.
