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Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, Scotland; Hôpital Antoine-Béclère, Clamart, France; and University of California, San Diego, La Jolla, California
Correspondence and requests for reprints should be addressed to Andrew Peacock, M.D., Scottish Pulmonary Vascular Unit, Level 8 Western Infirmary, Dumbarton Road, Glasgow, G11 6NT Scotland. E-mail: apeacock{at}udcf.gla.ac.uk
ABSTRACT
A number of controversies exist regarding the pathophysiology, natural history, diagnosis, and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Although CTEPH is regarded by many to be a complication of pulmonary embolism (PE) arising subsequent to venous thromboembolism (VTE)—the embolic hypothesis—it has been suggested that PE is rarely the sole cause of CTEPH and that primary arteriopathy with secondary in situ thrombosis may be relevant in the pathogenesis and progression of the disease—the thrombotic hypothesis. A number of lines of evidence support this. Only about half of patients referred with suspected CTEPH have a history of VTE. In addition, data suggest that acute PE is often diagnosed, and possibly misdiagnosed, in patients with preexisting pulmonary artery pathology. There has been much research and debate on the importance of distal arteriopathy in both the initiation and progression of CTEPH. Histopathologic studies have indicated distinct overlap in the microvascular pathology of CTEPH and idiopathic pulmonary arterial hypertension (IPAH), and it has been queried whether class IV CTEPH (increased pulmonary vascular resistance due to distal arteriopathy in the absence of central organized thrombi) and IPAH represent extremes of a disease continuum. Together, these issues may impact on effective diagnosis, preoperative screening criteria for pulmonary endarterectomy surgery, and the likelihood of persistent pulmonary hypertension or even mortality after surgery. They are particularly relevant when considering the possible future use of medical therapies in long-term disease management.
Key Words: arteriopathy • endarterectomy • idiopathic pulmonary arterial hypertension • pulmonary embolism • therapy
There are numerous areas of debate and controversy in terms of current understanding and treatment of chronic thromboembolic pulmonary hypertension (CTEPH), and many of these stem from a lack of detailed knowledge on the pathogenesis and natural history of the disease. For instance, a number of key questions remain open regarding the pathogenesis of CTEPH. The current consensus opinion that CTEPH arises from thromboembolic processes has been challenged, with speculation that, in many cases, CTEPH could result from a primary arteriopathy with secondary thrombosis (1). However, it is unclear exactly how increased downstream resistance could provoke proximal pulmonary artery thrombosis (2). More likely, it is believed that thromboembolism is the initiating event in the majority of cases, and that recurrent thromboembolism or in situ pulmonary artery thrombosis contributes to the persistence of thrombotic pathology and progression of hemodynamic dysfunction (3–5).
The relative contributions of proximal thromboembolism and distal disease in CTEPH is a matter of intense debate and research, primarily because the balance of total pulmonary vascular resistance (PVR) arising from either pathology is likely to be a strong influence on treatment decisions in the future (6). Extensive experience from key worldwide pulmonary endarterectomy (PEA) centers has taught us that the morphologic category of CTEPH and respective contributions of proximal versus distal pathology to preoperative PVR can determine outcomes from PEA and, indeed, whether PEA should be applied at all (4, 7–9).
Although PEA is the acknowledged treatment of choice for CTEPH, between 10 and 50% of referred patients may not be considered eligible for this procedure either because of inaccessible distal thromboembolism or due to other serious comorbidities, and in some cases, transplantation can be an alternative (4, 7, 10). Despite reports of positive postoperative outcomes in patients with CTEPH with very advanced disease (11), persistent pulmonary hypertension (PH) after PEA—the main contributor to perioperative mortality (8, 12)—is generally seen in patients where small-vessel arteriopathy associated with segmental or subsegmental thrombosis is the main cause of high preoperative PVR (4). There is ongoing debate on whether these patients should be considered as having class IV CTEPH or primary PH with associated pulmonary thrombosis (2, 13).
Distal disease is therefore a crucial factor in defining the optimal acute and long-term management of CTEPH. However, there are limited current data on alternatives to PEA, or adjunctive therapies for CTEPH (4). Transplantation can be applied in some patients not eligible for PEA (4). Balloon angioplasty has been used with some reported benefits in patients with distal thromboembolism (15, 16), although this procedure is still considered experimental and requires further investigation (5). Currently, there is also much debate on the potential applications of medical therapy in CTEPH (17, 18). However, as covered elsewhere in this issue (18), clinical trial evidence regarding medical therapy in CTEPH is limited, and a number of important questions remain: In which patients can medical treatment provide meaningful benefits? Are particular medical therapies suited to particular patients and/or stages of disease? When should medical treatment be initiated or stopped?
Discussions among experts at the International Scientific Advisory Board on CTEPH in Zurich, 2006, identified the main controversial issues in CTEPH as follows:
We review these issues in this article, and attempt to bring together key evidence covered during specific presentations at the meeting. We also highlight important future research needs relating to areas where relatively sparse information is available.
CTEPH ETIOLOGY: CURRENT KNOWLEDGE AND GAPS
A key question regarding the pathogenesis of PH is related to thrombotic pathology: Where do initiating thrombotic events occur? In the classical, accepted scheme (the embolic hypothesis), CTEPH develops after single or recurrent pulmonary emboli arise from sites of venous thrombosis (2, 19). CTEPH has previously been underrecognized in post-PE patients, and is estimated to occur in 0.1 to 0.5% of those surviving an acute PE (12, 20–22). Pengo and colleagues (22) showed that up to 3.8% of patients develop evidence of CTEPH within 2 yr of an acute PE (22). It is believed that failure of the single or recurrent PE to resolve adequately leads to segmental obstruction of pulmonary blood flow, high shear stress in nonoccluded areas, and progressive PH due to vascular remodeling in small (distal) pulmonary vessels (Figure 1) (4, 5, 12).
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Lang and coworkers (26, 27) investigated mechanisms that may contribute to the nonresolution of PE, and consequent chronic obstruction of pulmonary arteries in CTEPH. Gene expression analyses showed no abnormalities in the expression of fibrinolytic proteins or responses to thrombin stimulation in primary endothelial cells cultured from pulmonary arteries of patients with CTEPH (3). However, elevated endothelial plasminogen activator-inhibitor and factor VIII expression have been shown in areas of fresh thrombus and in endothelial cells and smooth muscle cells in regions of organized thromboembolic material typically seen in CTEPH (26). This suggests that in situ thrombosis within vascularized, fibromuscular obstructions may contribute to the persistence of thrombi in CTEPH lung (3, 22). In a study identifying differences in the composition of arterial plaques seen in IPAH or "secondary plexogenic" hypertension (Eisenmenger syndrome), compared with those seen in CTEPH, Arbustini and colleagues (28) suggested that thrombotic material may play a crucial role in the formation of plaques seen in CTEPH, whereas fibrous neointimal plaque formation involving foam cells and lymphocytes was a likely contributor to IPAH plaque pathology.
As summarized in Figure 2, there are a number of unresolved questions and limitations relating to the embolic hypothesis of CTEPH (1, 2). Several important gaps in knowledge relate to a lack of clarity on disease progression. Many patients with CTEPH present late in the course of disease, months or years after initial thromboembolic events, and the early natural history of CTEPH within this "honeymoon period" has not been well characterized. Similarly, despite huge advances into its pathogenesis, diagnosis, and therapy over the last 40 yr, the late natural history of acute PE remains unclear, particularly regarding progression of anatomic and hemodynamic changes (2, 10). Links between CTEPH and acute PE have therefore not been properly clarified (2, 12).
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On the basis of data from CTEPH case series reporting outcomes in PEA recipients, it is generally accepted that a disparity between the degree of central obstruction and the prevailing hemodynamic impairment/right-heart function during preoperative assessments indicates significant distal small-vessel disease (i.e., remodeling of small distal pulmonary arteries in nonoccluded areas or thromboembolism in segmental or subsegmental lung areas) (4, 7, 29). Persistent/residual PH is seen in approximately 10% of patients after "successful" PEA, which also indicates a significant contribution of small-vessel pathology (4, 15).
Data from studies of postoperative outcome versus pre- or intraoperative classification of disease support the embolic hypothesis in many respects. Good postoperative outcomes (e.g., improved function and a mortality rate of approximately 5%) are generally seen in patients where there is good correlation between the degree of proximal anatomic obstructions and pulmonary hemodynamics (3, 4). Such patients represent the standard case for operability (9). In contrast, poor outcomes (persistent PH and high risk of mortality) tend to occur where there is significant imbalance between PVR due to central organized thrombi and that arising from distal disease (3, 4, 8). These cases are typically represented by patients with thromboembolic pathology in distal lung areas that are inaccessible to surgery and in those who have developed severe pulmonary hypertensive changes (arteriopathy) in the distal vascular bed (2, 4).
The vascular steal phenomenon, indicated by postoperative reversal of blood flow characteristics after PEA, is another clinical marker of significant differential resistance due to small-artery disease (4), and can reflect poor postoperative outcome. In patients showing reversal, improved blood flow is seen in previously obstructed segments, whereas poor blood flow occurs in areas that were not obstructed before removal of a proximal clot (as visualized with pre- and postsurgery angiography). This is believed to be due to the greater vascular resistance in nonobstructed versus endarterectomized vessels, which is believed to signal established small-vessel pathology (30), including muscular hypertrophy in the nonobstructed vessels.
From a review of the literature, there appears to be a lack of direct evidence to show that a single PE or even recurrent thromboembolic events can produce vascular obliteration sufficient to cause the development of CTEPH (1). However, data from animal studies with chronic pulmonary artery ligation have characterized pulmonary vascular remodeling distal to the ligation, a so-called postobstructive vasculopathy, featuring muscular hypertrophy, development of precapillary bronchial-to-pulmonary vascular anastomoses, and abnormal pulmonary artery vascular reactivity with endothelial dysfunction (31, 32). These features are considered analogous to distal changes seen in lung from patients with CTEPH (4, 30, 33).
It has been suggested that CTEPH only appears when there is coexistent endothelial dysfunction (3, 4). However, although there is a range of possible contributory endothelial mechanisms (e.g., shear stress, inflammation processes, release of cytokines, and vasculotrophic factors), endothelium-derived vascular-mediating factors that promote pulmonary arterial remodeling in CTEPH lung remain to be fully identified (3, 17, 23).
SIMILARITIES AND DIFFERENCES BETWEEN CTEPH AND PULMONARY ARTERIAL HYPERTENSION
Clinically, both CTEPH and IPAH present with exertional dyspnea, pulmonary arterial hypertension (PAH), and signs of right-heart failure, and there is worthy debate on whether CTEPH and IPAH are clinical expressions of a similar underlying disease process and thus represent two ends of the same disease spectrum (2). Table 1 compares some of the main features of the two conditions. At the histopathologic level, autopsy and biopsy studies have shown that CTEPH lung is virtually indistinguishable from IPAH lung (3, 30, 36). Vascular changes commonly seen in both CTEPH and IPAH include medial hypertrophy, intimal hyperplasia, plexiform lesions, and small-vessel thrombi (30).
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Endothelial mechanisms at the site of the small muscular pulmonary arteries, with subsequent exaggerated vasoconstriction, impaired vasodilation, and intimal and luminal obstruction, are generally accepted as contributory mechanisms in the natural history of IPAH (4, 30, 36). Raised endothelin-1 expression, reduced production of nitric oxide and diminished prostacyclin are all suggested as possible mediators of endothelial dysfunction in PH in general (10, 37–40). As already discussed, whether similar endothelial involvement exists in CTEPH is not currently known. However, animal studies suggest some nitric oxide and endothelin involvement in postobstructive lung areas (32, 41, 42).
It is interesting to note that local pulmonary thrombosis, likely initiated by microscopic endothelial surface coagulation, is frequently observed in patients with IPAH (13, 43). A number of endothelial and prothrombotic mechanisms, including increased thrombin activity, thrombomodulin–tissue factor imbalance, and platelet-derived mediators, have been suggested as major predisposing factors for intrapulmonary thrombosis in IPAH (13). The possible role of local pulmonary thrombosis in IPAH progression is reinforced by the finding that long-term survival is improved in patients with IPAH receiving oral anticoagulant therapy and continuous infused prostacyclin (34, 43). Although the accepted model of thrombosis in CTEPH involves initial thrombus formation at extrapulmonary sites (VTE), in situ thrombosis (intrapulmonary thrombosis) has also been implicated in CTEPH progression. Studies of plasminogen activator-inhibitor 1 (PAI-1) alterations have provided some evidence of a molecular basis for the promotion of pulmonary arterial thrombosis and stabilization of vascular thrombi (23, 26). Such findings further blur the division between CTEPH and IPAH, and support the possible classification of patients with CTEPH class IV as having IPAH with associated thrombosis (44).
Overall, although there are areas of significant overlap in terms of histopathology, clinical signs, and symptoms between CTEPH and IPAH, there are also some distinct differences in the profiles of risk factors and predisposing conditions associated with the two conditions (Table 1). In terms of predisposing conditions and risk factors, patients with hemolytic disease have been shown to have a greater susceptibility to CTEPH, but this is possibly because splenectomy is frequently performed in these patients. Splenectomy has been shown to be an independent predisposing factor in CTEPH, although this relationship is not yet fully understood (45). There is often a long period (2–34 yr, but generally around 20 yr) before splenectomized patients display CTEPH, and there is speculation on what happens during this period. Current hypotheses include possible prothrombotic activity of abnormal erythrocytes, interactions between abnormal erythrocyte membranes and the pulmonary vasculature, and abnormal platelet activation (46–48). As evidence accrues on the nature of these links, it is worth questioning whether we should be monitoring or treating splenectomized patients to avoid CTEPH onset or delay its progression.
Genetic and epidemiologic studies have identified a number of key differentiators between IPAH and CTEPH. Gene mutations in bone morphogenetic protein receptor type 2 (BMPR-II), which may be associated with vascular remodeling, have been linked with familial PAH and IPAH, but not CTEPH (49, 50). In addition, although there does not appear to be a genetic basis for CTEPH (51), a familial pattern of inheritance has been indicated in 6 to 10% of cases of primary PH (34), with genetic linking factors identified in up to 30% of cases of sporadic IPAH (5). There is a well-established and significant sex predisposition (1.7:1) to IPAH in women (34), but sex differences have not been shown in CTEPH (52). Patients with CTEPH also show reduced vasoresponsiveness to acute vasodilator challenge testing. Further studies are required to establish the possible reasons for these variations, and whether they signal true differences in disease pathophysiology.
DIAGNOSTICS: WHAT SHOULD WE BE IMAGING?
A diagnosis of CTEPH is rarely made during long-term follow-up of patients presenting with acute PE, but is often identified during assessments for dyspnea, right-heart failure, syncopal episodes during effort or stress, angina, hemoptysis, or chest pain (12). CTEPH is occasionally uncovered through observation of unusually high pulmonary arterial pressure at the time of overt single or recurrent PE (4, 12). An important clinical learning point here is that the right ventricle cannot withstand acute large rises in outflow impedance, and if a high pulmonary artery pressure is measured after "acute PE," then chronic recurrent thrombosis or embolism should be considered a possibility. Follow-up assessment of medical history shows previous suspected or confirmed PE or DVT in the lower limbs in roughly half of patients, although past medical history is often not relevant. Up to 63% of patients have no documented history of acute PE (3), and the clinical course of deterioration in these patients is often indistinguishable from that seen in other forms of PH, especially IPAH. Diagnostic methods to confirm and characterize CTEPH are covered in detail elsewhere (4, 9, 53).
Patients with suspected PH usually undergo chest X-ray, followed by echocardiography in abnormal cases or in cases with normal X-ray but high suspicion of CTEPH based on symptomatology. Abnormal echocardiography indicating cardiac involvement can be followed by right- and left-heart catheterization, followed by confirmatory magnetic resonance imaging (MRI). In cases with non-cardiac-related PH, computed tomographic angiography can identify IPAH, CTEPH, or other lung disease (10, 53). In many centers, ventilation–perfusion scanning is considered a key differential test it often reveals multiple pulmonary segmental perfusion defects in CTEPH that are unmatched in ventilation scans (4, 5, 10, 53). In IPAH, perfusion scans are either normal or show nonhomogeneity of perfusion (54). Finally, the gold-standard method for full characterization of CTEPH is pulmonary angiography, which can be supplemented by confirmatory MRI. Vascular obstructions can be visualized on pulmonary angiograms in patients with CTEPH, whereas vascular obliteration is the main angiographic feature seen in IPAH. However, as discussed in detail elsewhere in this supplement (53), advanced computed tomography (CT) or MR angiography (MRA)–based imaging analyses are now starting to supersede some of these traditional techniques in the differential diagnosis of CTEPH.
Currently, effective imaging (angioscopy, CT, MRA) is now applied routinely to the large vessels in patients with suspected CTEPH. However, the question posed by recent opinion on the role of significant small-vessel involvement is whether imaging of small pulmonary vessels and the right heart should also be assessed in routine diagnostic and/or preoperative work-up. This is certainly possible with advances with high-resolution CT and MRA imaging (53). Preoperative imaging of both the right ventricle and small pulmonary vessels that show significant pathology may help in (1) assessing likely outcome and (2) evaluating whether supportive (e.g., bridging) medical therapy should be applied, or indeed whether PEA should be undertaken at an earlier stage. There is therefore a need to establish a preoperative process whereby small vessels and/or right heart displaying severe pathology can be targeted either with surgical or medical intervention. This aspect is discussed in detail by Kim (9).
WHAT IS THE ROLE OF INTRACAVAL FILTERS?
Inferior vena cava (IVC) filters are indicated to prevent PE in patients with DVT or PE, where anticoagulation therapy is contraindicated or has failed to prevent recurrent VTE, and there is some evidence indicating benefits with IVC filter use after surgical embolectomy (14, 55). Caval filters are widely used in patients with acute PE in North America and certain centers in the European Union. Furthermore, studies have suggested possible prophylactic applications, such as in elderly patients with a history of VTE, before thrombolysis of proximal DVT or massive PE, or in patients with PH to avoid PE (55, 56). However, there is only sparse published evidence to indicate that IVC filters provide benefits in CTEPH. On the basis of a small follow-up study (n = 18), Hajduk and colleagues (57) recommended IVC filter use to prevent PE recurrence both over the long term and during the high-risk perioperative period. Mo and coworkers (58) recommended IVC filters in conjunction with vigilant anticoagulation therapy as a means of avoiding reoperative surgery in PEA recipients.
Some experts feel that IVC filtration may actually increase the incidence of PE, and that controlled anticoagulation therapy is sufficient to combat PE recurrence. In addition, it has been suggested that perioperative management of some patients with severe disease (significant distal pathology) could be hampered if IVC filters are placed during PEA. Studies are required that compare outcomes in patients where filters are used versus patients where they are not, potentially also addressing the potential of temporary versus permanent filters (55, 59).
CAN CTEPH BE TREATED MEDICALLY?
Medical therapies that have traditionally been used in the management of post-PE patients come from a number of drug classes (anticoagulants, diuretics, digitalis, oxygen therapy), but, in general, these therapies do not affect the underlying disease processes of CTEPH. As in post-PE patients, lifelong anticoagulant therapy is recommended in patients diagnosed with CTEPH to avoid recurrent thromboembolism or in situ growth of existing pulmonary obstructions (5, 10, 55): treatment should be adjusted to a target international normalized ratio of 2.0–3.0 (5). Calcium channel blockers have also been applied in CTEPH but do not provoke any marked improvements due to the lack of vasoreactivity in the pulmonary vasculature in CTEPH lung.
The advent of a number of novel therapies with proven efficacy in IPAH, and increasing knowledge of the pathogenesis and natural history of CTEPH, require that we address ways in which medical therapy can further help in the long-term management of the disease. As discussed in detail elsewhere in this issue (18), similarities between CTEPH and nonthromboembolic PAH in terms of clinical presentation and possible underlying pathophysiologic mechanisms suggest that benefits seen with medical treatment in IPAH may also be seen in CTEPH. A significant proportion of patients with CTEPH are not suitable candidates for PEA, with transplantation being an alternative in some. If proven effective in controlled clinical trials, novel medical treatments for IPAH could provide valuable benefits to many patients with CTEPH who are not eligible for, or for other reasons do not undergo, PEA. With increasing knowledge on the role of microvascular disease in CTEPH progression and PEA outcome (9, 17), it is generally agreed that medical therapy might also provide preoperative improvements in patients awaiting surgery (to stabilize small-vessel function and preserve right-heart function) (60). In addition, improvements in pulmonary hemodynamics and clinical status are an important treatment goal in patients with persistent or residual PH after PEA (18). The possible applications have recently been addressed in a recommended treatment algorithm (44).
Although we have encouraging data from small, uncontrolled trials and case series assessing medical treatment (18), there are currently no efficacy or safety data from prospective, randomized, controlled trials in CTEPH. Important issues in the design and performance of such trials concern the definition of appropriate target populations and the choice of relevant and practicable clinical endpoints. Due to the apparent similarities between CTEPH and IPAH, many of the considerations in trial design for medical therapies in IPAH also apply in CTEPH (61, 62). In patients with surgically inaccessible CTEPH or in those with persistent PH after PEA, the following endpoints are applicable: exercise capacity (submaximal 6-min walk distance), time to indices of clinical worsening (hospitalization, need for transplant, or death), survival, hemodynamics (mean pulmonary arterial pressure, cardiac index [CI], mixed venous O2 saturation [SvO2]; right atrial pressure [RAP]), functional class (World Health Organization), symptomatic change (Borg dyspnea index), and quality of life. A randomized, placebo-controlled trial is currently under way to assess the efficacy and safety of the endothelin receptor antagonist bosentan in patients with inoperable CTEPH.
CONCLUSIONS
There are many controversial issues surrounding CTEPH that require further investigation (44). The natural history and pathophysiology of CTEPH is an important area for further clarification, primarily because it is a subject that affects many areas of disease management (diagnosis, treatment, and screening/monitoring of disease progression). The significance of distal arteriopathy in CTEPH, particularly in the context of disease management, remains to be fully established. The role of medical therapy in the treatment of CTEPH, and how it is best placed alongside surgical intervention to maximize outcomes, is an important priority.
FOOTNOTES
Supported by an unrestricted educational grant from Actelion Pharmaceuticals
Conflict of Interest Statement: A.P. is on advisory boards for Actelion and is a consultant to Pfizer and Encysive in the field of pulmonary hypertension. G.S. reports having received consulting and lecture fees from Actelion ($15,000/yr), Schering ($10,000), Pfizer ($7,500/yr), United Therapeutics ($15,000/yr), and Encysive ($3,000/yr). L.J.R. serves as a member of the steering committee of a study sponsored by Actelion on medical therapy of CTEPH for which he has received less than $5,000 in compensation.
(Received in original form May 11, 2006; accepted in final form June 30, 2006)
REFERENCES
This article has been cited by other articles:
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  L. J. Rubin, M. M. Hoeper, W. Klepetko, N. Galie, I. M. Lang, and G. Simonneau Current and Future Management of Chronic Thromboembolic Pulmonary Hypertension: From Diagnosis to Treatment Responses Proceedings of the ATS, September 1, 2006; 3(7): 601 - 607. [Abstract] [Full Text] [PDF]
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