Chronic thromboembolic disease (CTED) is characterized by persistent thrombosis in the pulmonary vascular bed but no resting pulmonary hypertension (PH) after 1 or more episodes of symptomatic pulmonary embolism (PE) and correct anticoagulation for at least 3 months. It has been speculated that the functional limitations associated with CTED might be due to pulmonary microvasculopathy capable of causing exercise PH with dyspnea on exertion.1,2 The incidence and natural history of CTED are unknown.3

Patients with dyspnea that persists after 1 or more episodes of PE are considered to have post-PE syndrome. The prevalence of this syndrome has been estimated at 60% in follow-up series of patients with a history of PE.4,5 Incomplete thrombus resolution has been observed in 23% to 50% of series; in asymptomatic patients, it is normally an incidental finding and does not per se indicate a diagnosis of CTED.6 Chronic thromboembolic pulmonary hypertension (CTEPH), in turn, has been detected in 2% to 3% of patients 2 years after acute symptomatic PE,5 but this does not mean that all patients with a history of PE should be systematically screened for CTEPH. Structured follow-up has helped characterize and identify patients potentially at risk of CTEPH, and has also contributed to the definition of new entities with possible prognostic implications, such as CTED.5,7 Exercise hemodynamics are a useful tool in this setting, as detection of PH during exercise might indicate incipient vascular disease or chronic thromboembolic occlusions in the pulmonary vascular bed.8 The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines define exercise PH as a mean pulmonary arterial pressure (mPAP)/cardiac output (CO) ratio of >3mmHg/L/min during exercise.9

Cardiopulmonary exercise testing (CPET) has become an important follow-up tool in the management of patients after PE.10,11 Ventilatory inefficiency, understood as an increasing need for ventilation to achieve effective gas exchange, is a hallmark of CTEPH (but not other forms of PH), and should raise alarms if detected during follow-up of PE.6,12

We hypothesize that functional limitations in patients with persistent thrombosis after PE can be explained by an impaired hemodynamic response to exercise that can be detected by exercise right heart catheterization (RHC) and predicted using noninvasive techniques such as CPET. The aim of our study was to analyze exercise-induced hemodynamic changes in a cohort of patients with dyspnea and persistent thrombosis after PE and to explore associations with CPET variables.

This is one of the largest cohorts to study the use of exercise RHC in the diagnostic evaluation of CTEPH. The main findings are a) 40.6% of patients with suspected CTEPH without PH at rest had an impaired hemodynamic response to exercise indicative of pulmonary vasculopathy, b) 88% of patients with mPAP of 20 to 25mmHg and PVR of 2 to 3 WU developed exercise PH, c) exercise RHC is a useful test for uncovering HFpEF as a cause of dyspnea, and d) ventilatory inefficiency during CPET is associated with exercise PH.

PE, with an incidence of 48 to 115 cases per 100 000 inhabitants, is the third leading cause of cardiovascular admissions, behind acute myocardial infarction and stroke.15 Structured follow-up of patients with a history of PE led to the formulation of a new concept known as post-PE syndrome, which covers different conditions ranging from asymptomatic persistent pulmonary thrombosis to CTEPH.4 The high proportion of patients with functional limitations or persistent dyspnea after acute PE, however, contrasts with the low incidence of CTEPH in prospective cohorts.5 CTEPH is characterized by vascular occlusions, which if left untreated, are associated with similar mortality to that of untreated group 1 PH.16 Concern about the magnitude of this problem among scientific societies is reflected in the creation of PE follow-up algorithms. The 2019 ESC guidelines, for example, recommend a multidisciplinary approach.17 Muscle weakness and cardiovascular comorbidities appear to play an important role in persistent dyspnea after PE, but they do not explain the functional limitations observed in other patients, largely, as in our study, young adults without comorbidities. Our cohort comprised middle-aged patients (49.4±13.7 years) with a deteriorated functional class or de novo dyspnea after PE who had persistent pulmonary artery thrombosis without PH at rest and no other causes of dyspnea. It has been speculated that residual thrombosis in CTED may lead to vascular dysfunction under stress conditions, manifested by an abnormal hemodynamic response, but it is unknown whether this a precursor to CTEPH.1,2,9

Exercise RHC produced 3 types of hemodynamic responses in our patients: a) precapillary exercise PH in 13 patients, b) postcapillary exercise PH in 3 patients, and c) a normal hemodynamic response in 16 patients. An abnormal precapillary response is indicative of vascular disease or residual thromboembolic material, that is, CTED. Compared with patients with a normal hemodynamic response to exercise, those with an abnormal precapillary response had higher mPAP at rest and a disproportionate increase in this variable during exercise, despite a similar increase in CO. Delcroix and colleagues, in a comprehensive cardiopulmonary assessment of patients with CTED and CTEPH, analyzed right ventricular volume changes using exercise cardiac magnetic resonance imaging and simultaneous invasive pressure measurements.18 The 14 patients with CTED had a similar profile to our cohort and their response to exercise was characterized by a disproportionate increase in afterload, reflected in a median mPAP/CO slope of 3.5 [2.2-4.4] mmHg/L/min. This response, in turn, was associated with an insufficient reduction in expected right ventricular end-systolic volume compared with a group of 13 healthy adults, indicating a reduction in right ventricular ejection fraction. These findings suggest that CTED represents an intermediate phenotype with respect to CTEPH, characterized by right ventricular dilation at rest and absence of contractile reserve, preventing an increase in output during exercise.

Surgical removal of thromboembolic material in symptomatic patients without PH at rest has been associated with clinical and hemodynamic benefits. Taboada et al.,19 the first authors to report on the use of thromboendarterectomy in patients with CTED, reported improved functional class in 95% of the 42 patients studied. Nonetheless, 40% of patients experienced complications, although there were no in-hospital deaths. Our group reported similar findings for patients with CTED without PH at rest who underwent the same procedure.20 Guth et al.21 showed that hemodynamic responses to exercise were restored to normal in a cohort of 12 patients with CTED who underwent pulmonary thromboendarterectomy (mean mPAP/CO ratio of 3.6±1.0mmHg/L/min before the intervention vs 2.3±0.8mmHg/l/min afterwards, P=.002). The patient profiles in the above series were similar: a mean age of 35 to 55 years, absence of comorbidities, surgically accessible proximal bilateral chronic thrombotic material, mPAP at rest of 20 to 25mmHg, and PVR of 1.8 to 3 WU. Pulmonary angioplasty for CTED has attracted interest due to its low complication rates and similar clinical outcomes to those observed with surgery.22,23 In line with the above findings, the 2002 ESC/ERS guidelines for the diagnosis and treatment of PH consider that pulmonary endarterectomy should be contemplated in selected patients with CTED in whom other causes of dyspnea have been ruled out (class IIa recommendation, level C evidence).9

CPET has gained popularity as an option for all groups of patients with PH in recent years, but its usefulness has traditionally been limited by the difficulty of establishing a threshold determining pathologic changes owing to variations in age, sex, and comorbidities across the studies.14 The recent ESC/ERS guidelines defined the criterion for exercise PH and reduced the thresholds for precapillary PH at rest to mPAP >20mmHg, PVR >2 WU, and PCWP ≤ 15mmHg.9 This new definition does not mean that patients exceeding these thresholds must necessarily be treated. The recommendation for patients with suspected CTED is to carefully rule out other potential causes of dyspnea by analyzing impaired responses to exercise (exercise PH) and checking for HFpEF. Our study sheds light on a group of patients previously considered to be in a gray zone and supports the recent guideline changes, as 8 of the patients studied met the new hemodynamic criterion for PH at rest. Within this group, all but 1 patient developed exercise PH. Of the 21 patients with normal resting hemodynamics (mPAP <20mmHg and PVR <2WU), 6 developed precapillary exercise PH. In our experience, thus, the current hemodynamic criterion identifies most patients who develop PH during exercise, although we also observed a subgroup of CTED patients with normal mPAP at rest but an abnormal hemodynamic response to exercise.

In our opinion, exercise RHC is a potentially useful tool for selecting which of the above patients could benefit from pulmonary endarterectomy. It is a safe diagnostic technique with similar complication rates to those observed for RHC without exercise.14 No complications occurred in our series. Furthermore, exercise RHC uncovered HFpEF as the origin of dyspnea on exertion in 3 patients, leading to reconsideration of the underlying cause based on the finding of a PCWP/CO ratio during exercise >2mmHg/L/ min, which in addition, had diagnostic and prognostic value.24 These considerations suggest that exercise RHC might be even more useful in the study of symptomatic patients with suspected CTED without PH at rest, as 9% of the patients in our series had postcapillary exercise PH, despite no evidence of this in the echocardiogram and normal left ventricular filling pressures (figure 4).

Figure 4.

Central illustration. Hemodynamic results in exercise RHC in patients with suspected CTED. CPET, cardiopulmonary exercise testing; CTED, chronic thromboembolic disease; mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PE, pulmonary embolism; PVR, pulmonary vascular resistance; RHC, right heart catheterization.

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CPET is also a very useful noninvasive test for characterizing dyspnea in multiple conditions. In our cohort, patients with normal and abnormal hemodynamic responses to exercise had slightly reduced peak VO2 values, similar to reports in other PE follow-up series.25 Those who developed exercise PH, however, showed altered ventilatory efficiency variables (PetCO2, VCO2, Ve/VCO2 slope), especially at AT. The degree of ventilatory inefficiency appears to be associated with hemodynamic status in CTEPH, and patients with CTED appear to have an intermediate phenotype, between that of healthy patients and patients with CTEPH at rest.18 Notably, we observed fewer alterations to mean Ve/CO2 and PetCO2 values compared with other studies of CTED,26 possibly because the patients in our series were on average younger and because we excluded patients with findings indicative of HFpEF during exercise. Despite our small sample, PetCO2 kinetics, especially when analyzed at AT, and the Ve/VCO2 ratio derived from PCWP had reasonable discriminatory ability to identify patients who would subsequently develop exercise PH. Based on our findings, which require external validation in a larger number of patients, it can be concluded that patients with normal CPET results during PE follow-up will not develop exercise PH. We therefore propose using CPET as a screening tool to investigate the causes of dyspnea before invasive tests, such as exercise RHC.

Precapillary exercise PH was associated with functional limitations in patients who had persistent dyspnea after PE and chronic pulmonary vascular bed thrombosis and no other causes that could explain their symptoms. CPET is a useful technique for exploring persistent idiopathic dyspnea, as it discriminates between precapillary exercise PH, potentially indicating underlying pulmonary microvasculopathy, and postcapillary exercise PH typically associated with HFpEF. CPET, in turn, is a noninvasive test capable of predicting exercise PH.

This project is supported by research grants received from the Spanish Society of Cardiology in 2019. Alejandro Cruz-Utrilla was awarded the Río Hortega grant by the Instituto de Salud Carlos III of the Spanish Ministry of Science and Innovation (CM20/00164).

S. Huertas, M. Velázquez, and P. Escribano conceived and designed the project. S. Huertas, M. Velázquez, F. Sarnago, N. Maneiro, C. Jiménez, and T. Segura de la Cal contributed to patient selection, performance of invasive tests, and data analysis.

A. Flox, T.A. Cruz, R. Aguilar, M.J. López, C. Andrés, Y. Revilla, S. Alonso, C. Gómez, and F. Arribas contributed to patient selection and follow-up. All the authors contributed to writing and critically reviewing this manuscript. They also all approved the final version and are responsible for its content.

The authors declare that they have no conflicts of interest.