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Chronic thromboembolic pulmonary hypertension: A review of current practice
Progress in Cardiovascular Diseases 55 (2012) 134 – 143 www.onlinepcd.com
Chronic thromboembolic pulmonary hypertension: A review of current practice Jennifer Haythe⁎ Department of Medicine, Columbia University, Center for Advanced Cardiac Care, New York, NY
Abstract
Pulmonary artery hypertension is a complex and multi-faceted disease process with numerous etiologies. Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed and highly treatable form of pulmonary hypertension. In this disease, certain patients with a history of pulmonary thromboembolic disease go on to develop elevated pulmonary artery pressures, shortness of breath, and progressive right heart failure. This article will review the epidemiology, pathophysiology, diagnosis and treatment of CTEPH with a review of pulmonary thromboendarterectomy surgery. (Prog Cardiovasc Dis 2012;55:134-143) © 2012 Elsevier Inc. All rights reserved.
Keywords:
Pulmonary artery hypertension; Chronic thromboembolic pulmonary hypertension; Pulmonary embolism; Pulmonary thromboendarterectomy
Definition Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as the persistence of pulmonary hypertension (defined as a mean pulmonary artery pressure greater than 25 mm Hg) after a single or recurrent pulmonary embolism (PE). It is characterized by the obstruction of pulmonary arteries by organizing thrombi, small vessel arteriopathy, and the development of a high pulmonary vascular resistance (PVR). It carries with it significant morbidity and mortality and early detection is the key to improved outcomes. Importantly, it is one of the few causes of pulmonary hypertension that can be treated for cure.
Incidence It is not entirely clear why some patients with a history of acute PE go on to develop CTEPH. While most patients Statement of Conflict of Interest: see page 141. ⁎ Address reprint requests to Jennifer Haythe, MD, Assistant Professor of Clinical Medicine, Columbia University, Center for Advance Cardiac Care, 622 West 168th Street, PH 1265, New York, NY 10032, USA. E-mail address: [email protected].
0033-0620/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.07.005
return to baseline functional status with normal hemodynamics after a pulmonary embolism, one meta-analysis showed that up to 52% of patients had residual emboli seen 11 months after the sentinel event. 1 Up to 35% of patients still had abnormal ventilation–perfusion scans 1 year after the acute event. 2 The incidence of CTEPH is not precisely known although estimates have ranged from 0.5% to 3.8 % of patients after an acute PE and in up to 10% of those with a history of recurrent PE. 2-5 A prospective cohort study by Pengo et al. 4 looked at 223 patients with acute PE without history of prior venous thromboembolism. The cumulative incidence of symptomatic CTEPH at 2 years was 3.8%. Risk of the development of CTEPH was increased in patients with a history of prior PE, a younger age, larger perfusion defects, and idiopathic pulmonary embolism at presentation. Numerous studies have demonstrated that with more effective treatment of acute PE (e.g., thrombolytics), the likelihood of developing CTEPH diminishes. A study by Kline et al. 6 looked at 200 patients with submassive PE treated with unfractionated heparin, 21 of whom went on to develop circulatory or respiratory failure resulting in administration of fibrinolytic therapy. Trans-thoracic echocardiography (TTE) was performed at baseline and at 6 months. A higher proportion of patients in the
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Abbreviations and Acronyms CTEPH = chronic thromboembolic pulmonary hypertension PAH = pulmonary arterial hypertension PE = pulmonary embolism PVR = pulmonary vascular resistance mPAP = mean pulmonary artery pressure PTE = pulmonary thromboendarterectomy V/Q = ventilation–perfusion RVSP = right ventricular systolic pressure PASP = pulmonary artery systolic pressure TTE = transthoracic echocardiography RV = right ventricle
fibrinolysis group had a reduction in right ventricular systolic pressure (RVSP) at 6-month follow-up. This study was not designed to assess for the presence of CTEPH and the results may be attributed to a higher baseline RVSP at the time of diagnosis in the fibrinolysis group. The study did show that a significant proportion of patients with submassive PE had echo findings consistent with pulmonary hypertension (elevated RVSP) at 6 months. 6 Routine fibrinolysis in submassive PE remains controversial. 7
Risk factors
RA = right atrium
Many identifiable risk factors for the development of CTEPH exist. DLCO = single-breath Piazza and Holdhaber. 7 diffusing capacity nicely summarized this in a recent review article. PaO2 = resting arterial oxygen They include factors spetension cific to pulmonary emboCT angiogram = computed lism (recurrent or tomographic angiography unprovoked PE, large RHC = right heart perfusion defect, young catheterization or old age, pulmonary artery systolic pressure NYHA = New York Heart (PASP) N50 mm Hg at Association time of initial PE, per6MWD = 6-min walk distance sistent elevated RVSP 6 months after PE), peak VO2 = peak ventilatory response to exercise chronic medical conditions (cancer, thyroid disease, splenectomy), thrombotic factors (lupus anticoagulant, antiphospholipid antibodies, increased factor VIII) and genetic factors (ABO blood groups, HLA polymorphisms). 4,7-13 Risk factors for venous thromboembolism have been clearly identified and include hyperhomocysteinemia, antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, factor VIII elevation, oral contraceptive use, plasminogen deficiency and anticardiolipin antibidodies. While the hypercoagulable state has been clearly associated with the development of PFT = pulmonary function test
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CTEPH, not all of the aforementioned factors have been clearly linked with CTEPH. Plasma levels of factor VIII were examined in an observational study of 122 patients with CTEPH. 14 Factor VIII levels are known to be elevated in primary and recurrent thromboembolism. Bonderman et al. 14 found that factor VIII levels were elevated in 41% of CTEPH patients. Lupus anticoagulant is present in 10% of CTEPH patients and up to 20% have anticardiolipin antibodies, lupus anticoagulant or both. 15-18 In contrast, protein C, protein S and antithrombin deficiencies have been found in fewer than 1% of patients with CTEPH 18 While evidence of fibrin resistance to lysis has been seen, no clear disorders of fibrinolysis have been identified. 19,20 This same lysis resistant fibrin has been found in non-thrombotic PAH. 21 Several studies have demonstrated an association between splenectomy and CTEPH. One prospective case-controlled study showed splenectomy to be an independent risk factor for CTEPH. 12,22 Additionally, in a retrospective chart review of 257 patients referred to an institution for CTEPH, the prevalence of prior splenectomy was significantly higher in the CTEPH group than in the idiopathic pulmonary hypertension group, or in the control group. 22,23 Patients with prior splenectomy also tended to have more distal disease which was less amenable to PTE surgery. 22 The pathophysiology of this relationship is not well understood although there are data to support a prothrombotic state after splenectomy for patients with hemolytic anemia (including priapism, arterial thrombosis, portal vein thrombosis) as well as an increased risk of myocardial infarction and stroke in patients who have had splenectomy for hereditary spherocytosis, and obstructive pulmonary lesions in patients with B-thalassemia. 22 It has been postulated that the loss of filtering function by the spleen results in abnormal erythrocyte retention and subsequent activation of the clotting cascade. 22
Pathophysiology Whether in situ thrombosis, rather than embolic phenomenon, is responsible for CTEPH is debated. It is not clear why some patients with a history of pulmonary embolism go on to develop CTEPH while others do not. Clearly the pathologic specimens from thromboendarterectomy surgery for CTEPH appear grossly different than that of an acute pulmonary embolism, the former being a fibrous, organized material replacing the normal intima as opposed to the less organized red clot found in acute embolectomy. 24 However, microscopic similarities between CTEPH and other forms of PAH have been demonstrated clearly and with reproducibility on lung biopsy. 25 In a study of 31 CTEPH patients (15 at the time of PTE surgery and 16 postoperatively during autopsy), pathology specimens
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demonstrated a wide range of pulmonary hypertensive lesions, including plexogenic lesions. 25 The study concluded that small pulmonary artery pathology in CTEPH patients was relatively indistinguishable from pulmonary hypertension from other causes. In addition, these pulmonary hypertensive lesions and plexogenic lesions were found in proximal open vessels exposed to high pressures and in vessels distal to obstructed vessels suggesting that release of cytokines and other endothelin-derived factors occurs in response to pulmonary hypertension and may contribute to its progression. 25 It appears that the progressive nature of pulmonary hypertension in CTEPH patients is related to these resistance changes in small vessels and not necessarily to recurrent pulmonary emboli. Thus, even pathologically, it may be difficult to distinguish whether CTEPH leads to the vasculopathic pathology of PAH or PAH leads to chronic thromboembolic disease.
Clinical presentation Patients with CTEPH have similar presentations to those patients with PAH from other causes. In patients with a known prior PE there may be a, asymptomatic period for many months or years after the initial event. Exertional dyspnea and exercise intolerance are the most common complaints and probably occur because of increased dead space ventilation with increased demand. 26 Unexplained dyspnea, dyspnea on exertion, dizziness, near-syncope, true syncope and exertional chest pain are all common complaints in these patients. 26 The findings on physical examination are similar to other PAH patients: increased jugular venous pressure, loud split second heart sound with an increased P2
component, a right ventricular (RV) heave, an RV S4 gallop, and tricuspid regurgitation murmur. The murmur of the tricuspid valve is likely secondary to a dilated tricuspid annulus in the setting of right ventricular volume and pressure overload. Often this murmur improves or resolves completely after thromboendarterectomy if the PASP is b40 mm Hg postoperatively. The improvement in the degree of tricuspid regurgitation seen by TTE postPTE surgery is shown in Fig 1. 27 With progression of RV failure, patients can develop hepatomegaly, ascites, and lower extremity edema. In one study, up to 30% of CTEPH patients had pulmonary flow bruits auscultated during an inspiratory breath hold probably from high turbulence across obstructed pulmonary beds and/or recanalized pulmonary arteries. 28
Diagnosis Diagnosis is the key to survival in CTEPH. A study by Ribiero et al. 29 demonstrated that in 78 patients with acute PE, a decline in RVSP and recovery of RV function occurred within 30 days in N90% of patients. A PASP of N50 mm Hg at the time of diagnosis of acute PE was associated with persistent PH after 1 year and only patients with persistent PH required pulmonary thromboendarterectomy within 5 years. 29 Similarly, Reidel et al. 30 found a positive correlation between a mean PAP (mPAP) and mortality; there was an 80% mortality in patients with amPAP N50 mm Hg. There are a number of modalities available to diagnose CTEPH. Routine chest x-ray (CXR) can be normal or can show signs of pulmonary arterial hypertension including enlarged pulmonary arteries, right atrial enlargement, and right ventricular enlargement with loss of the retrosternal
Fig. 1. Apical four-chamber echocardiographic images with Doppler of a patient with severe tricuspid regurgitation (A) that resolved after pulmonary thromboendarterectomy (B). Pulmonary artery systolic pressure declined from 74 to 29 mm Hg after pulmonary artery systolic pressure [27].
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airspace on lateral view. Features of pulmonary infarct can also be seen. Echocardiography is useful to estimate the RVSP and evaluate the degree of right heart disease including RA an RV size, RV function, presence of a pericardial effusion and the degree of tricuspid regurgitation. The RV Tei index which is an indicator for right ventricular performance, appears to correlate well with pulmonary vascular resistance. 31 Pulmonary function tests (PFTs) are routinely done in the evaluation of patients with dyspnea. In patients with CTEPH, spirometry can be normal, though up to 20% of patients can show a mild restrictive defect attributed to parenchymal scarring. 32 A moderate reduction of singlebreath diffusing capacity (DLCO) is often seen, as is hypoxemia attributed to ventilation–perfusion (V/Q) mismatch. 33 While resting arterial oxygen tension (PaO2) can be normal, most patients will develop a worsening alveolar–arterial oxygen gradient and a decline in PaO2 with exercise. This is attributed to increased dead space ventilation with exercise. 26 Ventilation–perfusion (V/Q) lung scanning is one of the most important diagnostic tests to help distinguish CTEPH from other forms of PAH. In an era where computed tomographic (CT) angiography is faster and easier to obtain, the importance of the V/Q scan should not be underestimated. In a retrospective study of 227 patients with pulmonary hypertension, V/Q scanning had a sensitivity of 97.4% for the detection of chronic thromboembolic disease while CT angiography was only 51%. 34 Patients with CTEPH usually have at least one, and often several, segmental or larger, mismatched perfusion defects as seen in Fig 2. 17 V/Q scanning can underestimate the degree of central obstruction seen by pulmonary angiography and/or surgery. 35 In pulmonary arterial hypertension from other causes the perfusion scan is normal or mottled in appearance with nonsegmental or subsegmental defects. It should be noted that segmental defects can be seen on V/Q scanning in the absence of embolic disease. Segmental defects from non-embolic causes include pulmonary veno-occlusive disease, pulmonary artery sarcoma, fibrosing mediastinitis and large vessel pulmonary vasculitides. 36
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While it is not recommended as the ideal screening tool for CTEPH, CT angiography is very useful and sensitive in the evaluation of CTEPH with more central and segmental disease burden. In a small study of 27 patients with CTEPH, 64-detector row CT scan had a diagnostic sensitivity of 98.3% at the main and lobar level and 94% at the segmental level when compared with digital subtraction angiography. 37 In comparison to conventional pulmonary angiography, detection rates for central emboli were similar in 55 patients suspected of having CTEPH, although detection of segmental disease was superior with conventional pulmonary angiography. 38 In addition, CT scanning provides additional valuable information in the evaluation of CTEPH including: (1) presence and extent of parenchymal disease; (2) anatomy and size of pulmonary arteries and vessels; (3) location of arterial webs and bands; and (4) location of collateral vessels in the mediastinum. 39 Right heart catheterization (RHC) remains the gold standard for diagnosis of pulmonary arterial hypertension for any WHO group. In CTEPH, RHC may only show moderately elevated pulmonary pressures at rest, in which case a full set of hemodynamics should be repeated after exercise. Vasodilator responsiveness is not necessary, although acute responsiveness predicts a better long-term hemodynamic outcome with surgery. 40 Furthermore, concomitant disease including CAD and abnormal left sided hemodynamics may need to be addressed and factored into the decision-making analysis for surgical intervention. Pulmonary arteriography is essential to determine whether or not a patient is a candidate for surgical intervention. Five findings are associated with CTEPH. They are as follows: (1) pouch defects, (2) pulmonary artery webs or bands, (3) abrupt, angular narrowing of major pulmonary arteries, (4) intimal irregularities and (5) complete obstruction of lobar or segmental vessels at their origin. 41 Though many clinicians fear that pulmonary angiography may precipitate contrast induced hypotension or worsening hypoxemia, it is generally safe and well tolerated. This was demonstrated in a study in which multiple contrast bolus injections were administered to CTEPH patients without significant adverse outcomes even in the presence of severe
Fig. 2. Representative perfusion lung scan in a patient with chronic thromboembolic pulmonary hypertension. The ventilation study (not pictured) showed no abnormalities. The perfusion scan shows multiple, segmental, mismatched defects. Panels A and B show the posterior and anterior views, respectively. In panel C, which shows the left lateral view, there is a segmental defect involving the lingula (arrow). In panel D, which shows the right lateral view, areas of hyperperfusion involving the posterior aspect of the right upper lobe as well as the right middle lobe (arrowheads) are interspersed with areas of relative hypoperfusion involving the anterior aspect of the right upper lobe (arrow) and the majority of the lower lobe. 17
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pulmonary hypertension. Normally, a single injection of non-ionic contrast into both pulmonary arteries with biplane acquisition should provide enough information to determine extent and anatomy of clot burden. 17,42
Surgical selection CTEPH is the only form of pulmonary hypertension that can be cured with surgical intervention. Pulmonary thromboendarterectomy is the surgery of choice in patients who qualify. It involves the removal of the fibrous, whitish, thromboembolic material lining the pulmonary arterial system with marked improvement in mean pulmonary artery pressures, pulmonary vascular resistance and cardiac output. 7,43,44 Resting hemodynamics, 6-min walk distance (6MWD), patient symptoms, and New York Heart Association functional class all improve dramatically after successful thromboendarterectomy surgery and these effects persist in the absence of recurrent emboli. 7 Right ventricular remodeling, improved right ventricular systolic function, and regression of tricuspid regurgitation result from improved pulmonary hemodynamics. 44,45 Generally, four indices help determine the feasibility of surgical intervention in CTEPH patients: accessibility of thrombi, presence of hemodynamic or respiratory impairment (NYHA class II or IV), presence of comorbidities, and patient willingness. 17,46 Fig 3 demonstrates the Jamieson classification of thrombus type and location. 46 In a prospective analysis of 202 patients undergoing PTE,
patients with type 1 and type 2 thromboembolic disease had lower postoperative mortality, better postoperative hemodynamics and less residual tricuspid regurgitation. 46 No fixed guidelines or consensus among physicians as to the hemodynamic goals of surgery currently exist. Whether surgery should be reserved only for patients expected to have postoperative normalization or relative reduction of their PVR is up for debate. In addition, the preoperative determination of feasibility of surgery based on location of disease remains subjective. Ideally, the amount of preoperative hemodynamic impairment should correlate with the amount of surgical approachable disease. 17 Patients with preoperative pulmonary vascular resistance less than 1200 dyne-s/cm 5 without other major comorbidities have a more favorable prognosis. 47 That is also true of patients who have a postoperative reduction in PVR of 50% to a level below 500 dyne-s/cm 5. In one study looking at postoperative mortality in 1100 patients, overall mortality was 4.7% and the majority of deaths were in patients with a postoperative PVR greater than 500 dyne-s/cm 5. 48 Patients with more proximal disease had reduced mortality and greater reductions in PVR. Patients who are extremely symptomatic despite modestly abnormal rest hemodynamics should still be considered for surgery if they have significant proximal unilateral disease, live at altitude, or are extremely active at baseline. Pulmonary endarterectomy in these patients relieves dead space ventilation and improves dyspnea and quality of life. 49
Fig. 3. Pulmonary angiograms and corresponding specimens removed at the time of pulmonary endarterectomy: type 1 disease, fresh thrombus in main lobar arteries (note abrupt cutoff of branches and lack of filling to the periphery on angiography; type 2 disease, organized thrombus and intimal thickening proximal to segmental arteries (note the poststenotic dilatation of the lower lobar vessel and lack of filling to the periphery on angiography); type 3 disease, intimal thickening-fibrosis in distal segmental arteries, with surgical plane raised at each segmental level; type 4 disease, distal arteriolar vasculopathy with removal of normal intimal layer and no intraluminal disease. 46
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Preoperative management Coronary angiography is normally performed at the time of pulmonary angiography in patients at risk for coronary artery disease. In addition, unless a contraindication exist, an inferior vena cava (IVC) filter should be placed preoperatively to prevent recurrent emboli. This is especially true of the high-risk immediate postoperative period in which bleeding complications may complicate or delay the use of appropriate anticoagulation in these patients. 17 At present, there are not sufficient data to support the use of advanced pulmonary vasodilator therapy preoperatively. 50 The use of pulmonary vasodilators such as bosentan and sildenafil preoperatively does not appear to have an impact on outcome postoperatively. 50 This is especially important to remember as the initiation and up-titration of these medications can delay referral to a PAH/PTE center.
Pulmonary thromboendarterectomy The current recommended approach to pulmonary thromboendarterectomy was developed at the University of California, San Diego. 51,52 The surgery requires a median sternotomy approach, cardiopulmonary bypass, and periods of hypothermic circulatory arrest. 17,48,51,52 Median sternotomy allows appropriate access to the pulmonary arteries and improved access to chronic embolic material while circulatory arrest provides a bloodless surgical field for dissection of segmental and lobar arteries. Intermittent episodes of circulatory arrest are limited to 20-min intervals (a unilateral endarterectomy can be completed in one 20-min period). After each episode of circulatory arrest, reperfusion is performed until the pulmonary venous saturation is 90% or at least 10 minutes have passed. Once the endarterectomy is complete, circulation is restored and the patient is rewarmed. If an atrial septal defect is detected, it is usually repaired at this time. Other procedures that may be indicated, including valvular repair/replacement and coronary artery bypass grafting are performed during the rewarming process.
Postoperative management Management of these patients in the postoperative period requires careful attention to volume status, preload conditions, cardiac output, and systemic oxygen consumption. Anticoagulation is a necessity and must be started cautiously. Assuming chest tube output is in an acceptable range, all patients should begin heparin prophylaxis (subcutaneous unfractionated heparin (UFH) 5000 units every 8 or 12 hours) on the evening of the
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surgery. Lifelong warfarin is indicated in all of these patients and is resumed postoperatively. 53,54 Pulmonary artery steal syndrome is a temporary redistribution of blood flow into newly endarterectomized regions and is seen in the majority of postoperative patients. It manifests as hypoxemia and treatment is supportive. New perfusion defects are seen in areas of the lung that were perfused normally preoperatively, supplied by normal arteries on pulmonary angiography, and were unaffected by clot by direct visualization in the operating room. 55 It is self-limited and usually resolves within 2 weeks of surgery. Reperfusion pulmonary edema is a form of noncardiogenic pulmonary edema that occurs in up to 30% of patients in the first 72 hours after PTE. It is believed to occur in areas of the lung that are reperfused during PTE surgery. In one study looking at anatomic location of clot removal, only regions of the lung distal to clot removal were affected and areas of the lung not reperfused in surgery were not affected. 56 In addition, pulmonary capillary wedge pressures were normal pre- and postoperatively. Clinical manifestations range in severity from mild hypoxemia to hemorrhagic pulmonary edema. These patients are managed with diuresis, oxygen supplementation, low-volume mechanical ventilation, and careful attention paid to cardiac output. Unnecessary inotropic therapy should be discontinued. Inhaled nitric oxide may help by vasodilating pulmonary vessels serving wellventilated areas of the lung and thereby reducing VQ mismatch. 57,58
Surgical outcome The 30-day mortality in experienced centers ranges as low as 4%–7%. 43,44 In relatively low-risk patients, mortality rates as low as 1.3% has been reported. 59 Most patients undergoing PTE have excellent short-term and long-term postoperative hemodynamics. Causes of death in these patients include reperfusion pulmonary edema, right ventricular failure, persistent pulmonary hypertension, cardiac arrest, bleeding, sepsis, multiorgan failure, and pulmonary hemorrhage. 17 The majority of patients demonstrate a significant decline in their mean pulmonary artery pressures and PVR in the immediate postoperative period. In one study looking at 29 patients, PVR initially fell from 897± 352 dyne-s/cm 5 to 278± 135 dyne-s/cm 5. 60 In patients who survive the first 3 months post-PTE surgery, long-term survival is excellent and mortality secondary to CTEPH is low. In one study, the 1-year and 3-year mortality in patients who survived the first 3months was 1% and 6% respectively. 61 In an observational study of 137 patients who survived to 3months postoperatively, only 4% died from CTEPH related causes over a 4-year follow-up period. 44 Also, fewer than 0.5% of PTE patients
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develop recurrent thromboembolic disease necessitating surgery. 62 Varying reports on the presence of residual or persistent pulmonary hypertension after PTE exist, most likely reflecting the variable definition of persistent pulmonary hypertension. Estimates range from 5% to 35%, and are probably due to the presence of residual, distal, unresectable disease. 17,47,61,63,64 Patients characterized as having persistent pulmonary hypertension can have survival benefits and functional class improvements similar to patients with normal pulmonary pressures after surgery. It is possible that reduction in PVR rather than absolute mean PA pressure is more indicative of outcome. 17 Generally, patients who are NYHA classes III and IV are NYHA classes I and II postoperatively. In a study of 20 patients undergoing PTE, cardiopulmonary exercise testing was performed preoperatively (baseline) and at 1 month and 4 months postoperatively to assess exercise capacity and ventilator efficiency. Peak oxygen consumption with exercise (peak VO2) increased steadily in patients while the slope of the ventilator-response to carbon dioxide production decreased. These findings correlated with a decline in PVR postoperatively. 65 Also, in a retrospective questionnaire driven study of 308 patients post-PTE, 62% of patients unemployed prePTE had returned to work, 93% were NYHA class I or II, disease-related/ER visits were minimal and a clear correlation existed between 48-hour postoperative PVR and walking and stair climbing ability. 66 Besides demonstrating the regression of tricuspid regurgitation post-PTE, echocardiography has also been used to demonstrate improvement in cardiac output and normalization of left ventricular diastolic filling patterns postoperatively. Mahmud et al. 67 looked at transmitral diastolic flow in patients with CTEPH pre-PTE surgery. Prior to surgery, patients with severe pulmonary hypertension all had an E/A ratio b1.25. Post-PTE, an E/A ratio of N1.5 predicted successful PTE, with restoration of normal cardiac output (Fig 4). 67
Medical treatment Surgery is the only potentially curative treatment for patients with CTEPH, and in many is curative for pulmonary hypertension. Thus, the use of pulmonary vasodilators is only indicated in select groups of people. These include the following: (1) patients who are not candidate for PTE because of patient choice, comorbidities, and/or the presence of distal unreachable disease (2) as a bridge to surgery in patients with severe disease although there are no data to suggest that this is beneficial and (3) postoperatively inpatients with residual pulmonary hypertension, poor hemodynamics and/or persistent functional limitations. 17,50
Fig. 4. (A) Doppler echocardiogram; pre-pulmonary thromboendarterectomy (PTE) transmitral inflow recording in a study patient. Note the E/A reversal. (B) Doppler echocardiogram; post-PTE transmitral inflow recording in the same study patient. Note the resolved E/A reversal predominately by a significant increase in the E-wave velocity and a relatively unchanged A-wave velocity. 67
Initiation of pulmonary vasodilator therapy should be limited to pulmonary hypertension centers familiar with the complexities of treating this disease. As with all pulmonary hypertension patients, baseline right heart catheterization should be performed to assess severity of disease. As mentioned earlier, vasoreactivity testing can be helpful to identify patients who may have better postoperative outcomes with PTE surgery. However, its use is limited in patients ineligible for PTE as most CTEPH patients tend to be non-reactive. 68 Most of the drugs used to treat pulmonary arterial hypertension have been studied in the CTEPH population. The use of intravenous epoprostenol was studied in a retrospective cohort of 27 patients with inoperable CTEPH. 69 After 3 months of therapy, half of patients had improvement in their NYHA functional class. Epoprostenol was also associated with a reduction in PVR and mean pulmonary artery pressure, and improved exercise capacity. 69 Interestingly, in a small series looking at 12 patients with severe CTEPH (PVRN 1200dyne-s/cm 5), IV epoprostenol infusion for a mean of 46 days prior to PTE
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demonstrated reduction in preoperative PVR but no evidence of postoperative benefit. 70 In patients with NYHA class III or IV symptoms, epoprostenol is the drug of choice. In an open-label uncontrolled study of 25 patients with inoperable CTEPH treated with subcutaneous treprostinil, treated patients demonstrated improved 6MWD, WHO functional class, PVR and survival. 71 Several studies have demonstrated that the inhaled prostanoidiloprost improves functional capacity, NYHA functional class, symptoms, quality of life and hemodynamics. 72-74 Its use in the perioperative period also demonstrates beneficial effects on hemodynamics. 74 The endothelin receptor antagonist bosentan has been studied in the CTEPH population as well. One randomizedcontrolled trial (BENEFiT) studied 157 patients with inoperable CTEPH or persistent pulmonary hypertension after PTE. 75 Seventy-seven patients were randomized to bosentan and 80 to placebo for 16 weeks. Patients treated with bosentan had statistically significant improvement in PVR and cardiac index. 75 Other observational studies of bosentan in the inoperable CTEPH population also confirm improved exercise capacity, 6MWD, pulmonary artery pressures and cardiac index when compared with baseline. 76 Finally, the phosphodiesterase-5 inhibitor sildenafil has also been studied in a double-blinded, placebo controlled pilot study of 19 patients with inoperable CTEPH. 77 The primary end-point was 6MWD. At 12 weeks no significant difference was seen between the two groups in respect to exercise capacity. The sildenafil arm had improved secondary end-points including WHO functional class and PVR. Placebo-controlled patients were then offered openlabeled sildenafil and follow-up was obtained on all patients at 12 months. Patients at 12-month follow-up were noted to have improved exercise capacity, symptoms, and PVR. 78 Conclusions Chronic thromboembolic pulmonary hypertension is the only cause of pulmonary artery hypertension that can be cured. Diagnosis remains the key to survival and outcome. Often it is initially elusive, but once hypothesized, it can be diagnosed and treated effectively in centers specializing in pulmonary hypertension and pulmonary thromboendarterectomy surgery. Even in patients who are inoperable for a variety of reasons, treatment improves exercise capacity, functional class, hemodynamics and symptoms. Early referral to a medical center specializing in pulmonary hypertension and pulmonary thromboendarterectomy surgery is essential. Statement of Conflict of Interest The author declares that there are no conflicts of interest.
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21. Miniati M, Fiorillo C, Becatti M, et al. Fibrin resistance to lysis in patients with pulmonary hypertension other than thromboembolic. Am J Respir Crit Care Med. 2010;181:992-996. 22. Lang I, Kerr K. Risk factors for chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3:568-570. 23. Jais X, Ioos V, Jardim C, et al. Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax. 2005;60:1031-1034. 24. Lang IM. Chronic thromboembolic pulmonary hypertension—not so rare after all. N Eng J Med. 2004;350:2236-2238. 25. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993;103:685-692. 26. Kapitan KS, Buchbinder M, Wagner PD, et al. Mechanisms of hypoxemia in chronic thromboembolic pulmonary hypertension. Am Rev Respir Dis. 1989;139:1149-1154. 27. Sadeghi HM, Kimura BJ, Raisinghani A, et al. Does lowering pulmonary artery pressure eliminate severe functional tricuspid regurgitation? Insights from pulmonary thromboendarterectomy. J Am Coll Cardiol. 2004;44:126. 28. Auger WR, Moser KM. Pulmonary flow murmurs: a distinctive physical sign found in chronic pulmonary thromboembolic disease [abstract]. Clin Res. 1989;37:145A. 29. Ribiero A, Lindmarker P, Johnson H, et al. Pulmonary embolism: one year follow up with echocardiography Doppler and five-year survival analysis. Circulation. 1999;99:1325-1330. 30. Reidel M, Stanek V, Widimsky J, et al. Long term follow up of patients with pulmonary thromboembolism. Chest. 1982;81: 151-158. 31. Blanchard DG, Malouf PF, Gurudevan SV, et al. Utility of the right ventricular Tei index in the noninvasive evaluation of chronic thromboembolic pulmonary hypertension before and after pulmonary thromboendarterectomy. J Am Coll Cardiol Image. 2009;2: 143-149. 32. Morris TA, Auger WR, Ysrael MZ, et al. Parenchymal scarring is associated with restrictive spirometric defects in patients with chronic thromboembolic pulmonary hypertension. Chest. 1996; 110:399-403. 33. Bernstein RJ, Ford RL, Clausen JL, et al. Membrane diffusion and capillary blood volume in chronic thromboembolic pulmonary hypertension. Chest. 1996;110:1420-1436. 34. Tunariu N, Gibbs SJ, Win Z, et al. Ventilation–perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med. 2007;48:680-684. 35. Ryan KL, Fedullo PF, Davis GB, et al. Perfusion scan findings understate the severity of angiographic and hemodynamic compromise in chronic thromboembolic pulmonary hypertension. Chest. 1988;93:1180-1185. 36. Bailey CL, Channick RN, Auger WR, et al. “High probability” perfusion lung scans in pulmonary veno-occlusive disease. Am J Respir Crit Care Med. 2000;162:1974-1978. 37. Reichelt A, Hoeper MM, Galanki M, et al. Chronic thromboembolic pulmonary hypertension: evaluation with a 64-detector row versus digital subtraction angiography. Eur J Radiol. 2009;71:49-54. 38. Bergin CJ, Sirlin CB, Hauschildt JP, et al. Chronic thromboembolism: diagnosis with helical CT and MR imaging with angiographic and surgical correlation. Radiology. 1997;204:695. 39. Castaner E, Gallardo X, Ballesteros E, et al. CT diagnosis of chronic pulmonary thromboembolism. Radiographics. 2009;29: 31-50. 40. Skoro-Sajer N, Hack N, Sadusha-Kolici R, et al. Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension. A pilot study. Circulation. 2009;119: 298-305. 41. Auger WR, Fedullo PF, Moser KM, et al. Chronic major-vessel chronic thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology. 1992;183:393-398.
42. Pitton MB, Duber C, Mayer E, et al. Hemodynamic effects of nonionic contrast bolus injection and oxygen inhalation during pulmonary angiography in patients with chronic major-vessel thromboembolic pulmonary hypertension. Circulation. 1996;94: 2485-2491. 43. Piovella F, D'armini AM, Barone M, et al. Chronic thromboembolic pulmonary hypertension. Semin Thromb Hemost. 2006;32: 848-855. 44. Corsico AG, D'armini AM, Cerveri I, et al. Long term outcome after pulmonary endarterectomy. Am J Respir Crit Care Med. 2008;178: 419-424. 45. Matsuda H, Ogino H, Minatoya K, et al. Long term recovery of exercise ability after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Ann Thorac Surg. 2006; 82:1338-1343. 46. Thistlewaite P, Makato M, Madani M, et al. Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy. J Thorac Cardiovasc Surg. 2002;124:1203-1211. 47. Bonderman D, Skoro-Sajer N, Jakowitsch J, et al. Predictors of outcome in chronic thromboembolic pulmonary hypertension. Circulation. 2007;115:2153-2158. 48. Thistlewaite PA, Kaneko K, Madani MM. Techniques and outcomes of pulmonary endarterectomy surgery. Ann Thorac Cardiovasc Surg. 2008;14:274-282. 49. van der Plas MN, Reesink HJ, Roos CM, et al. Pulmonary endarterectomy improves dyspnea by relief of dead space ventilation. Ann Thorac Surg. 2010;89:347-352. 50. Jensen KW, Kerr KM, Fedullo PF, et al. Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation. 2009;120: 1248-1254. 51. Jamieson SW, Auger WR, Fedullo PF, et al. Experience and results of 150 pulmonary thromboendarterectomy operations over a 29month period. J Thorac Cardiovasc Surg. 1993;106:116. 52. Madani MM, Jamieson SW. Technical advances of pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Semin Thorac Cardiovasc Surg. 2006;18:243. 53. Fedullo PF, Auger WR, Dembitsky WP. Postoperative management of the patient undergoing pulmonary thromboendarterectomy. Semin Thorac Cardiovasc Surg. 1999;11:172. 54. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest. 2012;141:e419s. 55. Moser KM, Metersky ML, Auger WR, et al. Resolution of vascular steal after pulmonary thromboendarterectomy. Chest. 1993;104: 1441. 56. Levinson RM, Shure D, Moser KM. Reperfusion pulmonary edema after pulmonary artery thromboendarterectomy. Am Rev Respir Dis. 1986;134:1241. 57. Lee KC, Cho YL, Lee SY. Reperfusion pulmonary edema after pulmonary thromboendarterectomy. Acta Anaesthesiol Sin. 2001;39:97. 58. Imanaka H, Miyano H, Takeuchi M, et al. Effects of nitric oxide inhalation after pulmonary thromboendarterectomy for chronic pulmonary thromboembolism. Chest. 2000;118:39. 59. Jamieson SW, Kapelanksi DP, Sakakibara N, et al. Pulmonary endarterectomy; experience and lessons learned in 1500 cases. Ann Thorac Surg. 2003;76:1457-1464. 60. Moser KM, Daily PO, Peterson K, et al. Thromboendarterectomy for chronic, major vessel thromboembolic pulmonary hypertension. Immediate and long term results in 42 patients. Ann Intern Med. 1987;107:560. 61. Condliffe R, Kiely DG, Gibbs JS, et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J RespirCrit Care Med. 2008;177:1122. 62. Mo M, Kapelanski DP, Mitruka SN, et al. Reoperative pulmonary thromboendarterectomy. Ann Thorac Surg. 1999;68:1770.
J. Haythe / Progress in Cardiovascular Diseases 55 (2012) 134–143 63. Freed DH, Thomson BM, Berman M, et al. Survival after pulmonary thromboendarterectomy: effect of residual pulmonary hypertension. J Thorac Cardiovasc Surg. 2011;141:383. 64. Thistlewaite PA, Kemp A, Du L, et al. Outcomes of pulmonary thromboendarterectomy for treatment of extreme thromboemebolic pulmonary hypertension. J Thorac Cardiovasc Surg. 2006;131:307. 65. Iwase T, Nagaya N, Ando M, et al. Acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilator efficiency in patients with chronic thromboembolic pulmonary hypertension. Heart. 2001;86:188. 66. Archibald C, Auger W, Fedullo P, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med. 1999;160:523. 67. Mahmud E, Raisinghani A, Hassankhani A, et al. Correlation of left ventricular diastolic filling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2002;40:318-324. 68. Ulrich S, Fischler M, Speich R, et al. Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties. Chest. 2006;130:841. 69. Cabrol S, Souza R, Jais X, et al. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant. 2007;26:357. 70. Nagaya N, Sasaki N, Ando M, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest. 2003;123:338.
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71. Skoro-Sajer N, Bonderman D, Weisbauer F, et al. Treprostinil for severe inoperable thromboembolic pulmonary hypertension. J Thromb Haemost. 2007;5:483. 72. Olschewski H, Simmoneau G, Gaile N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322. 73. Krug S, Hammerschmidt S, Pankau H, et al. Acute improved hemodynamics following inhaled iloprost in chronic thromboembolic pulmonary hypertension. Respiration. 2008;76:154. 74. Kramm T, Eberle B, Krummenauer F, et al. Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy. Ann Thorac Surg. 2003;76:711. 75. Jais X, D'Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects iNopErable Forms of chronic Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52:2127. 76. Becattini C, Manina G, Busti C, et al. Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis. Thromb Res. 2010;126:e51. 77. Suntharalingam J, Treacy CM, Doughty NJ, et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest. 2008;134:229. 78. Ghofrani HA, Schermuly RT, Rose F, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2003;167:1139.
Chronic thromboembolic pulmonary hypertension: A review of current practice Jennifer Haythe⁎ Department of Medicine, Columbia University, Center for Advanced Cardiac Care, New York, NY
Abstract
Pulmonary artery hypertension is a complex and multi-faceted disease process with numerous etiologies. Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed and highly treatable form of pulmonary hypertension. In this disease, certain patients with a history of pulmonary thromboembolic disease go on to develop elevated pulmonary artery pressures, shortness of breath, and progressive right heart failure. This article will review the epidemiology, pathophysiology, diagnosis and treatment of CTEPH with a review of pulmonary thromboendarterectomy surgery. (Prog Cardiovasc Dis 2012;55:134-143) © 2012 Elsevier Inc. All rights reserved.
Keywords:
Pulmonary artery hypertension; Chronic thromboembolic pulmonary hypertension; Pulmonary embolism; Pulmonary thromboendarterectomy
Definition Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as the persistence of pulmonary hypertension (defined as a mean pulmonary artery pressure greater than 25 mm Hg) after a single or recurrent pulmonary embolism (PE). It is characterized by the obstruction of pulmonary arteries by organizing thrombi, small vessel arteriopathy, and the development of a high pulmonary vascular resistance (PVR). It carries with it significant morbidity and mortality and early detection is the key to improved outcomes. Importantly, it is one of the few causes of pulmonary hypertension that can be treated for cure.
Incidence It is not entirely clear why some patients with a history of acute PE go on to develop CTEPH. While most patients Statement of Conflict of Interest: see page 141. ⁎ Address reprint requests to Jennifer Haythe, MD, Assistant Professor of Clinical Medicine, Columbia University, Center for Advance Cardiac Care, 622 West 168th Street, PH 1265, New York, NY 10032, USA. E-mail address: [email protected].
0033-0620/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.07.005
return to baseline functional status with normal hemodynamics after a pulmonary embolism, one meta-analysis showed that up to 52% of patients had residual emboli seen 11 months after the sentinel event. 1 Up to 35% of patients still had abnormal ventilation–perfusion scans 1 year after the acute event. 2 The incidence of CTEPH is not precisely known although estimates have ranged from 0.5% to 3.8 % of patients after an acute PE and in up to 10% of those with a history of recurrent PE. 2-5 A prospective cohort study by Pengo et al. 4 looked at 223 patients with acute PE without history of prior venous thromboembolism. The cumulative incidence of symptomatic CTEPH at 2 years was 3.8%. Risk of the development of CTEPH was increased in patients with a history of prior PE, a younger age, larger perfusion defects, and idiopathic pulmonary embolism at presentation. Numerous studies have demonstrated that with more effective treatment of acute PE (e.g., thrombolytics), the likelihood of developing CTEPH diminishes. A study by Kline et al. 6 looked at 200 patients with submassive PE treated with unfractionated heparin, 21 of whom went on to develop circulatory or respiratory failure resulting in administration of fibrinolytic therapy. Trans-thoracic echocardiography (TTE) was performed at baseline and at 6 months. A higher proportion of patients in the
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Abbreviations and Acronyms CTEPH = chronic thromboembolic pulmonary hypertension PAH = pulmonary arterial hypertension PE = pulmonary embolism PVR = pulmonary vascular resistance mPAP = mean pulmonary artery pressure PTE = pulmonary thromboendarterectomy V/Q = ventilation–perfusion RVSP = right ventricular systolic pressure PASP = pulmonary artery systolic pressure TTE = transthoracic echocardiography RV = right ventricle
fibrinolysis group had a reduction in right ventricular systolic pressure (RVSP) at 6-month follow-up. This study was not designed to assess for the presence of CTEPH and the results may be attributed to a higher baseline RVSP at the time of diagnosis in the fibrinolysis group. The study did show that a significant proportion of patients with submassive PE had echo findings consistent with pulmonary hypertension (elevated RVSP) at 6 months. 6 Routine fibrinolysis in submassive PE remains controversial. 7
Risk factors
RA = right atrium
Many identifiable risk factors for the development of CTEPH exist. DLCO = single-breath Piazza and Holdhaber. 7 diffusing capacity nicely summarized this in a recent review article. PaO2 = resting arterial oxygen They include factors spetension cific to pulmonary emboCT angiogram = computed lism (recurrent or tomographic angiography unprovoked PE, large RHC = right heart perfusion defect, young catheterization or old age, pulmonary artery systolic pressure NYHA = New York Heart (PASP) N50 mm Hg at Association time of initial PE, per6MWD = 6-min walk distance sistent elevated RVSP 6 months after PE), peak VO2 = peak ventilatory response to exercise chronic medical conditions (cancer, thyroid disease, splenectomy), thrombotic factors (lupus anticoagulant, antiphospholipid antibodies, increased factor VIII) and genetic factors (ABO blood groups, HLA polymorphisms). 4,7-13 Risk factors for venous thromboembolism have been clearly identified and include hyperhomocysteinemia, antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, factor VIII elevation, oral contraceptive use, plasminogen deficiency and anticardiolipin antibidodies. While the hypercoagulable state has been clearly associated with the development of PFT = pulmonary function test
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CTEPH, not all of the aforementioned factors have been clearly linked with CTEPH. Plasma levels of factor VIII were examined in an observational study of 122 patients with CTEPH. 14 Factor VIII levels are known to be elevated in primary and recurrent thromboembolism. Bonderman et al. 14 found that factor VIII levels were elevated in 41% of CTEPH patients. Lupus anticoagulant is present in 10% of CTEPH patients and up to 20% have anticardiolipin antibodies, lupus anticoagulant or both. 15-18 In contrast, protein C, protein S and antithrombin deficiencies have been found in fewer than 1% of patients with CTEPH 18 While evidence of fibrin resistance to lysis has been seen, no clear disorders of fibrinolysis have been identified. 19,20 This same lysis resistant fibrin has been found in non-thrombotic PAH. 21 Several studies have demonstrated an association between splenectomy and CTEPH. One prospective case-controlled study showed splenectomy to be an independent risk factor for CTEPH. 12,22 Additionally, in a retrospective chart review of 257 patients referred to an institution for CTEPH, the prevalence of prior splenectomy was significantly higher in the CTEPH group than in the idiopathic pulmonary hypertension group, or in the control group. 22,23 Patients with prior splenectomy also tended to have more distal disease which was less amenable to PTE surgery. 22 The pathophysiology of this relationship is not well understood although there are data to support a prothrombotic state after splenectomy for patients with hemolytic anemia (including priapism, arterial thrombosis, portal vein thrombosis) as well as an increased risk of myocardial infarction and stroke in patients who have had splenectomy for hereditary spherocytosis, and obstructive pulmonary lesions in patients with B-thalassemia. 22 It has been postulated that the loss of filtering function by the spleen results in abnormal erythrocyte retention and subsequent activation of the clotting cascade. 22
Pathophysiology Whether in situ thrombosis, rather than embolic phenomenon, is responsible for CTEPH is debated. It is not clear why some patients with a history of pulmonary embolism go on to develop CTEPH while others do not. Clearly the pathologic specimens from thromboendarterectomy surgery for CTEPH appear grossly different than that of an acute pulmonary embolism, the former being a fibrous, organized material replacing the normal intima as opposed to the less organized red clot found in acute embolectomy. 24 However, microscopic similarities between CTEPH and other forms of PAH have been demonstrated clearly and with reproducibility on lung biopsy. 25 In a study of 31 CTEPH patients (15 at the time of PTE surgery and 16 postoperatively during autopsy), pathology specimens
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demonstrated a wide range of pulmonary hypertensive lesions, including plexogenic lesions. 25 The study concluded that small pulmonary artery pathology in CTEPH patients was relatively indistinguishable from pulmonary hypertension from other causes. In addition, these pulmonary hypertensive lesions and plexogenic lesions were found in proximal open vessels exposed to high pressures and in vessels distal to obstructed vessels suggesting that release of cytokines and other endothelin-derived factors occurs in response to pulmonary hypertension and may contribute to its progression. 25 It appears that the progressive nature of pulmonary hypertension in CTEPH patients is related to these resistance changes in small vessels and not necessarily to recurrent pulmonary emboli. Thus, even pathologically, it may be difficult to distinguish whether CTEPH leads to the vasculopathic pathology of PAH or PAH leads to chronic thromboembolic disease.
Clinical presentation Patients with CTEPH have similar presentations to those patients with PAH from other causes. In patients with a known prior PE there may be a, asymptomatic period for many months or years after the initial event. Exertional dyspnea and exercise intolerance are the most common complaints and probably occur because of increased dead space ventilation with increased demand. 26 Unexplained dyspnea, dyspnea on exertion, dizziness, near-syncope, true syncope and exertional chest pain are all common complaints in these patients. 26 The findings on physical examination are similar to other PAH patients: increased jugular venous pressure, loud split second heart sound with an increased P2
component, a right ventricular (RV) heave, an RV S4 gallop, and tricuspid regurgitation murmur. The murmur of the tricuspid valve is likely secondary to a dilated tricuspid annulus in the setting of right ventricular volume and pressure overload. Often this murmur improves or resolves completely after thromboendarterectomy if the PASP is b40 mm Hg postoperatively. The improvement in the degree of tricuspid regurgitation seen by TTE postPTE surgery is shown in Fig 1. 27 With progression of RV failure, patients can develop hepatomegaly, ascites, and lower extremity edema. In one study, up to 30% of CTEPH patients had pulmonary flow bruits auscultated during an inspiratory breath hold probably from high turbulence across obstructed pulmonary beds and/or recanalized pulmonary arteries. 28
Diagnosis Diagnosis is the key to survival in CTEPH. A study by Ribiero et al. 29 demonstrated that in 78 patients with acute PE, a decline in RVSP and recovery of RV function occurred within 30 days in N90% of patients. A PASP of N50 mm Hg at the time of diagnosis of acute PE was associated with persistent PH after 1 year and only patients with persistent PH required pulmonary thromboendarterectomy within 5 years. 29 Similarly, Reidel et al. 30 found a positive correlation between a mean PAP (mPAP) and mortality; there was an 80% mortality in patients with amPAP N50 mm Hg. There are a number of modalities available to diagnose CTEPH. Routine chest x-ray (CXR) can be normal or can show signs of pulmonary arterial hypertension including enlarged pulmonary arteries, right atrial enlargement, and right ventricular enlargement with loss of the retrosternal
Fig. 1. Apical four-chamber echocardiographic images with Doppler of a patient with severe tricuspid regurgitation (A) that resolved after pulmonary thromboendarterectomy (B). Pulmonary artery systolic pressure declined from 74 to 29 mm Hg after pulmonary artery systolic pressure [27].
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airspace on lateral view. Features of pulmonary infarct can also be seen. Echocardiography is useful to estimate the RVSP and evaluate the degree of right heart disease including RA an RV size, RV function, presence of a pericardial effusion and the degree of tricuspid regurgitation. The RV Tei index which is an indicator for right ventricular performance, appears to correlate well with pulmonary vascular resistance. 31 Pulmonary function tests (PFTs) are routinely done in the evaluation of patients with dyspnea. In patients with CTEPH, spirometry can be normal, though up to 20% of patients can show a mild restrictive defect attributed to parenchymal scarring. 32 A moderate reduction of singlebreath diffusing capacity (DLCO) is often seen, as is hypoxemia attributed to ventilation–perfusion (V/Q) mismatch. 33 While resting arterial oxygen tension (PaO2) can be normal, most patients will develop a worsening alveolar–arterial oxygen gradient and a decline in PaO2 with exercise. This is attributed to increased dead space ventilation with exercise. 26 Ventilation–perfusion (V/Q) lung scanning is one of the most important diagnostic tests to help distinguish CTEPH from other forms of PAH. In an era where computed tomographic (CT) angiography is faster and easier to obtain, the importance of the V/Q scan should not be underestimated. In a retrospective study of 227 patients with pulmonary hypertension, V/Q scanning had a sensitivity of 97.4% for the detection of chronic thromboembolic disease while CT angiography was only 51%. 34 Patients with CTEPH usually have at least one, and often several, segmental or larger, mismatched perfusion defects as seen in Fig 2. 17 V/Q scanning can underestimate the degree of central obstruction seen by pulmonary angiography and/or surgery. 35 In pulmonary arterial hypertension from other causes the perfusion scan is normal or mottled in appearance with nonsegmental or subsegmental defects. It should be noted that segmental defects can be seen on V/Q scanning in the absence of embolic disease. Segmental defects from non-embolic causes include pulmonary veno-occlusive disease, pulmonary artery sarcoma, fibrosing mediastinitis and large vessel pulmonary vasculitides. 36
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While it is not recommended as the ideal screening tool for CTEPH, CT angiography is very useful and sensitive in the evaluation of CTEPH with more central and segmental disease burden. In a small study of 27 patients with CTEPH, 64-detector row CT scan had a diagnostic sensitivity of 98.3% at the main and lobar level and 94% at the segmental level when compared with digital subtraction angiography. 37 In comparison to conventional pulmonary angiography, detection rates for central emboli were similar in 55 patients suspected of having CTEPH, although detection of segmental disease was superior with conventional pulmonary angiography. 38 In addition, CT scanning provides additional valuable information in the evaluation of CTEPH including: (1) presence and extent of parenchymal disease; (2) anatomy and size of pulmonary arteries and vessels; (3) location of arterial webs and bands; and (4) location of collateral vessels in the mediastinum. 39 Right heart catheterization (RHC) remains the gold standard for diagnosis of pulmonary arterial hypertension for any WHO group. In CTEPH, RHC may only show moderately elevated pulmonary pressures at rest, in which case a full set of hemodynamics should be repeated after exercise. Vasodilator responsiveness is not necessary, although acute responsiveness predicts a better long-term hemodynamic outcome with surgery. 40 Furthermore, concomitant disease including CAD and abnormal left sided hemodynamics may need to be addressed and factored into the decision-making analysis for surgical intervention. Pulmonary arteriography is essential to determine whether or not a patient is a candidate for surgical intervention. Five findings are associated with CTEPH. They are as follows: (1) pouch defects, (2) pulmonary artery webs or bands, (3) abrupt, angular narrowing of major pulmonary arteries, (4) intimal irregularities and (5) complete obstruction of lobar or segmental vessels at their origin. 41 Though many clinicians fear that pulmonary angiography may precipitate contrast induced hypotension or worsening hypoxemia, it is generally safe and well tolerated. This was demonstrated in a study in which multiple contrast bolus injections were administered to CTEPH patients without significant adverse outcomes even in the presence of severe
Fig. 2. Representative perfusion lung scan in a patient with chronic thromboembolic pulmonary hypertension. The ventilation study (not pictured) showed no abnormalities. The perfusion scan shows multiple, segmental, mismatched defects. Panels A and B show the posterior and anterior views, respectively. In panel C, which shows the left lateral view, there is a segmental defect involving the lingula (arrow). In panel D, which shows the right lateral view, areas of hyperperfusion involving the posterior aspect of the right upper lobe as well as the right middle lobe (arrowheads) are interspersed with areas of relative hypoperfusion involving the anterior aspect of the right upper lobe (arrow) and the majority of the lower lobe. 17
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pulmonary hypertension. Normally, a single injection of non-ionic contrast into both pulmonary arteries with biplane acquisition should provide enough information to determine extent and anatomy of clot burden. 17,42
Surgical selection CTEPH is the only form of pulmonary hypertension that can be cured with surgical intervention. Pulmonary thromboendarterectomy is the surgery of choice in patients who qualify. It involves the removal of the fibrous, whitish, thromboembolic material lining the pulmonary arterial system with marked improvement in mean pulmonary artery pressures, pulmonary vascular resistance and cardiac output. 7,43,44 Resting hemodynamics, 6-min walk distance (6MWD), patient symptoms, and New York Heart Association functional class all improve dramatically after successful thromboendarterectomy surgery and these effects persist in the absence of recurrent emboli. 7 Right ventricular remodeling, improved right ventricular systolic function, and regression of tricuspid regurgitation result from improved pulmonary hemodynamics. 44,45 Generally, four indices help determine the feasibility of surgical intervention in CTEPH patients: accessibility of thrombi, presence of hemodynamic or respiratory impairment (NYHA class II or IV), presence of comorbidities, and patient willingness. 17,46 Fig 3 demonstrates the Jamieson classification of thrombus type and location. 46 In a prospective analysis of 202 patients undergoing PTE,
patients with type 1 and type 2 thromboembolic disease had lower postoperative mortality, better postoperative hemodynamics and less residual tricuspid regurgitation. 46 No fixed guidelines or consensus among physicians as to the hemodynamic goals of surgery currently exist. Whether surgery should be reserved only for patients expected to have postoperative normalization or relative reduction of their PVR is up for debate. In addition, the preoperative determination of feasibility of surgery based on location of disease remains subjective. Ideally, the amount of preoperative hemodynamic impairment should correlate with the amount of surgical approachable disease. 17 Patients with preoperative pulmonary vascular resistance less than 1200 dyne-s/cm 5 without other major comorbidities have a more favorable prognosis. 47 That is also true of patients who have a postoperative reduction in PVR of 50% to a level below 500 dyne-s/cm 5. In one study looking at postoperative mortality in 1100 patients, overall mortality was 4.7% and the majority of deaths were in patients with a postoperative PVR greater than 500 dyne-s/cm 5. 48 Patients with more proximal disease had reduced mortality and greater reductions in PVR. Patients who are extremely symptomatic despite modestly abnormal rest hemodynamics should still be considered for surgery if they have significant proximal unilateral disease, live at altitude, or are extremely active at baseline. Pulmonary endarterectomy in these patients relieves dead space ventilation and improves dyspnea and quality of life. 49
Fig. 3. Pulmonary angiograms and corresponding specimens removed at the time of pulmonary endarterectomy: type 1 disease, fresh thrombus in main lobar arteries (note abrupt cutoff of branches and lack of filling to the periphery on angiography; type 2 disease, organized thrombus and intimal thickening proximal to segmental arteries (note the poststenotic dilatation of the lower lobar vessel and lack of filling to the periphery on angiography); type 3 disease, intimal thickening-fibrosis in distal segmental arteries, with surgical plane raised at each segmental level; type 4 disease, distal arteriolar vasculopathy with removal of normal intimal layer and no intraluminal disease. 46
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Preoperative management Coronary angiography is normally performed at the time of pulmonary angiography in patients at risk for coronary artery disease. In addition, unless a contraindication exist, an inferior vena cava (IVC) filter should be placed preoperatively to prevent recurrent emboli. This is especially true of the high-risk immediate postoperative period in which bleeding complications may complicate or delay the use of appropriate anticoagulation in these patients. 17 At present, there are not sufficient data to support the use of advanced pulmonary vasodilator therapy preoperatively. 50 The use of pulmonary vasodilators such as bosentan and sildenafil preoperatively does not appear to have an impact on outcome postoperatively. 50 This is especially important to remember as the initiation and up-titration of these medications can delay referral to a PAH/PTE center.
Pulmonary thromboendarterectomy The current recommended approach to pulmonary thromboendarterectomy was developed at the University of California, San Diego. 51,52 The surgery requires a median sternotomy approach, cardiopulmonary bypass, and periods of hypothermic circulatory arrest. 17,48,51,52 Median sternotomy allows appropriate access to the pulmonary arteries and improved access to chronic embolic material while circulatory arrest provides a bloodless surgical field for dissection of segmental and lobar arteries. Intermittent episodes of circulatory arrest are limited to 20-min intervals (a unilateral endarterectomy can be completed in one 20-min period). After each episode of circulatory arrest, reperfusion is performed until the pulmonary venous saturation is 90% or at least 10 minutes have passed. Once the endarterectomy is complete, circulation is restored and the patient is rewarmed. If an atrial septal defect is detected, it is usually repaired at this time. Other procedures that may be indicated, including valvular repair/replacement and coronary artery bypass grafting are performed during the rewarming process.
Postoperative management Management of these patients in the postoperative period requires careful attention to volume status, preload conditions, cardiac output, and systemic oxygen consumption. Anticoagulation is a necessity and must be started cautiously. Assuming chest tube output is in an acceptable range, all patients should begin heparin prophylaxis (subcutaneous unfractionated heparin (UFH) 5000 units every 8 or 12 hours) on the evening of the
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surgery. Lifelong warfarin is indicated in all of these patients and is resumed postoperatively. 53,54 Pulmonary artery steal syndrome is a temporary redistribution of blood flow into newly endarterectomized regions and is seen in the majority of postoperative patients. It manifests as hypoxemia and treatment is supportive. New perfusion defects are seen in areas of the lung that were perfused normally preoperatively, supplied by normal arteries on pulmonary angiography, and were unaffected by clot by direct visualization in the operating room. 55 It is self-limited and usually resolves within 2 weeks of surgery. Reperfusion pulmonary edema is a form of noncardiogenic pulmonary edema that occurs in up to 30% of patients in the first 72 hours after PTE. It is believed to occur in areas of the lung that are reperfused during PTE surgery. In one study looking at anatomic location of clot removal, only regions of the lung distal to clot removal were affected and areas of the lung not reperfused in surgery were not affected. 56 In addition, pulmonary capillary wedge pressures were normal pre- and postoperatively. Clinical manifestations range in severity from mild hypoxemia to hemorrhagic pulmonary edema. These patients are managed with diuresis, oxygen supplementation, low-volume mechanical ventilation, and careful attention paid to cardiac output. Unnecessary inotropic therapy should be discontinued. Inhaled nitric oxide may help by vasodilating pulmonary vessels serving wellventilated areas of the lung and thereby reducing VQ mismatch. 57,58
Surgical outcome The 30-day mortality in experienced centers ranges as low as 4%–7%. 43,44 In relatively low-risk patients, mortality rates as low as 1.3% has been reported. 59 Most patients undergoing PTE have excellent short-term and long-term postoperative hemodynamics. Causes of death in these patients include reperfusion pulmonary edema, right ventricular failure, persistent pulmonary hypertension, cardiac arrest, bleeding, sepsis, multiorgan failure, and pulmonary hemorrhage. 17 The majority of patients demonstrate a significant decline in their mean pulmonary artery pressures and PVR in the immediate postoperative period. In one study looking at 29 patients, PVR initially fell from 897± 352 dyne-s/cm 5 to 278± 135 dyne-s/cm 5. 60 In patients who survive the first 3 months post-PTE surgery, long-term survival is excellent and mortality secondary to CTEPH is low. In one study, the 1-year and 3-year mortality in patients who survived the first 3months was 1% and 6% respectively. 61 In an observational study of 137 patients who survived to 3months postoperatively, only 4% died from CTEPH related causes over a 4-year follow-up period. 44 Also, fewer than 0.5% of PTE patients
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develop recurrent thromboembolic disease necessitating surgery. 62 Varying reports on the presence of residual or persistent pulmonary hypertension after PTE exist, most likely reflecting the variable definition of persistent pulmonary hypertension. Estimates range from 5% to 35%, and are probably due to the presence of residual, distal, unresectable disease. 17,47,61,63,64 Patients characterized as having persistent pulmonary hypertension can have survival benefits and functional class improvements similar to patients with normal pulmonary pressures after surgery. It is possible that reduction in PVR rather than absolute mean PA pressure is more indicative of outcome. 17 Generally, patients who are NYHA classes III and IV are NYHA classes I and II postoperatively. In a study of 20 patients undergoing PTE, cardiopulmonary exercise testing was performed preoperatively (baseline) and at 1 month and 4 months postoperatively to assess exercise capacity and ventilator efficiency. Peak oxygen consumption with exercise (peak VO2) increased steadily in patients while the slope of the ventilator-response to carbon dioxide production decreased. These findings correlated with a decline in PVR postoperatively. 65 Also, in a retrospective questionnaire driven study of 308 patients post-PTE, 62% of patients unemployed prePTE had returned to work, 93% were NYHA class I or II, disease-related/ER visits were minimal and a clear correlation existed between 48-hour postoperative PVR and walking and stair climbing ability. 66 Besides demonstrating the regression of tricuspid regurgitation post-PTE, echocardiography has also been used to demonstrate improvement in cardiac output and normalization of left ventricular diastolic filling patterns postoperatively. Mahmud et al. 67 looked at transmitral diastolic flow in patients with CTEPH pre-PTE surgery. Prior to surgery, patients with severe pulmonary hypertension all had an E/A ratio b1.25. Post-PTE, an E/A ratio of N1.5 predicted successful PTE, with restoration of normal cardiac output (Fig 4). 67
Medical treatment Surgery is the only potentially curative treatment for patients with CTEPH, and in many is curative for pulmonary hypertension. Thus, the use of pulmonary vasodilators is only indicated in select groups of people. These include the following: (1) patients who are not candidate for PTE because of patient choice, comorbidities, and/or the presence of distal unreachable disease (2) as a bridge to surgery in patients with severe disease although there are no data to suggest that this is beneficial and (3) postoperatively inpatients with residual pulmonary hypertension, poor hemodynamics and/or persistent functional limitations. 17,50
Fig. 4. (A) Doppler echocardiogram; pre-pulmonary thromboendarterectomy (PTE) transmitral inflow recording in a study patient. Note the E/A reversal. (B) Doppler echocardiogram; post-PTE transmitral inflow recording in the same study patient. Note the resolved E/A reversal predominately by a significant increase in the E-wave velocity and a relatively unchanged A-wave velocity. 67
Initiation of pulmonary vasodilator therapy should be limited to pulmonary hypertension centers familiar with the complexities of treating this disease. As with all pulmonary hypertension patients, baseline right heart catheterization should be performed to assess severity of disease. As mentioned earlier, vasoreactivity testing can be helpful to identify patients who may have better postoperative outcomes with PTE surgery. However, its use is limited in patients ineligible for PTE as most CTEPH patients tend to be non-reactive. 68 Most of the drugs used to treat pulmonary arterial hypertension have been studied in the CTEPH population. The use of intravenous epoprostenol was studied in a retrospective cohort of 27 patients with inoperable CTEPH. 69 After 3 months of therapy, half of patients had improvement in their NYHA functional class. Epoprostenol was also associated with a reduction in PVR and mean pulmonary artery pressure, and improved exercise capacity. 69 Interestingly, in a small series looking at 12 patients with severe CTEPH (PVRN 1200dyne-s/cm 5), IV epoprostenol infusion for a mean of 46 days prior to PTE
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demonstrated reduction in preoperative PVR but no evidence of postoperative benefit. 70 In patients with NYHA class III or IV symptoms, epoprostenol is the drug of choice. In an open-label uncontrolled study of 25 patients with inoperable CTEPH treated with subcutaneous treprostinil, treated patients demonstrated improved 6MWD, WHO functional class, PVR and survival. 71 Several studies have demonstrated that the inhaled prostanoidiloprost improves functional capacity, NYHA functional class, symptoms, quality of life and hemodynamics. 72-74 Its use in the perioperative period also demonstrates beneficial effects on hemodynamics. 74 The endothelin receptor antagonist bosentan has been studied in the CTEPH population as well. One randomizedcontrolled trial (BENEFiT) studied 157 patients with inoperable CTEPH or persistent pulmonary hypertension after PTE. 75 Seventy-seven patients were randomized to bosentan and 80 to placebo for 16 weeks. Patients treated with bosentan had statistically significant improvement in PVR and cardiac index. 75 Other observational studies of bosentan in the inoperable CTEPH population also confirm improved exercise capacity, 6MWD, pulmonary artery pressures and cardiac index when compared with baseline. 76 Finally, the phosphodiesterase-5 inhibitor sildenafil has also been studied in a double-blinded, placebo controlled pilot study of 19 patients with inoperable CTEPH. 77 The primary end-point was 6MWD. At 12 weeks no significant difference was seen between the two groups in respect to exercise capacity. The sildenafil arm had improved secondary end-points including WHO functional class and PVR. Placebo-controlled patients were then offered openlabeled sildenafil and follow-up was obtained on all patients at 12 months. Patients at 12-month follow-up were noted to have improved exercise capacity, symptoms, and PVR. 78 Conclusions Chronic thromboembolic pulmonary hypertension is the only cause of pulmonary artery hypertension that can be cured. Diagnosis remains the key to survival and outcome. Often it is initially elusive, but once hypothesized, it can be diagnosed and treated effectively in centers specializing in pulmonary hypertension and pulmonary thromboendarterectomy surgery. Even in patients who are inoperable for a variety of reasons, treatment improves exercise capacity, functional class, hemodynamics and symptoms. Early referral to a medical center specializing in pulmonary hypertension and pulmonary thromboendarterectomy surgery is essential. Statement of Conflict of Interest The author declares that there are no conflicts of interest.
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