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Frequency and characterization of CTEPH and CTEPD according to the mPAP threshold > 20 mm Hg: Retrospective analysis from data of a prospective PE aftercare program
Department of Internal Medicine, Respiratory Medicine and Ventilatory Support, Medical Mission Hospital Klinikum Würzburg Mitte, Academic Teaching Hospital of the Julius Maximilian University, Würzburg, Germany
Department of Internal Medicine, Respiratory Medicine and Ventilatory Support, Medical Mission Hospital Klinikum Würzburg Mitte, Academic Teaching Hospital of the Julius Maximilian University, Würzburg, Germany
Department of Internal Medicine, Respiratory Medicine and Ventilatory Support, Medical Mission Hospital Klinikum Würzburg Mitte, Academic Teaching Hospital of the Julius Maximilian University, Würzburg, Germany
Department of Radiology, Medical Mission Hospital Klinikum Würzburg Mitte, Academic Teaching Hospital of the Julius Maximilian University, Würzburg, Germany
Department of Thoracic Surgery, Medical Mission Hospital Klinikum Würzburg Mitte, Academic Teaching Hospital of the Julius Maximilian University, Würzburg, Germany
Department of Internal Medicine, Respiratory Medicine and Ventilatory Support, Medical Mission Hospital Klinikum Würzburg Mitte, Academic Teaching Hospital of the Julius Maximilian University, Würzburg, Germany
Two years after a PE event, CTEPH occurred in 5.25% of the cases and CTEPD without PH was 5.75% in the cohort (n = 400).
•
Using mPAP >20 mmHg for diagnosis of CTEPH leads to a relative increase of 23.5% of CTEPH diagnosis.
•
CPET seems to be a helpful tool to detect CTEPD without PH and CTEPH non-invasively.
Abstract
Background
The influence of the new pulmonary hypertension (PH) definition on the incidence of chronic thromboembolic PH (CTEPH) is unclear. The incidence of chronic thromboembolic pulmonary disease without PH (CTEPD) is unknown.
Objectives
To determine the frequency of CTEPH and CTEPD using the new mPAP cut-off >20 mmHg for PH in patients who have suffered an incidence of pulmonary embolism (PE) and were recruited into an aftercare program.
Methods
In a prospective two-year observational study based on telephone calls, echocardiography and cardiopulmonary exercise tests, patients with findings suspicious for PH received an invasive work-up. Data from right heart catheterization were used to identify patients with or without CTEPH/CTEPD.
Results
Two years after acute PE (n = 400) we found an incidence of 5.25% for CTEPH (n = 21) and 5.75% for CTEPD (n = 23) according to the new mPAP threshold >20 mmHg. Five of 21 patients with CTEPH and 13 of 23 patients with CTEPD showed no signs of PH in echocardiography. CTEPH and CTEPD subjects showed a reduced VO₂ peak and work rate in cardiopulmonary exercise testing (CPET). The capillary end-tidal CO2 gradient was comparably elevated in CTEPH and CTEPD, but it was normal in the Non-CTEPD-Non-PH group. According to the PH definition provided by the former guidelines, only 17 (4.25%) patients have been diagnosed with CTEPH and 27 individuals (6.75%) were classified having CTEPD.
Conclusions
Using mPAP >20 mmHg for diagnosis of CTEPH leads to an increase of 23.5% of CTEPH diagnosis. CPET may help to detect CTEPD and CTEPH.
Persistent right ventricular dysfunction, functional capacity limitation, exercise intolerance, and quality of life impairment following pulmonary embolism: systematic review with meta-analysis.
However, the definition of CTEPH has been changed over the years. The 6th World Symposium on Pulmonary Hypertension (WSPH) and the recently new published guideline on diagnosis and treatment of pulmonary hypertension (PH) recommended defining PH by a mean pulmonary artery pressure (mPAP) of above 20 mmHg [
Borderline mean pulmonary artery pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of developing pulmonary hypertension.
], although it can possibly be cured by pulmonary endarterectomy (PEA). PEA and balloon pulmonary angioplasty (BPA) in non-operable subjects can improve symptoms as well as hemodynamics and long-term outcome [
These are multiple reasons for a systematical follow-up after an incidence of acute PE.
Whereas CTEPH has been well studied over the last years, CTEPD without PH has been poorly characterizised so far and its incidence has not been investigated up to now. CTEPD without PH is characterized by thromboembolic pulmonary perfusion defects and signs of chronic organized fibrotic clots without PH at rest in symptomatic subjects [
]. The exact reasons why some subjects develop PH and some do not, having comparable perfusion defects, are not yet known. Coghlan et al. assume that in asymptomatic subjects, the number of obstructed segments is not high enough to impair the pulmonary vascular resistance at rest or that no secondary pulmonary arteriopathy has formed yet [
]. However, these subjects may have an increased risk to progress towards CTEPH in future, thus, identification and further observation may be indicated.
Since the yield of invasive diagnostic work-up of asymptomatic subjects might be low, it appears to be rational to perform a multistep diagnostic program primarily identifying symptomatic subjects. In these symptomatic patients, echocardiography and cardiopulmonary exercise test should be performed. If these non-invasive examinations strengthen the suspicion of disturbed pulmonary perfusion and PH, it is mandatory to confirm the diagnosis by invasive procedures as right heart catheterization and pulmonary angiography [
As CTEPD without PH is not associated with PH at rest, it will probably be overlooked by echocardiography. Since cardiopulmonary exercise testing (CPET) has the potential to detect features of CTEPD [
ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
]. This monitoring program included 400 adult subjects, being diagnosed with acute PE at the Medical Mission Hospital in Würzburg, Germany, between January 2011 and December 2016. We included all consecutive subjects with first or recurrent acute clinical manifestation of PE. All subjects gave their written informed consent. Approval was obtained by the local Ethics Committee of the Julius Maximilian University of Würzburg and the study was conducted according to the Helsinki Declaration. The primary aim was the detection of CTEPH. In brief, subjects were tracked by a telephone-based monitoring after three, six, twelve and 24 months in order to detect persistent symptoms. Using a predefined questionnaire developped for this program subjects were explored for dyspnea at rest, dyspnea on exertion, dizziness, fainting or syncope or thoracic pain. Symptomatic subjects with any positive item of the five-item questionnaire were examined by echocardiography and CPET. Subjects with signs of PH or gas exchange disturbance were fully examined according to the guidelines on diagnosis and treatment of PH [
ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
] in order to confirm or rule out the diagnosis. This included a ventilation/perfusion (VQ) scan, CT angiography (Activion 16, Toshiba Medical Systems, Neuss, Germany) and conventional pulmonary angiography (Integris Allura, Philipps Medical Systems, Best, the Netherlands, films stored digitally) in order to evaluate operability.
CTEPH was diagnosed when mismatch perfusion defects were detected by VQ scan (TechnegasGenerator® (Tetley Medical Limited, Australia); E Cam Variable® (Siemens Medical Solutions Inc, Hoffman Estates, Illinois, USA) or computed tomography showing filling defects, confirmed by conventional pulmonary angiography and right heart catheter revealed precapillary pulmonary hypertension. CTEPD without PH was defined by angiographically confirmed pulmonary perfusion defects without PH in symptomatic subjects.
There was a third group consisting of subjects who were symptomatic and in whom echocardiography led to suspicion of PH but finally PH and pulmonary perfusion defects have been excluded by right heart catheterization and VQ scan. This group was defined as “Non-CTEPD-Non-PH” and served as a control group.
We compared anthropometric, echocardiographic, hemodynamic and cardiopulmonary exercise test data of all three groups.
Echocardiography was performed with the device Vivid7® (GE Medical Systems, Solingen, Germany) according to the guidelines [
ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
CPET was performed with an E-bike basic PC plus (GE Medical Systems, Solingen, Germany) and a MasterScreen CPX® (CareFusion, Höchberg, Germany) according to the American Thoracic Society (ATS)/American College of Chest physicians (ACCP) Statement on cardiopulmonary exercise testing [
], including a 2-min registration at rest and a 2-min recording of unloaded pedaling. The following exercise protocol consisted of an increasing workload of 25 Watt/2 min per ramp. Exercise was terminated when withdrawal criteria were met or by symptom limitation. We measured temperature and air pressure continuously. Expiratory fraction of O2 and CO2 as well as respiratory rate and minute ventilation were measured breath by breath. AT was set at the minimum nadir of EQO2. The CPET procedure was described before [
EQO2AT>25 mmHg, EQCO2AT > 35 mmHg, VE/VCO2 > 35 mm Hg, PETCO2<35 mm Hg or decreasing during exercise, PAETCO2 > 0 m Hg at maximum work load and P(A-a)O2 > 35 mmHg at peak exercise were assumed to be suggestive for disturbed pulmonary perfusion.
A ventilation-perfusion scan has been conducted to detect thromboembolic perfusion defects defined as a mismatch between pulmonary perfusion and ventilation [
Right heart catheterization was performed with a Swan-Ganz catheter (Smith Medical, Grasbrunn, Germany) and recorded with an IntelliVue monitor system (MP70 (M8007A®), Philips Medizinsysteme, Böblingen, Germany) [
]. If mPAP at rest was normal, right heart catheterization was repeated under exercise with increasing load (25 W/2 min) at 50 W.
Exercise induced PH was defined by an increase of mPAP by > 3 mmHg per 1L/min of cardiac output.
Microsoft Excel and IBM SPSS Statistics 23 were used for statistical analysis. The anthropometric data are shown as mean ± standard deviation (SD). Significance was calculated with one-factor analysis of variance for age, height, weight and BMI, and with Fisher's exact test for sex and WHO FC distribution. Most functional data were not normally distributed so they are expressed as median and interquartile range (IQR). Significance between the three groups was calculated with Mann-Whitney-U tests for functional data. Significance was attained if the p value was <0.05.
3. Results
The PE cohort consisted of 400 subjects (age 64.0 years ± 17.0 years; BMI 29.0 ± 6.1, 54% females). Sixteen patients (4%) had a preexisting anticoagulation (Online Supplementary Table 1.
During the entire follow-up time of two years, 21 subjects were diagnosed with CTEPH (5.25%) and 23 (5.75%) were diagnosed with CTEPD without PH using the mPAP threshold of >20 mmHg as discussed by the 6th World Symposium on Pulmonary Hypertension and introduced by the new ESC-ERS-Guideline (Fig. 1 and online Supplementary Table 2). Further, 15 subjects with CTEPD showed an exercise induced PH (Fig. 1 and online Supplementary Table 2). The majority of CTEPH subjects (18 out of 21) were diagnosed 3 months after acute PE, CTEPD without PH was detected later on average (Fig. 1 and online Supplementary Table 2). Fig. 2 and Supplementary Table 2 illustrate the diagnoses of CTEPH and CTEPD without PH according to the different mPAP thresholds.
Fig. 1Diagnosis of CTEPH and CTEPD without PH according to the new definition during follow-up.
According to the PH definition provided by the former ESC/ERS-Guideline, only 17 (4.25%) subjects have been diagnosed with CTEPH and 27 individuals (6.75%) were classified having CTEPD without PH (Fig. 2). Thus, defining PH by 20 mmHg instead of ≥25 mmHg leads to a relative increase of 23.5% of the diagnosis rate of CTEPH.
43 out of 117 patients with pathological echocardiographic and CPET findings did not receive a complete invasive diagnostic work-up due to death, malignancy, a palliative care concept or clear alternative explanations for symptoms, as comorbidities or declined consent for further work-up (Fig. 3).
During the two-years follow-up, echocardiography and cardiopulmonary exercise testing led to the suspicion of CTEPH/CTEPD in nine symptomatic subjects, in whom neither CTEPH nor CTEPD without PH nor PH have been confirmed by the complete invasive diagnostic work-up (Non-CTEPD-Non-PH subjects). Arterial hypertension, COPD, asthma, interstitial lung disease (ILD), obesity and anemia were identified as comorbidities potentially explaining dyspnea in these subjects.
The anthropometric data and WHO functional class of the three groups CTEPH (mPAP >20 mmHg; n = 21), CTEPD without PH (mPAP ≤20 mmHg but with pulmonary perfusion defects; n = 23) and symptomatic Non-CTEPD-Non-PH subjects (mPAP ≤20 mmHg and without pulmonary perfusion defects; n = 9), shown in Table 1, did not differ significantly across the groups. The majority of subjects of the three groups had symptoms consistent with WHO functional class II. The differences in the WHO FC distribution were not statistically significant.
Table 1Anthropometric data at baseline of patients diagnosed with CTEPH, patients with CTEPD without PH and symptomatic patients with Non-CTEPD-Non-PH.
CTEPH
CTEPD without PH
Non-CTEPD-Non-PH
p
n = 21
n = 23
n = 9
n
%
n
%
n
%
Sex (m/w)
8/13
38.1/61.9
10/13
43.5/56.5
2/7
22.2/77.8
0.607
mean ± SD
mean ± SD
mean ± SD
Age [years]
73.1 ± 8.6
66.5 ± 12.7
62.2 ± 25.2
0.118
Height [cm]
167.4 ± 8.6
169.6 ± 11.0
166.1 ± 10.9
0.624
Weight [kg]
84.1 ± 15.5
82.5 ± 16.4
79.3 ± 23.1
0.785
BMI [kg/m2]
30.0 ± 5.4
28.6 ± 4.2
28.4 ± 6.4
0.595
n
n
n
WHO FC II/III/IV
12/8/1
16/6/1
4/2/3
0.178
%
%
%
WHO FC II/III/IV
57.1/38.1/4.8
69.6/26.1/4.3
44.4/22.2/33.3
0.178
Group Non-CTEPD-Non-PH = Symptomatic patients in whom PH has been invasively excluded and pulmonary perfusion defects have been excluded. SD = standard deviation; BMI = body mass index.
Concerning hemodynamics (Table 2a, Table 2 b), CTEPH subjects presented with a median mPAP of 28.0 (7.0) mmHg and median pulmonary vascular resistance (PVR) of 355.0 (342.5) dyn∙s/cm5. This was significantly higher compared to CTEPD and Non-PH/Non-CTEPD subjects. CTEPD subjects showed no significant hemodynamic differences in comparison to nine symptomatic individuals with excluded CTEPH/CTEPD (Table 2a, Table 2 b).
Table 2aData of right heart catheterization at rest.
Table 2 bData of right heart catheterization under exercise in CTEPD without PH.
right heart catheterization under exercise
CTEPD without PH Median (IQR) n
mPAP [mmHg]
32.0 (5.8) n = 20
sPAP [mmHg]
50.5 (16.3) n = 20
dPAP [mmHg]
20.0 (9.0) n = 20
PVR [dyn∙s/cm5]
188.5 (89.0) n = 20
CO [l/min]
8.8 (2.9) n = 20
CI [l/min/m2]
4.5 (1.4) n = 20
PAWP [mmHg]
11.5 (4.0) n = 20
RAP [mmHg]
6.0 n = 20
P* = P for comparison of CTEPH and CTEPD without PH. P# = P for comparison of CTEPD without PH versus non CTEPD-Non-PH. Wo = without. Group “Non-CTEPD-Non-PH” = Symptomatic patients in whom PH has been invasively excluded and pulmonary perfusion defects have been excluded. Values are given as the median (IQR). mPAP = mean pulmonary arterial pressure; sPAP = systolic pulmonary arterial pressure; dPAP = diastolic pulmonary arterial pressure; PVR = pulmonary vascular resistance; CO = cardiac output; CI = cardiac index; PAWP = pulmonary arterial wedge pressure; CVD = central venous pressure.
Under exercise, there was a disproportional rise in mPAP in subjects with CTEPD without PH in relation to the increase of CO. Subjects with CTEPD without PH also showed a mild increase of PVR under exercise. The 15 subjects with CTEPD without PH showed a mPAP/CO ratio higher than 3 mmHg/L under exercise.
There were five patients classified as CTEPD without PH at the 3 months follow-up, who did not show an exercise induced increase of pulmonary artery pressure. These five patients suffered from arterial hypertension (n = 4), coronary artery disease (n = 1) asthma (n = 1) or obesity hypoventilation syndrome (n = 1). Three of these patients showed persisting symptoms as dyspnea on exertion after a course of two years. The performed noninvasive tests did not show progressive limitations. Due to no suspicion of newly developed resting PH, a right heart catheterization has not been repeated. 2 other patients improved and did not show any more symptoms.
Echocardiography revealed a significantly higher sPAP [49.9 (20.2) mmHg] and enlarged right atrial area [18.8 (7.1) cm2] for the CTEPH cohort compared to the CTEPD group without PH [sPAP 29.7 (7.0) mmHg, RA 14.4 (4.1) cm2]. Tricuspid plane systolic excursion (TAPSE) was also lower in the CTEPH group than in subjects with CTEPD without PH (Table 3).
Table 3Echocardiographic data. Comparison of three groups.
CTEPH Median (IQR) n
P*
CTEPD without PH Median (IQR) n
P#
Non-CTEPD-Non-PH Median (IQR) n
sPAP [mmHg]
49.9 (20.2) n = 12
0.001
29.7 (7.0) n = 10
0.040
43.5 (17.3) n = 4
TAPSE [cm]
2.0 (1.0) n = 21
0.191
2.4 (0.6) n = 23
0.527
2.5 (0.5) n = 9
RA [cm2]
18.8 (7.1) n = 21
0.002
14.4 (4.1) n = 21
0.700
15.0 (1.0) n = 9
RVD1 [cm]
3.7 (0.8) n = 16
0.805
3.7 (0.7) n = 11
0.901
3.8 (0.9) n = 8
RIMP
0.4 (0.4) n = 14
0.446
0.3 (0.2) n = 15
0.906
0.3 n = 3
LVEI
1.0 (0.1) n = 19
0.304
1.0 (0.0) n = 16
0.265
1.0 (0.1) n = 8
P* = P for comparison of CTEPH and CTEPD without PH. P# = P for comparison of CTEPD without PH versus non CTEPD-Non-PH. Wo = without. Group “Non-CTEPD-Non-PH” = Symptomatic patients in whom PH has been invasively excluded and pulmonary perfusion defects have been excluded. Values are given as the median (IQR). sPAP = systolic pulmonary arterial pressure; TAPSE = tricuspid plane systolic excursion; RA = right atrial area; RVD1 = right ventricular diameter; RIMP = right ventricular index of myocardial performance; LVEI = left ventricular eccentricity index.
Table 4 shows data from CPET. CTEPH as well as CTEPD subjects without PH presented with a mean oxygen uptake <85% and a reduced maximum work rate underscoring the objective functional limitation of both groups. CTEPD subjects without PH showed an increased P(a-ET)CO₂ [6.1 (6.0) mmHg], similar to CTEPH [6.4 (5.7) mmHg] as a sign of disturbed pulmonary perfusion in both groups whereas P(a-ET)CO₂ was numerically lower in the Non-CTEPD/Non-PH group [3.4 (11.6) mmHg] (p = 0.425). CTEPH as well as CTEPD subjects without PH presented with higher P(Eta)O₂ values than the Non-PH/Non-CTEPD group indicating gas exchange disturbance in CTEPH and CTEPD patients. In total, CPET was indicative of CTEPD in 18 out of 22 CTEPD subjects who underwent CPET.
Table 4CPET data, comparison of three groups.
CTEPH Median (IQR) n
P*
CTEPD without PH Median (IQR) n
P#
Non-CTEPD-Non-PH Median (IQR) n
VO₂ peak [% pred.]
77.0 (21.5) n = 17
0.419
84.5 (34.3) n = 22
0.482
76.0 (35.0) n = 8
WR [W]
68.5 (26.0) n = 16
0.434
72.0 (38.0) n = 21
0.660
85.5 (87.8) n = 8
VE/VCO₂-slope
42.5 (19.3) n = 12
0.408
37.0 (8.5) n = 18
0.616
36.0 (20.0) n = 8
EqO₂ (AT)
31.0 (12.0) n = 13
0.413
29.0 (9.5) n = 21
0.136
25.5 (7.0) n = 8
EqCO₂ (AT)
33.0 (13.0) n = 13
0.915
36.0 (7.0) n = 21
0.230
33.5 (8.3) n = 8
PETCO₂(AT) [mmHg]
32.2 (9.4) n = 14
0.661
32.0 (5.5) n = 21
0.730
32.0 (14.6) n = 7
P(ETa)O₂ [mmHg]
36.5 (21.3) n = 16
0.117
27.8 (18.1) n = 22
0.289
14.9 (28.9) n = 5
P(a-ET)CO₂ [mmHg]
6.4 (6.7) n = 16
0.767
6.1 (6.0) n = 22
0.425
3.4 (11.6) n = 8
O₂-Pulse [% pred.]
84.0 (27.5) n = 17
0.011
110.0 (45.5) n = 21
0.150
80.5 (47.8) n = 8
BR [% pred.]
28.0 (18.0) n = 17
0.966
28.0 (35.5) n = 22
0.398
45.5 (15.0) n = 8
P* = P for comparison of CTEPH and CTEPD without PH. P# = P for comparison of CTEPD without PH versus Non CTEPD-Non-PH. Wo = without. Group “Non-CTEPD-Non-PH” = Symptomatic patients in whom PH has been invasively excluded and pulmonary perfusion defects have been excluded. Values are given as the median (IQR). VO₂ peak = oxygen uptake at peak exercise; WR = work rate; VE/VCO₂-Slope = Ratio of minute ventilation and carbon dioxide output; EqO₂ = breathing equivalent for oxygen; EqCO₂ = breathing equivalent for carbon dioxide; PET CO₂ = partial pressure of endtidal CO₂; P(ETa)O₂ = alveolar-arterial oxygen gradient; P(a-ET)CO₂ = arterial-endtidal carbon dioxide gradient; O₂-Pulse = oxygen uptake per heart beat; BR = breathing reserve.
Five of the 21 subjects with CTEPH and 13 of the 23 subjects with CTEPD without PH did not show any echocardiographic signs of PH but presented with a cardiopulmonary exercise test suspicious for a disturbed pulmonary perfusion (Fig. 4).
Fig. 4Number of Patients with CTEPD without PH or CTEPH showing no echocardiographic signs of PH despite CPET suggesting disturbed pulmonary perfusion.
ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
] did not change the results of the comparisons between the groups CTEPH, CTED, Non-CTEPD-Non-PH (Data not shown).
The majority of the patients with CTEPH and CTEPD without PH presented with a low risk status at the index PE (online Supplementary Tables 3 and 4). However, CT signs of right heart strain were common in the patients later on diagnosed with CTEPH (Online Supplementary Table 5). While three of the CTEPH patients and seven of the subjects diagnosed with CTEPD without PH reported dyspnea for more than four weeks, none of the CTEPH and only one of the CTEPD patients presented with dyspnea for longer than 180 days at the index PE (Online Supplementary Tables 3 and 4). Furthermore, only one out of 21 patients CTEPH patients and one out of the 23 patients diagnosed with CTEPD without PH had a preexisting anticoagulation at the timepoint of the index PE (Online Supplementary Tables 3 and 4).
4. Discussion
This manuscript deals with five innovative aspects: The incidence of CTEPD without PH, the new definition of PH using the mPAP threshold of >20 mmHg as recommended by the 6th World Symposium on PH [
] and its impact on the diagnosis of CTEPH, the symptom-based approach of PE follow-up, the complementary use of CPET during follow-up of subjects with acute PE and the comparative characterization of CTEPH and CTED following the new definition.
1.
The incidence of CTEPD without PH following acute PE has not been investigated previously. This is the first prospective study evaluating the frequency of CTEPD without PH after diagnosis of acute PE. With an incidence of 5.75% within 2 years after PE, CTEPD without PH seems to be as frequent as CTEPH with an incidence of 5.25%. The CTEPH incidence we found is comparable to previous studies [
Since CTEPD without PH is not defined by an elevated pulmonary artery pressure, CTEPD diagnosis can be missed by the use of echocardiography. The CTEPD detection rate depends on the diagnostic tools and the diagnostic approach of a PE follow-up program. Moreover, a CTEPH detection rate might depend on the length of an aftercare program, as CTEPD with and without PH might develop months and years after acute PE.
2.
The use of the newly recommended mPAP threshold of >20 mm Hg led to a shift of four subjects formerly diagnosed with CTEPD without PH to CTEPH. This means that using the new definition of CTEPH leads to an increase of the CTEPH diagnosis rate of 23,5% or that 19% of the current CTEPH diagnosis were driven by reclassification.
3.
The symptom-based approach is one of the main features of the presented follow-up strategy. We might have missed some CTEPH diagnoses, since only symptomatic subjects underwent further examinations. However, this approach seems to be reasonable under practical aspects of an aftercare program, because therapeutic consequences are questionable in asymptomatic subjects. Since subjects were called by phone and asked about their symptoms in regular intervals, we were able to detect symptoms at an early stage to initiate further examinations. The evaluation of subjects at given times instead of just once is also beneficial to derive information about the progress over time.
4.
The performed CPET in addition to echocardiography is a second key feature of the mentioned follow-up program and this may contribute to the relatively high CTEPH incidence we found. Indeed 5 out of 21 subjects with confirmed CTEPH and 13 of the 23 individuals with CTEPD without PH appeared without echocardiographic signs of PH, but CPET was suggestive for disturbed pulmonary perfusion. Previous approaches [
Incidence of recurrent venous thromboembolism and of chronic thromboembolic pulmonary hypertension in patients after a first episode of pulmonary embolism.
] were non-invasively based on echocardiography, which means that these approaches are prone to overlook CTEPD without PH and even CTEPH. Echocardiography alone might miss mild forms of PH if a tricuspid valve insufficiency is missing [
]. CPET is able to show functional signs of disturbed pulmonary perfusion which can be existent even in early CTEPH stages. Furthermore, CTEPD by definition a disease without PH cannot be detected by echocardiography, so CPET is the only non-invasive examination which can raise suspicion about the existence of CTEPD without PH. The implementation of CPET in the study procedure is a new approach following subjects with PE and has never been described elsewhere.
As expected, the CTEPH cohort was characterized by an increased echocardiographic sPAP, while the cohort with CTEPD without PH showed a normal sPAP. Surprisingly the Non-CTEPD-Non-PH group presented with a similar increased sPAP as the CTEPH group. This underscores that echocardiography is only valuable for an estimation of sPAP, but not for the definite diagnosis of PH. The cohort with CTEPD without PH as well as the CTEPH cohort presented with signs of pulmonary perfusion defects, especially shown by an elevated P(a-ET)CO₂. In contrast, P(a-ET)CO₂ was normal in the Non-PH/Non-CTEPD group. This underscores the value of CPET in the work-up process of identifying CTEPH and CTEPD without PH after PE. It also shows that in subjects with echocardiographic signs of PH but missing signs of disturbed pulmonary perfusion and increased dead space ventilation (normal P(a-ET)CO₂) in CPET, CTEPH and CTEPD without PH are rather unlikely.
5. Comparative characterization: On average, CTEPH and CTEPD without PH were diagnosed 4.3 and 8.5 months after PE respectively, and so CTEPH was diagnosed earlier after the index PE than in other programs [
]. The detection of CTEPH during a structured follow-up programs could be the explanation for the less severe PH. CPET can probably help to detect CTEPH at an early stage, in which only mild limitations of hemodynamic parameters are detectable. It might be speculated that some subjects have already had preexisting thromboembolic defects at study enrollment. Indications for an acute on chronic event could be that these subjects have a notedly increased sPAP already at the time of PE. A subsequent examination of the CTEPH subjects showed that 7 had a sPAP >50 mmHg and 3 had a sPAP >60 mmHg at study enrollment. Intravascular webs and dilated bronchial arteries are typical signs of chronic vascular abnormalities. Additionally, dilated pulmonary artery trunk, flattening of interventricular septum and right ventricular wall hypertrophy as signs of right heart strain have been proposed as signs of chronic pulmonary vascular disease by Boon et al. [
Prediction of chronic thromboembolic pulmonary hypertension with standardised evaluation of initial computed tomography pulmonary angiography performed for suspected acute pulmonary embolism.
]. Intravascular webs and RV hypertrophy have been rarely found in our patients at the timpoint of index PE. Only three patients diagnosed with CTEPH reported dyspnea for more than 28 days before the index PE and none of these patients suffered from dyspnea for more than 180 days before the index event. Only one patient diagnosed with CTEPH during follow-up had a preexisting anticoagulation before the index PE. Due to these findings, it seems not to be really probable that the CTEPH patients reported here had already a preexisting chronic pulmonary vascular disease before the index PE. The previously proposed criteria of the working group in Amsterdam and Leiden [
Prediction of chronic thromboembolic pulmonary hypertension with standardised evaluation of initial computed tomography pulmonary angiography performed for suspected acute pulmonary embolism.
] used a predefined threshold for ‘high risk’ (≥3 predictors) and the expert overall judgment on the presence of CTEPH. So far there are no criteria for CTEPD without PH. Since in the cohort of Boon et al. any sign of chronic thrombi was already present in 74/341 patients (22%) at the index CTPA, but CTEPH had been confirmed only in nine cases, we assume a too low specifity of these signs, Furthermore the authors report a low sensitivity between 30 and 44% in this paper. Thus, it might not help to estimate the true incidence of CTEPH and CTEPD after acute PE.
However, from the clinical perspective and in order to detect CTEPH the follow-up after an index event should cover both scenarios and both groups of patients, these with acute and these with acute on chronic PE.
CTEPD without PH was more frequently detected after 1 and 2 years after PE. Since these subjects did not show pathological findings after 3 and 6 months, this could indicate a new development of CTEPD in these subjects rather than the result of an acute on chronic event.
Hence, it could be worthwhile to extend aftercare to more than 2 years after PE to detect CTEPD and to observe the natural course of disease in CTEPD without PH.
By definition, CTEPH subjects presented with a higher mPAP >20 mmHg at rest, whereas mPAP at rest was normal in subjects with CTEPD without PH. Under exercise however, mPAP increased disproportionately to CO in CTEPD without PH. There was also a small increase in PVR under exercise instead of a decrease as it appears in healthy individuals [
]. This could be the result of a pathological reaction of pulmonary vasculature under exercise. Due to chronic thromboembolic obstruction there is no sufficient recruiting and dilatation of pulmonary vessels under exercise, resulting in pulmonary pressure increase when cardiac output increases. This could be responsible for symptoms under exercise in such subjects. This is consistent with data by van Kan et al. [
]. It remains unclear whether patients with CTEPD without PH are a different phenotype or will show a progression towards PH.
The WHO FC distribution was similar among CTEPH and CTEPD without PH indicating that both groups suffer from comparable limitations of their exercise capacity, despite the lack of PH in CTEPD. This argues for performing PEA or balloon angioplasty (BPA) also in subjects with CTEPD without PH and not only CTEPH subjects after careful risk benefit analysis, because PEA and BPA can improve symptoms markedly [
The right atrial area was significantly increased in CTEPH subjects compared to CTEPD without PH. Furthermore, TAPSE was lower and the right ventricular index of myocardial performance (RIMP) higher in CTEPH subjects compared to the other two groups. In contrast the function of the right ventricle in CTEPD without PH seems to be normal, which can probably be attributed to the absence of PH. It would be interesting to see if the findings of subjects with CTEPD without PH worsen over a longer time span of years and decades.
In all three groups we found an objective functional limitation with a VO₂ peak <85% and a reduced maximum work rate. There were no significant differences between the cohorts with CTEPH and CTEPD without PH in cardiopulmonary exercise testing except for the O₂-pulse. Overall, CTEPD and CTEPH subjects showed similar objective functional impairment with signs of perfusion defects, gas exchange disturbance and inefficient ventilation.
4.1 Limitations
Not all the tests which had to be performed according to the protocol have been performed during the clinical process. The reasons were disability explained by comorbidities as extreme obesity or malignant disease, comorbidities leading to a palliative care concept or comorbidities clearly explaining the symptoms, e.g. acute coronary syndrome or declined consent for the planned testing.
The used questionnaire has not been validated elsewhere.
Another limitation was that right heart catheterization under exercise has only been performed in subjects with thromboembolic perfusion defects and normal pulmonary artery pressure at rest. Asymptomatic PE survivors have not been examined by echocardiography and CPET. However, this seems to be reasonable, because therapeutic consequences in asymptomatic subjects are questionable.
In summary, this work deals with several innovative aspects and characterization, follow-up and further diagnostic strategies are robust.
5. Conclusion
This is the first prospective follow-up program after diagnosis of PE investigating the frequency of CTEPH and CTEPD without PH. Using the new PH definition with the mPAP threshold of >20 mmHg recommended by the World Conference on PH and the new ESC/ERS-Guideline, we found a cumulative two-year incidence of 5.25% for CTEPH and 5.75% for CTEPD without PH. This leads to a 23.5% higher diagnosis rate for CTEPH than using the former definition of PH. CPET seems to be a useful complementary diagnostic tool for the detection of CTEPD without PH and CTEPH.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
This study was approved by the local Ethics Committee of the Julius Maximilian University of Würzburg (Ethic Committee Number AZ-160/10).
Informed consent was obtained from all individual participants included in the study.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Funding
The pulmonary embolism aftercare program was sponsored by Actelion Pharmaceuticals Germany.
CRediT authorship contribution statement
Matthias Held: Conceptualization, Investigation, Formal analysis, Writing – original draft, Writing – review & editing, Visualization, Supervision. Elena Pfeuffer-Jovic: Formal analysis, Writing – original draft, Writing – review & editing, Visualization. Heinrike Wilkens: Conceptualization, Investigation, Formal analysis, Writing – original draft, Writing – review & editing, Visualization. Gülmisal Güder: Formal analysis, Writing – original draft, Writing – review & editing. Franziska Küsters: Formal analysis, Writing – original draft, Writing – review & editing. Hans Joachim Schäfers: Formal analysis, Writing – original draft, Writing – review & editing. Heinz Jakob Langen: Writing – original draft, Writing – review & editing. Danjouma Cheufou: Writing – original draft, Writing – review & editing. Delia Schmitt: Formal analysis, Writing – original draft, Writing – review & editing, Visualization.
Declaration of competing interest
Matthias Held reports fees for consultation and/or lectures from Astra Zeneca, Bayer Healthcare, Berlin Chemie, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, MSD, OMT, Pfizer, Santis.
Elena Pfeuffer-Jovic reports fees for lectures from Janssen and for travel/accommodation from Boehringer Ingelheim, and OMT, outside the submitted work.
Heinrike Wilkens has received fees for lectures and/or consultations from Bayer, Biotest, Boehringer, GSK, Janssen and Roche.
Gülmisal Güder has no conflicts of interest.
Franziska Küsters has no conflicts of interest.
Hans Joachim Schäfers has no conflicts of interest.
Heinz Jakob Langen has no conflicts of interest.
Danjouma Cheufou has no conflicts of interest.
Delia Schmitt has no conflicts of interest.
Acknowledgements
Not applicable.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
Persistent right ventricular dysfunction, functional capacity limitation, exercise intolerance, and quality of life impairment following pulmonary embolism: systematic review with meta-analysis.
Borderline mean pulmonary artery pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of developing pulmonary hypertension.
ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
Incidence of recurrent venous thromboembolism and of chronic thromboembolic pulmonary hypertension in patients after a first episode of pulmonary embolism.
Prediction of chronic thromboembolic pulmonary hypertension with standardised evaluation of initial computed tomography pulmonary angiography performed for suspected acute pulmonary embolism.
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