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The pulmonary hypertension (PH) and right heart dysfunction that results from chronic thromboembolic involvement of the pulmonary vascular bed is potentially curable with surgical endarterectomy. Over the past several decades, growing clinical experience has brought about increased recognition of this treatable form of PH. Moreover, advances in cardiothoracic surgical techniques have given an increasing number of patients with chronic thromboembolic PH (CTEPH) a surgical remedy with decreasing perioperative morbidity and mortality risks. The availability of pulmonary hypertensive—specific medical therapy for CTEPH patients with surgically inaccessible disease also has been a positive therapeutic advance over the past several years. However, despite this progress, chronic thromboembolic disease as a sequela of acute pulmonary emboli continues to be underappreciated. Furthermore, even if CTEPH has been appropriately diagnosed, misinterpretation of diagnostic information may lead to the inappropriate exclusion of patients from surgical consideration. This may result in the prescription of pulmonary hypertensive medical therapy in CTEPH patients with potentially surgically correctable disease. This difficulty arises from a lack of objective criteria as to what constitutes surgical chronic thromboembolic disease, which primarily is a result of the variability in surgical experience in specialty centers in the United States. Consequently, clinicians must be wary about using pulmonary hypertensive medications in CTEPH patients. Before prescription, it is important to exclude patients from surgical consideration by consulting a specialized center with expertise in this discipline.
Chronic thromboembolic residua may occur following a single or recurrent episode of acute pulmonary embolism. In patients with pulmonary embolism, the mechanical obstruction of the pulmonary vascular bed, along with the gradual development of a small vessel vasculopathy in the unobstructed vascular bed, may result in pulmonary hypertension (PH) [1•]. Estimates of the incidence of chronic thromboembolic PH (CTEPH) after acute pulmonary embolism range from 0.5% to 3.8% [2, 3]. If unrecognized or left untreated, progressive right ventricular dysfunction with the ultimate development of right heart failure is the expected outcome. Additional observations relevant to the diagnosis of CTEPH include the following: There appears to be no age or gender bias for the diagnosis of CTEPH; this disease has been observed in pediatric patients . A history of acute venous 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, elevated pulmonary pressures at presentation of an acute pulmonary embolic event, and greater than 50% occlusion of the pulmonary vascular bed after a “single” embolic occurrence [2, 5]. Thrombophilic states associated with CTEPH include the presence of a lupus anticoagulant, elevated levels of antiphospholipid antibodies, and elevated levels of factor VIII . Deficiencies of protein C, protein S, and 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.
The symptoms and signs of CTEPH are similar to those of other forms of PH and depend on the severity of the disease at presentation (Table 1). Exertional dyspnea and/or an unexplained decline in functional status are the most frequent presenting complaints. With the development of a significant degree of right ventricular dysfunction, symptoms such as exertional presyncope and physical signs including peripheral edema, jugular venous distention, and hepatomegaly may become evident. A unique physical finding in 30% of patients with CTEPH is the presence of flow bruits over the lung fields, a finding not encountered in patients with small vessel variants of pulmonary arterial hypertension (PAH).
Unlike other variants of PAH, CTEPH is potentially amenable to surgical correction. Although vessel obstructions with chronic thromboemboli may occur at any level in the pulmonary arterial system, only those involving the main, lobar, or segmental arteries are amenable to surgical correction. Therefore, the primary purpose of the diagnostic evaluation is to quantify the degree of PH and right heart dysfunction (ie, right heart catheterization), to establish its etiology, and to determine the proximal extent of disease (Fig. 1) [7••].
The preferred therapy for appropriate patients with CTEPH is surgical removal of the chronic thromboembolic lesions within the proximal vessel with the intent to restore normal cardiopulmonary hemodynamics, improve functional status, and positively affect survivorship . However, medical therapies directed at treating PH have been investigated and increasingly used in subcategories of CTEPH patients [9, 10]: 1) patients deemed inoperable because of extensive distal precapillary vasculopathy not amenable to surgery or those who have significant comorbidities that contraindicate surgery ; 2) the 10% to 15% of patients who have residual PH following thromboendarterectomy surgery ; and 3) patients with severe hemodynamic compromise, as a bridge to surgery.
Endothelin receptor antagonists Endothelin 1 is a potent vasoconstrictor that appears in higher levels in patients with PH and affects the vasculature via endothelin receptors A and B. ERAs block pulmonary vasoconstriction via one receptor (selective) or both receptors (nonselective).Bosentan, a nonselective ERA, is the most thoroughly and rigorously studied to date of all pharmacologic therapies (via the BENEFiT trial) for patients with inoperable CTEPH or post-PEA residual PH. Bosentan improves cardiopulmonary hemodynamics, as evidenced by significant decreases in PVR and significantly improved cardiac indices. Decreased levels of pro-brain natriuretic peptide (pro-BNP) also suggest reduced right ventricular strain [20••].
Phosphodiesterase 5 inhibitors PH is associated with upregulation of vascular PDE5, which rapidly degrades cGMP, leading to reduced levels of nitric oxide, a potent vasodilator. PDE5 inhibitors enhance nitric oxide-mediated vasodilation. They also may have additional beneficial effects on platelet activation and pulmonary vascular remodeling.Sildenafil, a selective PDE5 inhibitor, significantly decreases PVR within 3 months of starting therapy in patients deemed inoperable or with residual PH after PEA surgery. This initial improvement translates into significantly improved hemodynamics (including cardiac index), BNP level, 6-min walk distance, and symptom scores with 12 months of therapy, possibly suggesting that sildenafil has disease-modifying effects on the pulmonary vasculature .
Prostanoid therapy Prostanoids have several important effects on the vasculature; they are potent vasodilators that also inhibit vascular smooth muscle proliferation and platelet aggregation.Continuous IV administration of epoprostenol via infusion pump to patients with PVR greater than 1200 dynes·s·cm−5 before PEA surgery may significantly increase preoperative cardiac output and reduces PVR [10, 22]. These effects translate into reduced right ventricular strain, as measured by decreased preoperative BNP levels .Open-label trials have shown that continuous subcutaneous administration of treprostinil improves hemodynamics, functional capacity, and survivability in patients with inoperable CTEPH . An inhaled prostanoid, iloprost, also has been studied with variable results in CTEPH patients [19, 23]. One small study demonstrated improved pulmonary hemodynamics with acute administration of inhaled iloprost in 20 CTEPH patients (14 inoperable), suggesting a component of pulmonary vasoreactivity in these patients. However, sustained benefit with this therapy was not examined .
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