Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary arterial hypertension (PAH) resulting from the fibrotic transformation of pulmonary artery clots causing chronic obstruction of the pulmonary arteries, leading to vascular remodeling in the microvasculature. Consequently, pulmonary arterial pressure and vascular resistance increase, leading inexorably to right heart failure, functional impairment and premature death.

Not all patients with CTEPH report a history of acute pulmonary embolism (PE); the incidence of CTEPH after PE is around 1.5% and registry data indicate a prevalence of 3-30 per million in the general population.1 However, most CTEPH patients present with a previous PE. The International CTEPH Registry reports a previous acute PE event in 74.8% of CTEPH patients, and the cumulative incidence is reported to be 0.1-9.1% within two years of any symptomatic pulmonary embolic event.

Although the exact prevalence and annual incidence of CTEPH are unknown, some data suggest that the condition may occur in approximately five per million population per year. Its prevalence in European countries is 3.2 cases per million per year, and is 0.9 cases per million in Spain,2 which, due to similarities in the populations of the two countries, means that a reasonable estimate for Portugal would be nine new cases yearly.

The true incidence and prevalence of CTEPH in the Portuguese population are unknown, although according to Gouveia et al.3 the estimated incidence of acute pulmonary embolism in Portugal in 2013 was 35 per 100 000 population. In a nationwide study by Baptista et al.,4 after excluding patients in World Health Organization (WHO) PAH groups 2, 3 and 5, CTEPH patients comprised 41.8% of all those with PAH. This study, based on a small number of patients followed at dedicated PAH centers, remains the sole nationwide data available for CTEPH.

Predisposing factors such as thrombophilic disorders, lupus anticoagulant and antiphospholipid antibody syndromes, protein S and C deficiency, activated protein C resistance including factor V Leiden mutation, thrombotic gene mutations, antithrombin III deficiency and elevated factor VIII have been reported in 31.9% of patients and previous splenectomy in 3.4%.2

A diagnosis of CTEPH is based on findings obtained after at least three months of effective anticoagulation, in order to differentiate this condition from subacute forms of PE.2

The clinical criteria for diagnosis according to the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines were mean pulmonary artery pressure (mPAP) ≥25 mmHg (revised in 2018 to ≥20 mmHg), pulmonary artery wedge pressure ≤15 mmHg, and specific diagnostic signs for CTEPH on imaging studies. These include mismatched perfusion defects on lung scan (a normal V/Q scan effectively excludes CTEPH with a sensitivity of 90-100% and specificity of 94-100%), and ring-like stenoses, webs/slits and chronic total occlusions (pouch lesions or tapered lesions).2 Imaging studies – multidetector computed tomography (CT) angiography, magnetic resonance imaging (MRI), or conventional pulmonary cineangiography – are essential for diagnosis and lesion characterization and to guide surgical intervention. At least two imaging methods are recommended; elective pulmonary cineangiography can be replaced by MRI or CT scan.

In addition to imaging studies, patients should undergo right heart catheterization, an echocardiogram, and cardiorespiratory functional testing such as the 6-min walk test or treadmill exercise testing.6,7

Pulmonary thromboendarterectomy (PTE) is the treatment of choice for patients with CTEPH, both for symptomatic relief and for improvement or normalization of pulmonary hemodynamics.

There is general agreement in the literature that PTE should be offered to every operable patient with CTEPH if the risk is acceptable, since this provides survival benefit.

According to the guidelines, operability is determined by multiple factors that are not easily standardized. Certain features such as the degree of pulmonary vascular resistance (PVR) and location of thrombotic lesions are strongly related to outcomes.8,9

To be considered operable, a patient must have sufficient surgically accessible thromboembolic material, and more importantly, a good correlation between the extent of disease and the degree of PVR. Extensive secondary peripheral vasculopathy should be excluded.1,6,9

Patients of advanced age, frail or in poor general condition, or with serious comorbidities, are generally deemed to be inoperable due to their overall surgical risk. Operability is best established based on a case-by-case analysis, and borderline cases will certainly need a second opinion.

Although registry data suggest that in the past more than one third of patients diagnosed with CTEPH did not proceed to PTE surgery, PTE should be offered to the majority of patients.1,6,9,10

Although PTE is the treatment of choice for CTEPH, it is still not widely available to the Portuguese population, with only a small number of patients being referred to international centers, at considerable personal and societal cost.11

Since 2008, the cardiothoracic surgery department of Hospital de Santa Marta in Lisbon has been operating a PTE program, providing surgical treatment to Portuguese patients with CTEPH. The department provides the full range of services needed to perform and support this type of surgery, including cardiothoracic surgery, structural cardiology, cardiac and thoracic anesthesiology, extracorporeal membrane oxygenation (ECMO) and lung transplantation programs. We hereby present the initial experience with this ongoing program.

We retrospectively analyzed data from all patients who underwent PTE at our center. These patients were referred by our local PAH team, as well as by other expert PAH teams in the country.

All patients were diagnosed and assessed according to the ESC/ERS guidelines, at least two imaging tests (CT scan and pulmonary angiography) being required to determine the diagnosis and establish operability.

Baseline patient characteristics are described in Table 1.

All patients were operated electively, by the same surgical team, following the same standard perioperative protocol.

All procedures were performed with aortic and double venous cannulation, right superior pulmonary vein and main pulmonary artery venting, single-shot cold blood cardioplegia and standard circulatory arrest periods of 20 min at 18°C nasopharyngeal temperature. If circulatory arrest periods longer than 20 min were needed, 10-min reperfusion periods were mandatory between arrest periods.

Standard modified ultrafiltration and cerebral protection measures were routinely used.

The central pulmonary arteries were mobilized up to the hilum, taking care not to open the pleurae, then, under periods of complete hypothermic circulatory arrest and total exsanguination, pulmonary endarterectomies were carried out sequentially, first on the right, then on the left side.

The critical step is the development of the correct dissection plane, followed by meticulous circumferential dissection, extending distally to the segmental and subsegmental branches. This enables the removal of full casts and webs, leading to effective relief of obstruction (Figures 1-3).

Figure 1.

Typical surgical specimen of molded casts.

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Figure 2.

Surgical specimen of predominant webs.

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Figure 3.

Surgical specimen from patient 3. Note the large quantity of clot casts and webs removed, which, together with the reduction in pulmonary artery pressure confirmed immediately after surgery, led us to expect a good outcome. However, the patient did not survive.

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After direct closure of the pulmonary arteriotomies with 5-0 nylon sutures, patients are fully rewarmed and weaned off cardiopulmonary bypass. Inotropic support is used according to our protocol, typically in low to moderate dosages. Meticulous hemostasis is achieved.

Only the first patient (in 2008) underwent tricuspid annuloplasty; none of the other patients had their functional tricuspid regurgitation addressed at surgery, since recovery is expected after removing right ventricular afterload, as stated in the literature.12

Operative specimens are systematically documented (Figures 1-3).

Mean surgical times are displayed in Table 2 and some operative specimens are shown in Figures 1 and 2.

Postoperative care is conducted according to published protocols, paying particular attention to prevention and management of reperfusion edema.

Inotropic support use was determined by hemodynamic and echocardiographic monitoring. Low-dose dobutamine and noradrenaline are most frequently used, other inotropes or vasodilators being added according to clinical circumstances.

Negative fluid balance (by fluid restriction and intravenous furosemide) is crucial in the management of these patients, as is early adequate anticoagulation. Anticoagulant therapy consists of low molecular weight heparin (1 mg/kg, twice daily), started as early as possible (ideally in the first 24 hours if surgical bleeding is <50 cc/h), and switched over to oral anticoagulation with vitamin K antagonists, until therapeutic international normalized ratio levels (around 3) are achieved.

Postoperative data are summarized in Table 3.

This paper presents data on the initial experience with PTE performed at a single center in Portugal.

Results achieved so far by our center show acceptable survival and complication rates, well within the expected range, given the level of our present experience.

The importance of a comprehensive multidisciplinary approach cannot be overestimated. Such an approach has undoubtedly helped to smooth the effects of the learning curve, keeping patients safe and within expected functional outcomes.

As for any complex surgical procedure, PTE requires high surgical volumes and accumulation of experience in order to achieve reproducible results and clinical excellence, as stated in the updated recommendations from the 2018 Cologne Consensus Conference.13 In-hospital fatalities correlate inversely with the number of cases performed yearly. Specialized centers (those performing over 50 PTE procedures/year) show case fatality rates of ≤3.5%. For centers performing between 11 and 50 PTE procedures/year, mortality averages 4.7%, and for centers that perform fewer than 11 PTE/year it averages 7.4%. Our center is presently in the latter group.

The recommended minimum number of PTE procedures to be performed annually is 20; an expert center should perform at least 20 PTE operations per year with less than 10% mortality.6 Also in line with these recommendations, an experienced surgeon is defined as one who performed over 20 PTEs in the year they were first assessed, and cumulatively over 40 procedures in the previous three years.6,10

For Portugal, a yearly case load of 20 PTEs could easily be achieved, allowing for reproducible results and making Hospital de Santa Marta an expert center.

We believe that by increasing referrals, we are now building up a solid experience with PTE. Nevertheless, we might still occasionally have to refer more complex and challenging cases for surgery abroad, particularly those with severe associated comorbidities or more severe peripheral disease, in order to provide patients with the best possible treatment.

The recognition of our center as a national reference center for adult PAH and PTE, following a nationwide open contest, would enable us, in close collaboration with every PAH unit in Portugal, to build up a robust national PTE center. Only by increasing the PTE case load and closely monitoring our results and auditing our data in a transparent way will this aim be achieved.

This is a brief report of an initial series of PTE procedures, performed at a single center. The numbers are still small, but results are encouraging, reflecting a rapidly rising learning curve, without undue complications or mortality.

Complication rates are consistent with those published in the literature, including transient pulmonary dysfunction, which occurred in less than half of cases.

Long-term outcomes showed a consistent improvement in NYHA class and hemodynamic parameters, with all patients in NYHA class I or II.

Late mortality occurred in a few patients, due to a combination of pre-existing clinical severity and residual, though moderate, pulmonary hypertension.

Present numbers are still too small for any meaningful long-term survival analysis.

We conclude that, with a multidisciplinary team, it is possible to start a local program for PTE and to manage the learning curve, with reproducible results.

Undoubtedly, more patients will be needed to further improve results, but we feel our initial findings are encouraging.

José Fragata: Surgeon performing the cases, critical revision and final approval of the version to be submitted.

Helena Telles: acquisition, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content.

The authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

The authors have no conflicts of interest to declare.