**2. Pathogenesis of CTEPH**

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

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

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

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‐

hypertension.

170 Pulmonary Hypertension

1. Symptomatic PH

2. mPAP ≥ 25 mmHg, PAOP ≤ 15 mmHg

segmental, or subsegmental level)

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

arteriopathy (Dartevelle et al., 2004).

participating countries (from 12 to 61%) (Mayer et al., 2011).

namic improvement and early mortality after PEA.

**The final diagnosis of CTEPH is based on the presence of:**

4. After at least three months of effective anticoagulation.

3. With chronic/organized thrombi/emboli in the elastic pulmonary arteries (main, lobar,

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 arteries.

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; Kim & 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 arteries; 2) PH progresses in the absence of recurrent thromboembolic events; and 3) PVR is still significantly higher in CTEPH patients than in acute PE patients with a similar percentage of vascular bed obstruction (Sacks et al., 2006).

**3. Diagnostic evaluation**

The diagnosis of CTEPH is often delayed because the onset of symptoms is insidious and the symptoms themselves are nonspecific. Like patients with other forms of PH, CTEPH patients suffer from symptoms of progressive right ventricular failure. At early stages, exertional dyspnoea, fatigue and rapid exhaustion are typical. At more advanced stages, signs and symptoms (resting dyspnoea and fluid retention) of overt right heart failure are predominant. In contrast to a progressive course of disease in PAH, CTEPH progresses episodically. Episodes of desaturation and deterioration occur, interrupting apparent health (so-called honeymoon period). Thus a high degree of suspicion is required to detect CTEPH. Symptoms are related to impaired cardiac output and RV failure due to obstruction of the PA by unresolved thrombus and associated vasculopathy (Hoeper et al., 2006). The 1-year untreated mortality rate in CTEPH ranges from 12-24% and is predicted by the PA pressure at diagnosis (Condliffe et al., 2008). In contrast to other subtypes of pre-capillary PH, CTEPH is amenable to surgery. With PEA, patient survival improves to 89% and 75% at 5 and 6 years, respectively. Therefore, the main goal of the diagnostic evaluation of patients with an established diagnosis of precapillary PH is to test for the presence of thrombotic obstructions in major PA and refer patients

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

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

173

to specialized expert centres for this life-saving surgery (Ryan et al., 2011).

incidence of CTEPH after a first episode of PE (Table 2) (Poli et al., 2010).

All patients with unexplained PH should be evaluated for the presence of CTEPH. Suspicion should be high when the patient presents with a history of previous venous thromboembolism. Patients who survive an episode of acute PE are treated with anticoagulants for at least 3 months as secondary prevention to avoid recurrence (Kearon et al., 2012). However, the optimal duration of anticoagulant therapy is still unclear. After a first episode of PE, three major problems need to be considered: the risk of recurrence when anticoagulation is stopped, the risk of bleeding when anticoagulation is continued, and the risk of CTEPH. CTEPH is a rare complication of PE but it is associated with severe morbidity and mortality. There is no generally accepted strategy of follow-up of acute PE survivors. This is related to the relatively low incidence of clinically relevant CTEPH after an embolic episode (1 to 4%) which is diagnosed early and adequately treated. Echocardiographic follow-up after discharge (usually 3-6 months) is certainly advisable in all survivors of acute PE who remain symptomatic or develop exercise limitation due to dyspnoea at any time during their hospital stay to determine whether or not PH has resolved (Torbicki, 2010). Few prospective data are available on the

The initial diagnosis of CTEPH is established by echocardiography and ventilation/perfusion (V/Q) scan. Evidence of PH on echocardiography associated with mismatched segmental perfusion defects on the V/Q scan provides enough information to warrant referral to a centre with expertise in PEA (Fig. 2). A V/Q lung scan is recommended to exclude CTEPH; it is more sensitive than pulmonary computed angiotomography (CT). A normal V/Q lung scan virtually excludes CTEPH, with few exceptions (Skoro-Sajer et al., 2004), while unmatched perfusion defects can also occur in other conditions, such as mediastinal fibrosis, pulmonary artery sarcoma, schistosomiasis, and non-thrombotic embolism. In clinical practice, an abnormal perfusion study alone is diagnostic for CTEPH, if pulmonary parenchymal disease is absent.

Several lines of evidence suggest that increased pulmonary arterial pressures in CTEPH are caused by both vascular obstruction by organized thrombi tightly attached to the pulmonary arterial medial layer in the elastic PA, replacing the normal intima, and remodeling of small distal pulmonary arterioles in non-occluded areas (including plexiform lesions), a pulmonary arteriopathy indistinguishable from idiopathic pulmonary arterial hypertension (Lang & Klepetko, 2008; Auger et al., 2010). Therefore, as proposed by Moser and Braunwald, CTEPH is considered a 'dual' pulmonary vascular disorder, consisting of a large vessel vascular remodeling process of thrombus organization combined with a small vessel vascular disease secondary to redistribution of blood flow within the pulmonary vasculature causing the development of overflow and postobstructive vasculopathy (Moser & Braunwald, 1973; Hoeper et al., 2006) (Fig. 1).

**Figure 1.** Current hypothesis for the pathogenesis of CTEPH.

Many fundamental questions persist about the risk factors and pathogenesis of CTEPH: 1) why many patients with PE do not develop CTEPH; 2) why many CTEPH patients have postoper‐ ative residual PH and; 3) whether patients with CTEPH who have poor postoperative outcome have cellular, molecular, and genetic abnormalities in the pulmonary vasculature similar to those in idiopathic PAH patients. Answering these questions poses a challenge for years ahead. However, a growing body of evidence suggests that in affected patients, minor o major thromboemboli do not resolve under conditions of concomitant inflammation, infection or malignancy, leading to fibrotic transformation of thrombus tissue (major vessel fibrosis) and small-vessel remodeling (Bonderman & Lang, 2012).
