Diagnostics and therapy of CTEPH

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subtype of pulmonary hypertension (PH). The diagnosis is overall very rare, although CTEPH is also often unrecognized and thus underdiagnosed, and therefore the underreporting rate is probably higher.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subtype of pulmonary hypertension (PH), class 4 according to the ESC/ERC classification [1]. The diagnosis of CTEPH can be made when precapillary symptomatic PH (mPAP minimum 20-25 mmHg and pulmonary capillary occlusion pressure ≤15 mmHg) combined with perfusion disturbances in the lungs are present after a minimum of 3 months of reliable anticoagulation [2] for differentiation to acute pulmonary embolism (LE). The diagnosis is very rare overall, although CTEPH is also often unrecognized and thus underdiagnosed, and thus the underreporting rate is probably higher.

In this article, the diagnosis and therapy of CTEPH are presented with the aim of making general practitioners and also specialized colleagues more aware of this disease, because there is curative therapy for these patients, quite the opposite of all other forms of PH.

Incidence, risk factors and pathogenesis

The annual incidence for CTEPH in the United States, Europe, and Japan is approximately 3 to 5 cases per 100 000 population [2]. The cumulative incidence for CTEPH in the first 2 years after acute LE ranks between 0.1-9.1% [2–10], a wide range; for Switzerland, even one study reported only 0.79% [11]. To make matters worse, more than 25% of newly diagnosed cases do not have a history of acute LE [12]. There are other known risk factors besides thromboembolic events, such as autoimmune and hematologic disorders [13], the presence of ventriculo-atrial shunt or infected pacing electrodes, a history of splenectomy, a non-0 blood group, the presence of lupus anticoagulant/antiphospholipid antibodies, thyroid hormone replacement therapy, and a history of tumor [14], which are also prognostically unfavorable.

The exact pathophysiology of CTEPH is complex, remains unclear, and multiple causative mechanisms are likely present, such as persistent organized thrombi and scarring in the proximal pulmonary arteries (main, lobe, and segmental) and/or microangiopathy [15]. Various processes have been associated with incomplete thrombus resolution [16]: inflammatory [17–19], genetic factors [20–22], abnormalities of fibrinolysis [23–27] and many others [28].

Clinical picture and case description

The clinical picture always includes exertional dyspnea, the leading symptom [29,30]. Other symptoms include fatigue in about 30% of cases, chest pain in 15%, an episode of syncope in about 14%, and hemoptysis in 5% [12,31,32]. These symptoms are all not uncommon, especially in older patients with additional comorbidities such as chronic obstructive pulmonary disease, deconditioning, and often associated obesity [33,34]. To make matters worse, approximately half of all patients with acute LE report persistent shortness of breath, even years after an event, thus termed “post-PE syndrome.” Despite this, these patients should be further diagnostically worked up to rule out CTEPH.

Clinical examination reveals progressive edema of the lower extremities and other signs of congestion (neck veins, liver enlargement) [33]. Furthermore, auscultation may reveal an accentuation of the pulmonary component of the second heart sound.

Diagnosis

Unfortunately, to date, there is no biomarker that clearly differentiates CTEPH from other forms of PH; some circulating inflammatory markers (for example, CRP, interleukins -6, -8, and -10) have been studied [17,18,35], but none of these tests has routine use to date. Signs of right ventricular strain can be seen on the ECG, such as right-type, (in)complete right bundle branch block or T-wave negativities in anterior leads V1-V4 (“right ventricular strain pattern”). On chest x-ray, there are only nonspecific signs of right heart strain with an enlarged right ventricle and atrium, for example.

In further diagnostics, transthoracic echocardiography (TTE) is usually used first, which is also listed in the consensus conference of 2016 as the first diagnostic measure in the diagnostic algorithm (Fig. 1). It also represents a good initial screening test in differentiation from post-PE syndrome. Pulmonary hypertension is defined in TTE by the expression of tricuspid regurgitation velocity [36], from which sPAP can be measured. On Doppler-derived measurement of regurgitation velocity (Vmax) across the tricuspid valve, the simplified Bernoulli equation (_{∆P=4×Vmax2}) is used to estimate the pressure gradient between the right ventricle and the right atrium. Right atrial pressure is usually approximated by inferior vena cava width and respiratory variability. Other signs include size and dilation of the right ventricle and atria, “D-shaping” of the septum, and tricuspid plane motion (“tricupsid annulat plane systlic excursion,” TAPSE). However, a normal echo does not rule out CTEPH.

The first imaging screening method is represented by ventilation/perfusion scintigraphy (Fig. 2), which, if normal (i.e., without “unmatched” perfusion deficits) one can exclude CTEPH with a sensitivity of 90-100% and a specificity of 94-100% [37,38]. New “dual-energy” techniques with a hybrid combination of SPECT and CT have the advantage of simultaneously imaging the lung parenchyma in addition to perfusion deficits [39,40], but are not available in every hospital.

Computed tomographic pulmonary angiography (CTPA) has many advantages in the diagnosis and also assessment of operability for CTEPH. In particular, it has sensitivity and specificity for detecting thromboembolic changes at the lobar level (97-100% and 95-100%, respectively), and somewhat lower at the more peripheral segmental level (86-100 and 93-99%, respectively) [33,41–43]. The classic signs are eccentric thrombi (Fig. 3 above), so-called “webs,” and occluding “pouch-lesions,” as well as prominent collaterals from the intercostal arteries, for example. These signs are all also evident on pulmonary angiography (Fig. 3 bottom), which also has the advantage of invasive PA pressure measurement. However, other differential diagnoses (DD) can be detected on CT, and one also detects signs of “mosaic perfusion” in the lung parenchyma as well as infarcts, if any. Another advantage is the representation of the accessibility of chronic thromboembolic changes in identifying how proximal a dissection layer presents and whether it is accessible for pulmonary endarterectomy. To interpret these, reconstructions in sagittal and also coronal planes are needed in addition to the axial slice, and the CT should have been run with a slice thickness of 1 mm. Magnetic resonance imaging (MRI) has not yet played a role in CTEPH diagnosis in a standardized application; however, the simultaneous assessment of right ventricular function is an advantage, and in the future, MRI is expected to play an increasing role for screening, but also for follow-up of CTEPH patients after surgery or other therapy, as appropriate.

Hemodynamic diagnostic confirmation of CTEPH is made by right heart catheterization: Mean pulmonary arterial pressure (mPAP) should be ≥20-25 mmgHg [1] and precapillary (“wedge pressure”/pulmonary capillary occlusion pressure ≤15 mmHg). The acquisition of cardiac output by thermodilution or the direct Fick method is a prerequisite for a correct calculation of pulmonary vascular resistance (PVR), an important factor regarding prognosis and surgical risk [44].

Spiroergometry represents another functional examination in the delineation of CTEPH: Here, the typical signs of ventilation-perfusion mismatch with increased respiratory equivalents at the anaerobic threshold, an increased alveo-arterial _pO2 gradient, positive _{capillary-end-tidal} CO2 gradient, exercise hypoxemia, and clearly decreased exercise capacity are evident [45–48].

It is particularly important that if CTEPH is suspected, the patient should be referred to a specialized center for further interdisciplinary diagnosis and therapy allocation.

The following is a classic case with the entire patient history:

A 50-year-old patient with multiple pulmonary emboli and history of thromboembolic events presents with NYHA III-IV shortness of breath. In the 6-minute walk test, the patient reached 270 meters at Borg 2 (Table 1).

Ventilation/perfusion scintigraphy showed bilateral “unmatched” perfusion defects (Fig. 2) . Transthoracic echocardiography showed elevated systolic pulmonary artery pressure (sPAP) and dilated right ventricle. CT shows central lesions (fig. 3 , top), which were removed to the periphery during pulmonary entarterectomy (fig. 4B) . Postoperatively, the patient recovered rapidly and had normal hemodynamics and NYHA 0 at the 1-year follow-up (Table 1).

Forecast

Once the diagnosis is made, treatment should be discussed immediately because, if left untreated, a mPAP of >50 mmgHg has a 2-year mortality of >80% and a mPAP of >30 mmgHg is associated with a 3-year mortality of 90% [49].

Since 2015, an interdisciplinary CTEPH program has been offered at the University Hospital Zurich (USZ), providing the entire treatment spectrum from surgery to angioplasty and drug therapy. Once or twice a month, a national CTEPH board is offered through the Swiss Pulmonary Hypertension Society for referring physicians to contact for case presentation and discussion (CTEPH@usz.ch, CTEPH@sgph.ch).

Therapy

Surgical therapy: according to current ERS/ESC guidelines, pulmonary endarterectomy (PEA) is recommended as first-line therapy in patients with surgically accessible CTEPH [1]. (Fig. 4A). In PEA, the pulmonary arteries are sequentially opened (always bilaterally) on the heart-lung machine and in deep hypothermia (20°C), and the chronic thromboembolic material is removed in 20-minute circulatory arrests; this is technically possible well into the periphery (Fig. 4B). In any case, the decision for surgery and patient selection should be made by an interdisciplinary team of specialists, consisting of PH specialists, radiologists, and PEA surgeons [50]. The determining factors for PEA are: the severity of symptoms, the extent of PH, the function of the right ventricle, the patient’s comorbidity profile, and surgically accessible material. This last point in particular is a challenging assessment because it is well known that imaging almost always underestimates the extent of chronic thromboembolic material. Patients with segmental and subsegmental disease can also benefit from PEA with excellent short- and long-term outcomes in experienced centers [51,52]. Recommendations made during the World Symposium on PH state that a “second opinion” should be obtained from a surgical CTEPH expert center when a patient has been deemed inoperable at a non-CTEPH center [50]. Also, severity of PH and limitation of right heart dysfunction are not contraindications per se for PEA and symptomatic patients should be offered surgical therapy [53]. Age is also not an absolute contraindication, as data show that patients >70 years benefit as much as younger patients [54]. However, mortality from the procedure is not entirely insignificant and is reported in the literature to be 2.4-13.2%, the latter being from earlier periods [55].

Successful surgery can significantly improve patients’ quality of life and expectancy (survival rates of >90% after 1 year >70%, after 6 to 10 years [31,55,56]): Dyspnea, 6-minute walk test, and increased oxygen uptake, improved respiratory equivalent for_CO2, and decreased need for oxygen were demonstrated [57,58]. Increased life expectancy has been reported in the medium to long term.

Pulmonary Balloon Angioplasty (BPA)

If surgery is not an option, interventional BPA can treat peripheral segmental or subsegmental chronic changes in multiple sessions. Convincing improvements in hemodynamics, 6-minute walk test, and NYHA/WHO class can be achieved. Currently, long-term data are still missing [59].

Drug therapy: patients with distal, nonsurgically accessible CTEPH and residual pulmonary hypertension after PEA can be treated with medication [50,60]. Drugs similar to those used in PAH are used [61–64]. Regardless of pressure-lowering therapy, which acts particularly on the distal component of CTEPH, every patient with CTEPH must be anticoagulated for life, regardless of other therapies. Therapeutic decisions should be made only after at least 3 months of OAC [1,65]. Currently, patients are still treated with vitamin K antagonists. Due to their comparable efficacy and good safety profile, NOAKs (new oral anticoagulants) are also increasingly used, especially also in cases of dose-finding problems and in cases where the INR (International Normalized Ratio) is often outside the target range of 2.5-3.5 [65,66].

Take-Home Messages

• Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as symptomatic pulmonary hypertension with persistent pulmonary perfusion defects despite adequate anticoagulation for at least 3 months.
• CTEPH patients should be referred to a specialized CTEPH center for confirmation of the diagnosis by right heart catheterization and subsequent therapy.
• The Swiss Pulmonary Hypertension Society offers a national CTEPH board for referring physicians to contact for case presentation and discussion (CTEPH@usz.ch, CTEPH@sgph.ch).
• Patients’ functional capacity, exercise tolerance, and even life expectancy can be increased by pulmonary endarterectomy. For this reason, a PEA should be evaluated in every case.
• Drug therapy and/or balloon angioplasty may help patients with unresectable CTEPH or postoperative residual pulmonary hypertension.
• CTEPH mandatorily requires lifelong oral anticoagulation.

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