Objectives

1. Understand the natural history of chronic thromboembolic pulmonary hypertension (CTEPH).

2. Characterize the clinical presentation of CTEPH.

3. Delineate the appropriate diagnostic evaluation for patients with suspected CTEPH.

4. Define the criteria for surgical referral.

5. Identify the common complications following pulmonary thromboendarterectomy.

Key words

chronic thromboembolic pulmonary hypertension; pulmonary embolism; pulmonary hypertension; pulmonary thromboendarterectomy; venous thromboembolism

Abbreviation

CTEPH = chronic thromboembolic pulmonary hypertension

Natural History

Although complete anatomic recovery after acute pulmonary embolism may not occur, the natural history of acute pulmonary embolic disease under most circumstances involves sufficient thromboembolic resolution to restore normal pulmonary hemodynamics, gas exchange, and exercise tolerance. Chronic thromboembolic pulmonary hypertension (CTEPH), which occurs in a minority of patients following acute embolism, represents an alternate natural history. Although exact incidence figures are not available, it is likely, based on the number of embolic survivors and the number of patients referred for thromboendarterectomy, that CTEPH occurs in no more than 0.1 to 0.2% of patients who experience an embolic event.¹ Survival without intervention is poor and, as in other forms of pulmonary hypertension, it is proportional to the degree of pulmonary hypertension and right ventricular dysfunction at the time of diagnosis. In one study, the 5-year survival rate was 30% when the mean pulmonary artery pressure was > 40 mm Hg and 10% when it was > 50 mm Hg.² In another study, a mean pulmonary artery pressure > 30 mmHg appeared to serve as a threshold value portending a poor prognosis.³

Why certain patients experience incomplete thromboembolic embolic resolution has not been established. A defect in fibrinolytic activity has not been identified and the only identifiable thrombophilic tendency in patients referred for pulmonary thromboendarterectomy has been the presence of antiphospholipid antibodies and/or a lupus anticoagulant in approximately 10 to 20% of patients.^4,5 In many patients presenting with CTEPH, the initial embolic event may have been subclinical, overlooked, or misdiagnosed. However, even in patients in whom the diagnosis of acute venous thromboembolism is made and appropriate therapy instituted, recent data would suggest that incomplete anatomic and hemodynamic recovery may be more common than previously suspected. In a review of 157 patients with symptomatic, acute pulmonary embolism from the THESEE (Tinzaparine ou Heparine Standard: Evaluations l’Embolie Pulmonaire) study, 104 patients (66%) had residual perfusion defects 3 months after the acute event. Of these, 13 patients (8.2%) had residual pulmonary vascular obstruction of Ž 50% as determined by perfusion scanning.⁶

Given what appears to be a large number of patients with persistent postembolic pulmonary vascular obstruction, it also remains uncertain why only a relatively small number develop pulmonary hypertension and what factors determine the rate of progression of their disease. Although the overall extent of pulmonary vascular obstruction appears to play a central role, the effects of circulating vasoconstrictors, immune-related events, the development of a hypertensive pulmonary arteriopathy, or an individual genetic predisposition to pulmonary hypertension may contribute to this outcome.

Months to years may pass between the initial thromboembolic event and the onset of clinical decline. Diagnostic oversight following symptom onset, often of a prolonged duration, is also common. As a result, the diagnosis of CTEPH usually is not made until the degree of pulmonary hypertension is advanced, with most patients manifesting a pulmonary vascular resistance of > 600 dyne·s·cm^-5. The pathophysiologic events responsible for progression of the pulmonary hypertension during this time frame remain uncertain. It is possible that in certain patients the hemodynamic and symptomatic decline is related to recurrent embolic events or in situ pulmonary artery thrombosis. However, in the overwhelming majority of patients with sequential perfusion scans available for review, the pulmonary hypertension has progressed in the absence of perfusion scan change, suggesting that the increasing pulmonary vascular resistance is arising from events in the distal pulmonary vascular bed rather than from obstruction of the central arteries. This premise is supported by lung biopsy findings obtained at the time of thromboendarterectomy that demonstrate changes in the microvasculature, similar to those seen in other forms of small-vessel pulmonary hypertension, distal to both obstructed and nonobstructed central arteries.⁷

Diagnostic delay appears to be related to various causes: the often nonspecific clinical presentation of the disease and, early in its natural history, its subtle physical examination findings; failure by practitioners to consider disorders of the pulmonary vascular bed in patients with unexplained dyspnea; a tendency to discount the possibility of chronic thromboembolic disease in the absence of a documented history of acute thromboembolism; and a lack of awareness of the disease entity by many physicians.

Clinical Presentation

As in other forms of pulmonary arterial hypertension, the complaint common to all patients with CTEPH is exertional dyspnea, which is related to increased dead space ventilation and limitation in cardiac output. Patients accustomed to higher levels of activity on a daily basis recognize the decline in exercise capacity at an earlier point than those who lead a sedentary lifestyle. In certain patients, tolerable dyspnea at sea level is amplified by ascent to altitude. As the disease progresses, symptoms of lightheadedness or presyncope may occur with exertion, with coughing, or when bending at the waist, the latter symptom perhaps related to a transient decrease in venous return and cardiac output. Late in the course of the disease, as right coronary artery perfusion and right ventricular function become incapable of responding to increased demands, syncopal events and exertional chest pain may develop.

Early in the course of the disease, physical examination findings may be subtle and limited to an accentuation of the pulmonic component of the second heart sound. As the pulmonary hypertension progresses, findings consistent with pulmonary hypertension develop: a right ventricular lift, a closely split second heart sound with further accentuation of its pulmonic component, a right ventricular S₄ gallop, and varying degrees of tricuspid regurgitation. Even at this stage of the disease, however, physical findings can be deceptive, particularly for physicians unfamiliar with the physical diagnostic manifestations of pulmonary hypertension and in patients who are obese or have coexisting cardiopulmonary disease. As right ventricular failure ensues, elevated jugular venous pressure with a prominent v wave, a right-sided S₃, lower-extremity edema, hepatomegaly, ascites, and cyanosis develop. The intensity of the tricuspid regurgitant murmur may diminish as the tricuspid annulus dilates and the transvalvular pressure gradient decreases.

The presence of pulmonary flow bruits is an important physical diagnostic finding in approximately 30% of patients with chronic thromboembolic disease.⁸ The bruits appear to result from turbulent flow across partially obstructed central pulmonary vascular segments. These bruits are not unique to chronic thromboembolic disease, having been described in other disease states associated with focal narrowing of large pulmonary arteries, such as congenital branch stenosis and large vessel pulmonary arteritis. They have not, however, been described in primary pulmonary hypertension, the most common competing diagnostic possibility.

Diagnosis

Once the diagnosis of pulmonary hypertension has been considered, the diagnostic pathway is straightforward but must be undertaken in a sequential fashion. Transthoracic echocardiography, when performed with a contrast study, commonly provides the initial objective evidence that pulmonary hypertension is present and that it is not the result of primary left ventricular dysfunction, valvular disease, or an intracardiac shunt. Typical findings in all forms of pulmonary arterial hypertension include enlargement of the right cardiac chambers, an increased velocity of the tricuspid regurgitant envelope from which the pulmonary artery systolic pressure can be estimated, flattening or paradoxical motion of the interventricular septum, and encroachment of an enlarged right ventricle on the left ventricular cavity.

Once the diagnosis of pulmonary hypertension has been confirmed, distinguishing between the multiple etiologic possibilities is the next critical step (Table 1). Depending on the clinical circumstances, pulmonary function testing, chest CT, sleep testing, serologic studies, or abdominal ultrasound may be required. However, once the differential possibility has been narrowed to a primary problem of the pulmonary vasculature, ventilation-perfusion lung scanning represents a simple, noninvasive means of differentiating disorders of the peripheral pulmonary vascular bed from those of the central. In chronic thromboembolic disease, at least one segmental or larger mismatched perfusion defect is present (more commonly, several are noted).⁹ In disorders of the distal pulmonary vascular bed, perfusion scans either are normal or exhibit a “mottled” appearance characterized by subsegmental defects. It should be recognized that mismatched segmental or larger defects in patients with pulmonary hypertension may also arise from other processes that result in obstruction of the central pulmonary arteries or veins, such as pulmonary artery sarcoma, large-vessel pulmonary vasculitides, extrinsic vascular compression by mediastinal adenopathy or fibrosis, and pulmonary veno-occlusive disease.¹⁰

Table 1—Classification of Pulmonary Hypertension

The magnitude of the perfusion defects in chronic thromboembolic disease often understates to a considerable extent the actual degree of pulmonary vascular obstruction determined angiographically or at surgery.^11,12 Therefore, the presence of even a single, mismatched, segmental ventilation-perfusion scan defect in a patient with pulmonary hypertension should raise concerns regarding a potential thromboembolic basis.

In the evaluation of a patient with pulmonary hypertension, CT scanning is invaluable in detecting disorders of the pulmonary parenchyma, interstitium, chest wall, and mediastinum. However, it has a limited role in the diagnosis of chronic thromboembolic disease. Although a variety of CT abnormalities have been described in patients with chronic thromboembolic disease, the absence of these findings does not preclude the possibility of surgically accessible chronic thromboembolic disease. Furthermore, central thrombi have been described in primary pulmonary hypertension and other forms of chronic lung disease.¹³

The alveolar-arterial oxygen gradient is typically widened and the majority of patients have a decrease in the arterial Po₂ with exercise.¹⁴ Profound hypoxemia, however, is not a usual component of the disease unless a large right-to-left shunt develops through a patent foramen ovale. Results of pulmonary function testing are usually within normal limits but may demonstrate a mild to moderate restrictive impairment, caused to a large extent by parenchymal scarring related to prior infarcts.¹⁵ Although a mild to moderate reduction in single-breath diffusing capacity for carbon monoxide can be observed, a normal value does not exclude the diagnosis. Chest radiography, although often normal, may demonstrate one or more findings that suggest the diagnosis of pulmonary hypertension, such as right ventricular prominence, asymmetry in the size of the central pulmonary arteries, or enlargement of both pulmonary arteries. Areas of mosaic oligemia also may be present (Fig 1). Results of routine hematologic and blood chemistry studies are usually unremarkable. A prolonged activated partial thromboplastin time in the absence of heparin therapy or a decreased platelet count may suggest the presence of a lupus anticoagulant or anticardiolipin antibody.

Figure 1. Chest radiograph in a patient with CTEPH. Note markedly enlarged right pulmonary artery, absence of descending left pulmonary artery, oligemic left lower lobe, and nodule representing infarct in the peripheral left mid-lung field.

Right-heart catheterization with pulmonary angiography remains the gold standard in terms of both diagnosis and surgical referral.¹² Symptom-limited exercise hemodynamic measurements are obtained when the level of pulmonary hypertension at rest is only modest. In patients in whom the central pulmonary vascular obstruction has abolished the normal compensatory mechanisms of recruitment and dilation, exercise-related increases in cardiac output are associated with an almost linear elevation of the pulmonary artery pressure.

The angiographic appearance of chronic thromboembolic disease bears little resemblance to that of acute pulmonary embolism. Well-defined, intraluminal filling defects found in acute disease are not present. Instead, the angiographic patterns encountered in chronic thromboembolic disease are reflective of the complex patterns of organization and recanalization that occur following an acute thromboembolic event (Fig 2). Five angiographic patterns have been described in chronic thromboembolic disease that correlate with findings at the time of surgery.¹² These include (1) pouch defects; (2) pulmonary artery webs or bands; (3) intimal irregularities; (4) abrupt, often angular narrowing of the major pulmonary arteries; and (5) complete obstruction of main, lobar, or segmental vessels at their point of origin. In most patients with extensive chronic thrombembolic disease, two or more of these angiographic findings are present and the findings are present bilaterally.

Figure 2. Left, right anteroposterior angiogram, and right, lateral pulmonary angiogram in a patient with chronic thromboembolic disease. Interlobar artery is markedly irregular. Lateral view demonstrates abrupt cut-off of descending pulmonary artery with complete absence of flow to the right lower lobe. Right middle lobe artery is dilated and tortuous.

Even in the presence of severe pulmonary hypertension, pulmonary angiography can be performed safely if simple precautions are taken.¹⁶ In terms of technique, multiple selective injections are not required. A single injection of nonionic contrast into both proximal pulmonary arteries, with the volume and injection rate adjusted based on cardiac output, appears to be sufficient. The patient is also carefully monitored and supplemental oxygen is provided during the procedure. Biplane acquisition provides optimal anatomic detail, the lateral projection providing more detailed definition of lobar and segmental anatomy than can be achieved with an anterior-posterior view alone. If the findings of pulmonary angiography are not conclusive, fiberoptic pulmonary angioscopy has proven valuable in confirming the presence of chronic thromboembolic obstruction and in determining whether it is amenable to surgical intervention.¹⁷

If the patient is considered to be an operative candidate, several other interventions must be undertaken before surgery. Given the risk of embolic recurrence—both over the long term and especially during the high-risk perioperative period when bleeding complications may contraindicate the administration of even prophylactic doses of anticoagulation—an inferior vena caval filter is routinely placed. For those at risk of coronary artery disease, coronary angiography is routinely performed before surgery, usually at the time of the right-heart catheterization and pulmonary angiogram. Coronary artery bypass grafting, if necessary, can be performed at the time of the thromboendarterectomy.

Surgical Selection, Surgical Approach, and Outcome

The intent of the extensive evaluation process is to establish the need for surgical intervention, determine the surgical accessibility of the chronic thromboemboli, and estimate the risk of thromboendarterectomy as well as the anticipated hemodynamic outcome in the individual patient. The majority of patients who undergo thromboendarterectomy exhibit a pulmonary vascular resistance > 300 dyne·s·cm^-5. At centers reporting their experience with thromboendarterectomy surgery, preoperative pulmonary vascular resistance is typically in the range of 700 to 1,100 dyne·s·cm^-5 (Table 2).^18-29 Patients without substantially altered pulmonary hemodynamics, such as those with involvement of one main pulmonary artery, those with unusually vigorous lifestyle expectations, and those who live at altitude, may also be considered for surgery to alleviate the exercise impairment associated with their high dead-space and minute ventilatory demands. Surgery is also offered to patients with normal pulmonary hemodynamics or only mild levels of pulmonary hypertension at rest who develop significant levels of pulmonary hypertension with exercise.

Table 2—Published Results for Pulmonary Thromboendarterectomy Since 1997*

An absolute criterion for surgery is the presence of accessible chronic thrombi. Current surgical techniques allow removal of organized thrombi whose proximal extent is in the main and lobar arteries and, depending on surgical skill and experience, those involving the proximal segmental arteries. The presence of comorbid conditions that may adversely affect perioperative mortality or morbidity as well as long-term survival must also be considered before surgical referral. Advanced age and the presence of collateral disease do not represent absolute contraindications to thromboendarterectomy, although they do influence risk assessment. The one exception to this guideline is the presence of severe underlying obstructive or restrictive parenchymal lung disease. In this circumstance, thromboendarterectomy may result in hemodynamic improvement but often does not ameliorate the gas exchange consequences of the underlying parenchymal lung disease.

The only therapeutic alternative for patients not deemed to be candidates for thromboendarterectomy is lung transplantation. Preliminary results suggest that selected patients may benefit from chronic epoprostenol therapy.³⁰

The details of the surgical procedure itself are beyond the scope of this review but have been comprehensively reviewed elsewhere.²⁴ However, several features of the procedure should be emphasized. First, although a thoracotomy approach has been utilized in the past, the standard approach now involves median sternotomy, cardiopulmonary bypass, and periods of hypothermic circulatory arrest. A sternotomy approach provides access to the central pulmonary vessels of both lungs and avoids the potential for disruption of the extensive bronchial collateral circulation and pulmonary adhesions that may develop following pulmonary artery obstruction. Second, the procedure is a true thromboendarterectomy and not an embolectomy. The neointima must be meticulously dissected away from the native intima, and considerable surgical experience with this procedure is required to identify the correct operative plane (Fig 3).

Figure 3. Specimen obtained at the time of pulmonary thromboendarterectomy. Note fibrotic appearance with extensions into multiple segmental-level pulmonary arteries.

In series of patients undergoing thromboendarterectomy since 1996, in-hospital mortality rates as high as 24% have been reported (Table 2).^18-29 In experienced, larger-volume programs with a programmatic commitment to the care of these patients, however, mortality rates of 4 to 7% are typical (Fig 4). The major causes of death, beyond those associated with other open-heart cardiac procedures, are reperfusion pulmonary edema and residual pulmonary hypertension.^18,31 For survivors, both the short-term and long-term hemodynamic outcomes are favorable. The pulmonary artery pressure and pulmonary vascular resistance are dramatically reduced and at times normalized. In published series, the mean reduction in pulmonary vascular resistance has approximated 70% and a pulmonary vascular resistance in the range of 200 to 350 dyne·s·cm^-5 can be achieved.^18-29 A corresponding improvement in right ventricular function determined by echocardiography, gas exchange, exercise capacity, and quality of life has also been reported.^32-35 Most patients initially in New York Heart Association functional Class III or IV before surgery return to Class I or II postoperatively and are able to resume normal activities.

Figure 4. Number of surgically treated cases and deaths in 1,389 patients undergoing thromboendarterectomy at University of California, San Diego Medical Center between 1986 and 2001.

Lifelong anticoagulant therapy is strongly recommended after thromboendarterectomy. A number of patients in whom anticoagulation was discontinued or maintained at a subtherapeutic level experienced recurrent thromboembolism, and several of them required a second thromboendarterectomy.

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