Peter F. Fedullo and William R. Auger
Chronic thromboembolic pulmonary hypertension (CTEPH) represents an aberrant outcome that occurs in a minority of patients following an acute or recurrent episode of pulmonary embolism (PE). Estimates of disease prevalence vary and range from 0.6% to 3.8%. In the largest published study, a cohort screening study involving 866 survivors of acute PE, 4 patients (0.6%) were ultimately diagnosed with CTEPH.
The pathophysiologic events leading to CTEPH are not entirely understood. Although anatomic resolution of acute embolism is often incomplete, sufficient resolution occurs in the majority of patients to restore normal hemodynamics and functional status. Incomplete thrombus resolution and hemodynamic recovery following an acute thromboembolic event, even with appropriate antithrombotic therapy, can occur in some patients. It is also apparent that many patients with CTEPH have had an asymptomatic or misdiagnosed thromboembolic event. Because appropriate antithrombotic therapy was not initiated at the time of the initial embolic event, it is possible that endogenous fibrinolytic mechanisms were overcome by the age, extent, or location of the obstructing embolus.
Despite extensive investigation, identifying a thrombophilic tendency or a defect in fibrinolytic activity has been elusive in most patients with established chronic thromboembolic disease. The presence of a lupus anticoagulant or anticardiolipin antibodies can be established in 10% to 24% of CTEPH patients. The frequency of protein S or C deficiency, factor V Leiden mutation, and the prothrombin 20210G mutation have not consistently been found to be more common in CTEPH than in the general population. In terms of medical conditions, CTEPH has been associated with myeloproliferative syndromes as well as chronic inflammatory states, chronic ventriculoatrial shunts, splenectomy, recurrent episodes of venous thromboembolism, and chronic indwelling central venous catheters.
The diagnosis of CTEPH usually is not made until the degree of pulmonary hypertension is advanced. As a result, the exact hemodynamic evolution of the disease has not been established. The symptomatic history has been well described. A patient may carry on relatively normal activities following a pulmonary embolic event, whether clinically apparent or occult, and even when extensive pulmonary vascular occlusion has occurred. Following an asymptomatic period, which may range from months to years, exertional dyspnea worsens and hypoxemia and right ventricular failure ensue. The basis for this asymptomatic (“honeymoon”) period followed by gradual hemodynamic and symptomatic decline has only recently been elucidated.
The progressive nature of the pulmonary hypertension in the majority of patients with chronic thromboembolic disease does not appear to be the result of recurrent embolic events or in situ thrombosis, as initially postulated. The increase in pulmonary artery pressures arises from two different sources: a decrease in the cross-sectional area of the pulmonary vascular bed associated with the unresolved thromboembolic component of the disease, and the development over time of a distal, small-vessel arteriopathy pathologically indistinct from that seen in a wide range of pulmonary hypertensive disorders. It appears that these secondary pulmonary hypertensive changes, perhaps induced by high pulmonary artery pressures or flows, result in an incremental increase in right ventricular afterload, progressive pulmonary hypertension, and, ultimately, right ventricular failure.
Progressive dyspnea is a complaint common to all patients with CTEPH. The subjective complaint of dyspnea must be considered in the context of the patient’s usual lifestyle. The sensation of dyspnea and development of exercise intolerance are more troubling and lead to earlier evaluation in patients who are normally active than in those who live a sedentary lifestyle. Later in the course of the disease, exertional chest pain, near-syncope or syncope, and lower extremity edema may develop.
Although a history of documented thromboembolism may be absent, many patients provide a history consistent with an acute embolic event such as an episode of “pleurisy,” lower extremity “muscle strain,” or prolonged, atypical “pneumonia.” Alternatively, they may describe a hospitalization or surgical procedure from which they never fully recovered.
Diagnostic delay occurs commonly, particularly in the absence of an acute history of venous thromboembolism. Progressive dyspnea and exercise intolerance from CTEPH are often erroneously attributed to coronary artery disease, cardiomyopathy, interstitial lung disease, asthma, deconditioning, or psychogenic dyspnea.
The nonspecific and often subtle clinical presentation of CTEPH especially early in the course of the disease demands that a high level of suspicion be maintained in patients presenting with unexplained dyspnea. Careful consideration should be given to prior medical conditions and the circumstances surrounding the onset of dyspnea and/or exercise intolerance. In retrospect, patients without a documented history of venous thromboembolism often provide a history consistent with that diagnosis, such as an episode of pneumonia or an operative procedure with persistent symptoms and functional impairment. Findings on physical examination may be subtle early in the course, thereby contributing to the diagnostic delay. Prior to the development of significant right ventricular hypertrophy or overt right ventricular failure, abnormalities can be limited to a widening of the second heart sound or a subtle accentuation of its pulmonic component. In time, more obvious findings of pulmonary hypertension and right ventricular dysfunction develop, which may include a right ventricular heave, jugular venous distension, prominent A and V wave venous pulsation, fixed splitting of S2, a right ventricular S4 or S3, a murmur of tricuspid regurgitation, hepatomegaly, ascites, and peripheral edema. A distinctive physical finding in certain patients with chronic thromboembolic disease is the presence of flow murmurs over the lung fields. These subtle bruits, which appear to originate from turbulent flow through partially obstructed or recanalized pulmonary arteries, are high pitched and blowing in quality, heard over the lung fields rather than the precordium, accentuated during inspiration, and frequently heard only during periods of breath-holding. Their importance lies in their not having been described in primary pulmonary hypertension, which is the most common alternative diagnostic possibility. The flow murmurs, however, are not unique to chronic thromboembolic disease and may be encountered in congenital stenotic lesions of the pulmonary vasculature, and in major-vessel pulmonary vasculitides.
The diagnostic approach is relatively straightforward once an abnormality of the pulmonary vascular bed has been considered as a basis for the patient’s complaints. The goals of diagnostic evaluation are: (1) to establish the presence and degree of pulmonary hypertension; (2) to define its etiology; and (3) to determine if major vessel thromboembolic disease is present and accessible to surgical intervention. Findings on standard laboratory tests are nonspecific, depending on when in the natural history of the disease they are obtained, and reflect the hemodynamic and gas exchange consequences of the thromboembolic obstruction and the accompanying cardiac dysfunction. The chest radiograph is often normal, although it may demonstrate one or more of the following findings that suggest the diagnosis: (1) enlargement of both main pulmonary arteries or asymmetry in the size of the central pulmonary arteries, (2) areas of hypoperfusion or hyperperfusion, (3) evidence of old pleural disease, unilaterally or bilaterally, or (4) evidence of right ventricular hypertrophy. Pulmonary function testing is often within normal limits, although approximately 20% of patients demonstrate a mild-to-moderate restrictive abnormality. The majority of patients have a reduction in the single breath diffusing capacity for carbon monoxide (DLCO); however, a normal value does not exclude the diagnosis. When a spirometric abnormality is present (reflecting either restrictive or obstructive disease), the degree of the abnormality is almost always less impressive than the patient’s gas exchange abnormalities, symptomatic complaints, and degree of pulmonary hypertension. Although the arterial Po2 may be within normal limits, the alveolar–arterial oxygen gradient is typically widened, and the majority of patients have a decline in arterial Po2 with exercise. Dead space ventilation (Vd/Vt) is often elevated at rest and increases with exercise.
Echocardiography commonly provides the initial objective evidence for pulmonary hypertension. Findings include evidence of right atrial and right ventricular enlargement, abnormal septal position and motion related to the right ventricular pressure and volume overload, and evidence of pulmonary hypertension as determined from the tricuspid regurgitant jet.
Ventilation–perfusion lung scanning provides an excellent noninvasive means of distinguishing between potentially operable major-vessel thromboembolic pulmonary hypertension and small-vessel pulmonary hypertension. In chronic thromboembolic disease, at least one (and, more commonly, several) segmental or larger mismatched ventilation–perfusion defects are present. In primary pulmonary hypertension, perfusion scans are either normal or exhibit a “mottled” appearance characterized by subsegmental defects. However, it is important to recognize that the ventilation–perfusion scan often understates the actual extent of central pulmonary vascular obstruction. Channels through or partial flow around partially recanalized or organized central obstructing lesions allow the radioisotopic agent to reach the periphery of the lung. Depending on the distribution of flow, these areas may appear normal or as relatively hypoperfused “grey zones.” Ventilation–perfusion scanning, therefore, is capable of suggesting the potential presence of chronic thromboembolic obstruction, but it is unable to determine the magnitude, location, or proximal extent of the disease, information critical to the question of surgical accessibility.
Right-heart catheterization and pulmonary angiography are essential to determine the degree of pulmonary hypertension, to exclude competing diagnoses, and to define the surgical accessibility of the obstructing thrombotic lesions. If hemodynamic measurements at rest demonstrate only modest degrees of pulmonary hypertension, measurements should be obtained following a short period of exercise. In patients with chronic thromboembolic obstruction sufficient to abolish normal compensatory mechanisms, exercise-related increases in cardiac output will be accompanied by an excessive elevation in pulmonary artery pressure.
Five distinct angiographic patterns different from those encountered in acute embolism have been described that correlate with the finding of organized thromboembolic material at the time of thromboendarterectomy: (1) defects with a pouch configuration, (2) pulmonary artery webs or bands, (3) intimal irregularities, (4) abrupt narrowing of the major pulmonary arteries, and (5) obstruction of lobar or segmental vessels at their point of origin, with complete absence of blood flow to pulmonary segments normally perfused by those vessels. In experienced hands, pulmonary angiography can be performed safely, even in patients with severe pulmonary hypertension. The use of nonionic contrast media, provision of supplemental oxygen to avoid hypoxemia, and minimizing contrast volume with separate proximal pulmonary artery injections (i.e., avoiding right ventricular injections) are some of the technical safeguards necessary to prevent adverse outcomes in the evaluation of this patient population.
Computed tomography (CT) can be useful in the evaluation of competing diagnostic possibilities, such as pulmonary artery sarcoma, fibrosing mediastinitis, and extrinsic vascular compression related to malignancies or inflammatory disease. Large vessel pulmonary arteritis can also mimic certain of the angiographic findings of chronic thromboembolic disease. Arch aortography may be useful if this diagnosis is being considered.
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