Chronic thromboembolic pulmonary hypertension (CTEPH) is a common condition that is severely under diagnosed. The disease is caused by chronic obstruction of the pulmonary vasculature as a result of longstanding pulmonary thromboembolism. Once the diagnosis is made, there is only one curative option: surgical removal. Medical therapy remains palliative at best, and lung transplantation for this condition is outdated. Pulmonary endarterectomy (PEA) is a curative procedure for the treatment of CTEPH with excellent short- and long-term outcomes, but unfortunately it remains an uncommonly performed operation.

Acute pulmonary embolism (PE) is one of the more common cardiovascular diseases affecting Americans. Despite clinical and statistical evidence of progression of the disease in survivors, the majority of patients continue to be misdiagnosed. Perhaps one contributing issue is the fact that there are no specific signs and symptoms associated with this condition. Furthermore, most patients do not have a definitive history of deep vein thrombosis (DVT) or acute PE. The vague nature of symptoms, including dyspnea on exertion and occasional angina-like chest pains, coupled with lack of awareness among common practitioners, makes the diagnosis quite difficult; unfortunately these patients often progress to severe degrees of pulmonary hypertension and right heart failure before a diagnosis is established and treatment strategy is sought.

The precise incidence of PE remains unknown, but there are some legitimate estimates. It is estimated that acute PE occurs in about 1 person out of 1000,^1,2 which puts the annual incidence of acute PE at about 300,000 in the United States alone. The majority of patients with acute PE will resolve their clots with conventional treatments. However, it is estimated that about 3.8 percent of affected patients will go on to develop chronic pulmonary hypertension by 2 years.¹ This is, however, a low estimate, since in 70 to 80 percent of patients where the primary cause of death was PE, a premortem diagnosis was unsuspected.^3,4 The disease is particularly common in hospitalized elderly patients. Of hospitalized patients who develop PE, 12 to 21 percent die in the hospital, and another 24 to 39 percent die within 12 months.^5–7 Another unrecognized subgroup of patients comprises those with intracardiac catheters, shunts, or leads. The true incidence of chronic thromboembolic disease in these patients is unknown, but clearly these devices carry an inherent risk which is usually overlooked by the implanting physicians.

The mainstay of treatment of patients with DVT and acute PE is medical management. There are few indications for surgical intervention in the acute setting and they are specific to patients who have suffered a massive embolus that causes life-threatening acute right heart failure and severe hemodynamic compromise. The presence of large embolic material in the right atrium or right ventricle evidenced by echocardiography in the setting of severe right heart failure and hemodynamic compromise is another instance where surgery would be indicated. These indications are, however, few and far between. In contrast, in the chronic form of this disease, the only treatment is the surgical removal of the thromboembolic material with PEA. The role of medical therapy in these patients remains unclear and may be limited to patients with residual pulmonary hypertension after endarterectomy. For the most part, medical management is only palliative and does not address the obstructive nature of this disease. The only other potential surgical cure is transplantation. However, lung or heart–lung transplantation as a surgical cure for this condition is an outdated form of therapy and should be considered an inappropriate use of resources that yields less than satisfactory results.

The prognosis for patients with pulmonary hypertension is poor, and it is worse for those who do not have intracardiac shunts. Thus, patients with primary pulmonary hypertension and those with pulmonary hypertension secondary to PE fall into a higher risk category than those with Eisenmenger syndrome, and have a higher mortality rate. In fact, once the mean pulmonary arterial pressure in patients with thromboembolic disease reaches 50 mm Hg or more, the 3-year mortality approaches 90 percent.

Regardless of the exact incidence or the circumstances, it is clear that acute embolism and its chronic relation, fixed chronic thromboembolic occlusive disease, are both much more common than generally appreciated and are significantly under diagnosed. Calculations extrapolated from mortality rates and the random incidence of major thrombotic occlusion found at autopsy would support a postulate that more than 100,000 people in the United States currently have pulmonary hypertension that could be relieved by operation. The procedure appears to be permanently curative, but fewer than 200 of these are performed annually; most of them at the authors’ center, the University of California, San Diego (UCSD). This chapter provides an overview of the pathophysiology of this disease and outlines the surgical management as it is performed at UCSD.

In 1856 Rudolf Virchow made the association between DVT and PE and suggested that the causes of DVT were related to venous stasis, vein wall injury, and hypercoagulopathy. This triad of etiologic factors remains relevant today and is supported by an ever-growing body of evidence. Although a majority of individuals with chronic pulmonary thromboembolic disease are unaware of a precedent thromboembolic event and give no history of DVT, the foundation of most cases of unresolved PE is based on acute embolic episodes. Why some patients have unresolved emboli is not certain, but a variety of factors must play a role, alone or in combination.

In some cases, the volume of acute embolic material may overwhelm the lytic mechanisms. In other cases, total occlusion of a major arterial branch may prevent lytic material from reaching, and therefore dissolving, the embolus completely. Recurring emboli may not be able to be resolved. The embolic material may be made of substances that cannot be resolved by normal mechanisms (already well-organized fibrous thrombus, fat, or tumor). In some patients, the lytic mechanisms themselves may be abnormal, and other patients may have a propensity for thrombus formation or a hypercoagulable state.

Synchronized preservation of the fluidity of blood and the integrity of the vascular system entails a balance between blood pro- and anticoagulants. Some patients have deficiencies in natural anticoagulants. Three uncommon familial deficiencies associated with venous thrombosis are deficiencies in antithrombin, protein C, and protein S. Antithrombin is a natural plasma protease that inhibits thrombin after it is formed and, to a lesser extent, before it is formed. Antithrombin is also the cofactor that is accelerated 1000-fold by heparin. Protein C is a potent inhibitor of factor V and platelet-bound factor VII and requires protein S as a cofactor for anticoagulant activity. Both protein C and S are vitamin K–dependent zymogens that are activated by thrombin and accelerated by thrombomodulin produced by endothelial cells.

A much more common coagulation deficiency that results from a mutation of factor V (factor V Leiden) that prevents its degradation by protein C has been described and is present in approximately 6 to 7 percent of study populations of Swedish and North American males.^8–11 Both the homozygous and heterozygous mutants are strongly associated with venous thrombosis and PE but are not associated with stroke, myocardial infarction, and other manifestations of arterial thrombosis.^11,12

The presence of the lupus anticoagulant, which is an acquired immunoglobulin G (IgG) or IgM antibody against prothrombinase, increases the likelihood of venous thrombosis.¹² The disease may be associated with lupus-like syndromes, immunosuppression, or the intake of specific drugs, such as procainamide.

In most cases, regardless of the etiology of the embolus, after the clot becomes wedged in the pulmonary artery, one of two processes occurs¹³: (1) organization of the clot proceeding to canalization, producing multiple small endothelialized channels separated by fibrous septa (i.e., bands and webs) or (2) complete fibrous organization of the fibrin clot, leading to a solid mass of dense fibrous connective tissue totally obstructing the arterial lumen.

In addition to the usual pattern of venous thrombosis and subsequent embolization, usually from the legs or pelvis, there are other special circumstances that may lead to PEs. Chronic indwelling central venous catheters and pacemaker leads sometimes are associated with PEs. Rare causes include tumor emboli, and tumor fragments from stomach, breast, and kidney malignancies, which have been demonstrated to cause chronic pulmonary arterial occlusion. Right atrial myxomas may also fragment and embolize.

In addition to the embolic material, a propensity for thrombosis or a hypercoaguable state may result in spontaneous thrombosis within the pulmonary vascular bed, or encourage proximal propagation of thrombus after an embolus. Whatever the predisposing factors to residual thrombus within the vessels, the final genesis of the resultant pulmonary vascular hypertension may be complex. With the passage of time, the increased pressure and flow as a result of redirected pulmonary blood flow in the previously normal pulmonary vascular bed can create a vasculopathy in the small precapillary blood vessels similar to that seen with Eisenmenger syndrome.

Factors other than the simple hemodynamic consequences of redirected blood flow are probably also involved in this process. For example, after a pneumonectomy, 100 percent of the right ventricular output flows to one lung, yet little increase in pulmonary pressure occurs, even with follow-up to 11 years.¹⁴ In patients with thromboembolic disease, however, one frequently detects pulmonary hypertension even when less than 50 percent of the vascular bed is occluded by thrombus. It thus appears that sympathetic neural connections, hormonal changes, or both might initiate pulmonary hypertension in the initially unaffected pulmonary vascular bed. This process can occur when the initial occlusion is in the same lung or the contralateral lung.

Regardless of the etiology, the advancement of pulmonary hypertension as a consequence of changes in the previously unobstructed bed is serious, since this process may lead to an inoperable condition. Thus, with accumulating experience in patients with thromboembolic pulmonary hypertension, the authors increasingly have been inclined toward early operation so as to avoid these changes.

CTEPH is severely underdiagnosed because there are no specific clinical features. Although the majority of pulmonary thromboembolic material originates from a DVT, more than half of the patients with CTEPH do not have a history of DVT or PE. The clinical history may therefore not be helpful, making the diagnosis even more difficult. Nevertheless, during clinical evaluation, predisposing factors for DVT should be sought, as should a history of leg swelling, chest pain, hemoptysis, or any symptom to indicate episodes of PE.

The diagnosis in most patients may be quite difficult since the onset of the disease is insidious. The most frequent symptom coupled with thromboembolic pulmonary hypertension, as with all other sources of pulmonary hypertension, is exertional dyspnea. This dyspnea is out of proportion to any anomalies found on clinical examination. Similar to complaints of easy fatigability, dyspnea that initially occurs only with exertion is often attributed to anxiety or being “out of shape.” Syncope or presyncope (light-headedness during exertion) is another frequent symptom in pulmonary hypertension. Generally, it occurs in patients with more advanced disease and higher pulmonary arterial pressures.

Another relatively common complaint with CTEPH is nonspecific chest pain or chest pressure. These occur in approximately 50 percent of patients with more severe pulmonary hypertension. Hemoptysis can occur in all forms of pulmonary hypertension including CTEPH. It probably results from abnormally dilated vessels distended by increased intravascular pressures. Peripheral edema, early satiety, and epigastric or right upper quadrant fullness or discomfort may develop as the right heart fails (cor pulmonale). Some patients with CTEPH present after a small acute pulmonary embolus that may produce acute symptoms of right heart failure. A careful history brings out symptoms of dyspnea on minimal exertion, easy fatigability, diminishing activities, and episodes of angina-like pain or light- headedness. Further examination may reveal signs of pulmonary hypertension.

As is the case with symptoms, the physical signs of CTEPH are far from uniform. The physical examination may be surprisingly unrewarding if right heart failure has not occurred, even if the patient complains of severe dyspnea. Another challenge in diagnosis is that the physical signs of pulmonary hypertension are the same no matter what the underlying pathophysiology.

In the early stages, the jugular venous pulse is characterized by a large A wave. As the right heart fails, the V wave becomes predominant. The right ventricle is usually palpable near the lower left sternal border, and pulmonary valve closure may be audible in the second intercostal space. Occasional patients with advanced disease are hypoxic and slightly cyanotic. Cyanosis, if it is present at all, is usually peripheral and related to low cardiac output. Central cyanosis may be present from a persistent foramen ovale or atrial septal defect with right-to-left shunting. Clubbing is an uncommon finding.

Examination of the chest may be initially normal. Later, jugular venous distension with prominent A and V waves, as described above, may become evident. Auscultation of the chest may reveal some specific and nonspecific anomalies. The second heart sound is often narrowly split and varies normally with respiration; P2 is accentuated. A sharp systolic ejection click may be heard over the pulmonary artery. As the right heart fails, a right atrial gallop usually is present, and tricuspid insufficiency develops. Because of the large pressure gradient across the tricuspid valve in patients with pulmonary hypertension, the murmur is high pitched and may not exhibit respiratory variation. These findings are quite different from those usually observed in patients with tricuspid valvular disease. A murmur of pulmonic regurgitation may also be detected.

One specific sign is a flow murmur, which is heard especially over the back, beneath the scapula. Moser and colleagues¹⁵ pointed out that murmurs are often heard in patients with CTEPH. The murmur is portrayed as maximal over the lung fields, increasing in intensity with inspiration, and frequently spilling beyond the second sound.¹⁵ These murmurs probably result from turbulent flow past a segmental tapering, or it is also conceivable that they correspond to aggressive bronchial flow. An important observation is that these flow murmurs have not been described in patients with primary pulmonary hypertension, the major differential diagnosis for this condition.

Signs of chronic venous stasis may be present in the legs, with skin discoloration, and perhaps with healed varicosities or varicose ulcers. Peripheral edema is variable among patients and, if present, may be especially difficult to detect if the patient has chronic lower extremity venous stasis with or without ulceration.

Thus, the clinical signs and symptoms of CTEPH are not by any means specific and far from uniform. Suspicion for the diagnosis should be raised once the degree of symptomatology is out of proportion to the patient’s general condition. Once the suspicion is made, the clinician should then pursue key points in the patient’s past history and physical findings that may relate to this condition. The diagnosis, however, is only and finally confirmed with the aid of a broad variety of diagnostic modalities. Table 45-1 summarizes some of the patient characteristics at the authors’ center encompassing the last 12 years, from 1998 to 2010, amongst over 1500 patients.

To ensure the diagnosis in patients with CTEPH, a consistent evaluation is recommended for all patients who present with unexplained pulmonary hypertension. The non-specificity of the clinical presentation and symptoms contribute to the diagnostic delay that most patients with CTEPH experience. In the authors’ center it is common to see patients who have gone undiagnosed for several years, typically for 2 to 3 years.

The workup generally starts with a chest radiograph. Chest radiography may be deceptively normal in the early stages of CTEPH. However, with the development of significant pulmonary hypertension and right heart enlargement, some characteristic findings may tip the examiner toward the diagnosis. Central pulmonary arteries may be enlarged, and the right ventricle may also be enlarged without enlargement of the left atrium or ventricle, unlike mitral stenosis (Fig. 45-1). The chest radiograph may also show either apparent vessel cutoffs of the lobar or segmental pulmonary arteries, or regions of oligemia that suggest vascular occlusion. However, one should keep in mind that despite these classic findings, a large number of patients might present with a relatively normal chest radiograph, even in the setting of severe degrees of pulmonary hypertension. The electrocardiogram demonstrates findings of right ventricular hypertrophy (right axis deviation, dominant R wave in V₁).

Pulmonary function tests are necessary to exclude obstructive or restrictive intrinsic pulmonary parenchymal disease as the cause of the hypertension, but generally are not helpful. They reveal minimal changes in lung volume and ventilation; patients by and large have normal or slightly restricted pulmonary mechanics. Diffusing capacity of the lung for carbon monoxide (DLCO) often is reduced and may be the only abnormality on pulmonary function testing.

Most of these patients are hypoxic; room air arterial oxygen tension ranges between 50 and 83 torr, the average being 65 torr.¹⁶ CO₂ tension is slightly reduced and is compensated by reduced bicarbonate. Dead space ventilation is increased. Ventilation–perfusion studies show a moderate mismatch with some heterogeneity among various respirator units within the lung and correlate poorly with the degree of pulmonary obstruction.¹⁷

The ventilation–perfusion lung scan is the essential test for establishing the diagnosis of unresolved pulmonary thromboembolism. An entirely normal lung scan excludes the diagnosis of both acute or chronic, unresolved thromboembolism. Patients with CTEPH invariably demonstrate one or more segmental or larger perfusion defects in lung regions that typically have normal ventilation (Fig. 45-2). The usual lung scan pattern in most patients with pulmonary hypertension either is relatively normal or shows diffuse non-uniform perfusion.^18–20 The magnitude of perfusion defects in chronic thromboembolic disease often underestimates the actual degree of vascular obstruction. When subsegmental or larger perfusion defects are noted on the scan, even when they are matched with ventilatory defects, pulmonary angiography is appropriate to confirm or rule out thromboembolic disease.

Right-heart catheterization and pulmonary angiography should be pursued in any patient with suspected chronic thromboembolic disease. Despite advances in computed tomography (CT) and the increasing reliance upon this imaging modality in the evaluation of the pulmonary vascular bed, its role in this population remains somewhat undefined, and pulmonary angiography should still be considered the gold standard in establishing the diagnosis of CTEPH. Organized thromboembolic lesions do not have the appearance of the intravascular filling defects seen with acute pulmonary emboli, and experience is essential for the proper interpretation of pulmonary angiograms in patients with unresolved, chronic embolic disease. Organized thrombi appear as unusual filling defects, webs, or bands, or completely thrombosed vessels that may resemble congenital absence of the vessel (Fig. 45-3).²⁰ Organized material along a vascular wall of a recanalized vessel produces a scalloped or serrated luminal edge. Because of both vessel-wall thickening and dilatation of proximal vessels, the contrast-filled lumen may appear relatively normal in diameter. Distal vessels demonstrate the rapid tapering and pruning characteristic of pulmonary hypertension (Fig. 45-3).