Introduction
Chronic thromboembolic pulmonary disease (CTEPD) is characterised by the presence of chronic thromboembolic material in the pulmonary arteries without pulmonary hypertension at rest. CTEPD patients represent a small proportion of the patients referred to expert centres, with symptoms and quality of life that may be as poor as those of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Therefore, some of these patients are currently offered the same surgical or interventional treatment as patients with CTEPH [
1,
2].
However, there are a number of gaps of evidence regarding this pathological condition.
It is yet unclear why pulmonary hypertension does not develop at rest in such patients; this could be either because the number of occluded segments is insufficient to affect resistance at rest or because no distal vasculopathy has developed as in CTEPH patients. In addition, it is unknown whether exercise limitation is due to exercise-induced pulmonary hypertension, developing in CTEPD due to an increased slope of the pulmonary arterial pressure-flow relationship, or to dead-space ventilation, with increased ventilatory equivalents for carbon dioxide [
3,
4]. The natural history of CTEPD is unknown and there is no evidence that CTEPD necessarily evolves to CTEPH [
5].
Finally, a relevant gap of evidence in clinical practice is that the radiological features of CTEPD are not systematically described in the literature. Current belief is that angiography, whether computed tomography pulmonary angiography (CTPA) or digital subtraction angiography (DSA), shows in CTEPD patients the typical findings of CTEPH patients [
5].
Accordingly, the aim of this study was to compare imaging scores of vascular obstruction and distal perfusion in patients with CTEPD and CTEPH [
6‐
9]. We reasoned that, in the hypothesis that pulmonary hypertension does not develop in CTEPD because the number of occluded segments is insufficient to affect resistance at rest, imaging should demonstrate lesser degree of arterial obstruction in CTEPD. On the contrary, in the hypothesis that pulmonary hypertension does not develop in CTEPD because no distal vasculopathy has developed, imaging could demonstrate better indices of distal perfusion in CTEPD than in CTEPH patients.
Materials and methods
Study subjects
Between April 1994 and April 2019, a total number of 936 patients were referred to our centre and underwent pulmonary endarterectomy (PEA); out of these, we retrospectively evaluated all consecutive patients with CTEPD who underwent PEA (n = 46). A similar number of consecutive patients (n = 45) with CTEPH who underwent PEA in our centre between January 2014 and June 2016, having similar age and sex, was used as the control group, selected from a total number of 97 patients.
The only comorbidity which was considered as an exclusion criterion in both groups was the concomitant presence of parenchymal lung disease, on the basis of ventilation/perfusion scintigraphy data and of the presence of advanced pulmonary emphysema and/or fibrosis at CT (30 patients were excluded only in the CTEPH group).
None of the patients enrolled in our study was referred to our centre for acute pulmonary embolism.
Patients were diagnosed as CTEPH or CTEPD on the basis of all examinations, including right heart catheterisation (RHC) at rest and imaging (CTPA and V/Q scintigraphy), consistently suggested by international guidelines over the study enrollment period [
10].
Preoperatively, patients also underwent echocardiographic and respiratory function evaluations.
The respiratory evaluation included spirometry, single-breath transfer factor of the lung for carbon monoxide (TLCO) and arterial blood gas analyses.
The study was approved by the Institutional Review Board of Fondazione IRCCS Policlinico San Matteo (protocol number 20200031903).
Methods
In CTEPD patients studied before 2009 (n = 6), examinations were performed on a 16-slice single-source CT scanner (Somatom Sensation, Siemens Healthineers); all other examinations (both in CTEPD and in CTEPH patients) were performed on a dual-source 64-slice CT scanner (Somatom Definition, Siemens Healthineers).
CT protocols
In all patients, two consecutive angiographic scans were performed, in full inspiration.
• Scan parameters for 16-slice CT were as follows: 120 kV with tube current 150 mA; collimation 16 × 0.75; gantry rotation time 50 ms; pitch 0.85. Modulation of the milliamperage was routinely used (Care Dose 4D, Siemens Healthineers).
Pulmonary angiographic acquisition was made with bolus tracking technique, ROI (region of interest) on the main pulmonary artery (threshold 100 HU, scan delay 7 s) and aortic angiographic acquisition with an 8-s delay, with caudo-cranial acquisition for both scans.
We used 100 ml of contrast agent (iomeprol 400 mgI/mL; Iomeron, Bracco), flush at 4 ml/s, followed by 40 ml of normal saline, flush at 4 ml/s.
• Scan parameters for 64-slice dual-source CT were as follows: tube A, 140 kV with tube current 60 mA, FoV diameter 50 cm; tube B, 80 kV with tube current 300 mA, FoV diameter 26 cm; collimation 14 × 1.2 mm; gantry rotation time 30 ms; pitch 0.7. Modulation of the milliamperage was routinely used (Care Dose 4D, Siemens Healthineers).
Pulmonary angiographic acquisition was made with bolus tracking technique, ROI on the main pulmonary artery (threshold 100 HU, scan delay 4 s), and aortic angiographic acquisition with a 4-s delay, with cranio-caudal acquisition for both scans.
We used 65 ml of contrast agent (iomeprol 400 mgI/mL; Iomeron, Bracco), flush at 5 ml/s, followed by 40 ml of normal saline, flush at 5 ml/s.
CTPA data reconstruction
From the raw spiral projection data acquired with both tubes of the dual-source CT, “fused” lung and mediastinal images were generated by merging 60% of 140-kV data with 40% of 80-kV data via the process of linear blending [
11‐
13], using medium-soft (D30) convolution kernel for mediastinal images and sharp (B80) convolution kernel for lung images, with 3-mm and 1.5-mm thickness. Reconstructed images were transferred to a commercially available workstation (Leonardo, Siemens Healthineers) running Syngo software (Siemens Healthineers).
From both 80-kV and 140-kV images of the pulmonary angiographic scan, the software generated a dual-energy CT perfusion map, deriving the iodine content of each voxel using a three-material-decomposition algorithm for air, soft tissue and iodine [
14]; colour-coded lung PBV images 7 mm in thickness were reconstructed at 14-mm intervals in both the axial and coronal planes using the same dual-energy application software.
From raw data of the single-source scanner, mediastinal and lung images were generated using very smooth (B10) convolution kernel for mediastinal images and ultra-sharp (B80) convolution kernel for lung images, with 1-mm thickness.
Image analysis
One cardiothoracic radiologist with more than 10 years of experience and a 5th year radiology resident independently reviewed lung and pulmonary CTPA images and dual-energy CT perfusion maps in a blinded non-consecutive manner, using scores as described by Hoey et al [
6].
Analysis
Continuous data were described as median and interquartile range (IQR) and categorical data as counts and percent; data were compared with the Mann-Whitney U test and the Fisher exact test, respectively. Bonferroni correction was applied for post hoc subgroup comparisons. The Spearman R and its 95% confidence interval (95% CI) were computed to assess the association of continuous variables. The Lin’s concordance correlation coefficient and 95% CI were calculated to measure the interobserver agreement in CT readings.
Stata 16 (StataCorp) was used for computations. A two-sided p value < 0.05 was considered statistically significant.
Discussion
The main result of the present study is the identification of substantial differences in radiological findings of CTEPD and CTEPH patients. Such differences can be clinically helpful to distinguish the two populations. Most importantly, these differences point at a different pathological substrate underlying CTEPD or CTEPH.
Patients with CTEPD showed a vascular obstruction burden which was similar to patients with CTEPH. As a matter of fact, proximal arterial obstruction (in particular of the right pulmonary artery) was more frequently observed in CTEPD patients than in the CTEPH population; to the best of our knowledge, this finding was never described before. Nevertheless, CTEPD patients had a lesser extension of perfusion defects in the iodine map. Peripheral vascular disease is not clearly visible in morphologic CTPA images, but it can be assessed as perfusion defects in iodine maps. In addition, mosaic hyperaemia, which is also an expression of microvascular peripheral disease, was found in a significantly smaller number of patients with CTEPD. Overall, these data strongly suggest that the absence of peripheral disease (i.e. of small vessel remodelling) might be the cause of the absence of pulmonary hypertension in CTEPD as compared to CTEPH patients.
No significant difference was found between the two groups considering the presence of collateral systemic supply; it is known that the presence of collateral systemic supply can help differentiating CTEPH from other forms of PH [
16], but in our analysis, this finding was not useful to distinguish CTEPD from CTEPH patients. The hypothesis is that the development of collateral supply is a direct consequence of vascular obstruction, similarly present in both groups as a response to chronic lung ischemia, rather than a consequence of pulmonary hypertension.
Accordingly, no significant difference was found between the two groups in TLCO. In fact, TLCO is overestimated because of back-perfusion of the capillary bed by the extensive bronchial arterial collateral flow. This “luxury perfusion” plays a role in the maintenance of pulmonary parenchymal viability and in carbon monoxide exchange, although it does not improve the oxygen exchange [
17,
18].
As expected, the two groups significantly differed substantially considering the indirect signs of pulmonary hypertension, such as an increased PA diameter and a PA/aorta diameter ratio > 1 and RV/LV ratio > 1, which have already been described to correlate with the presence of pulmonary hypertension [
19‐
22].
The main limitation of the present study is that the number of CTEPD patients evaluated is relatively small since it has been enrolled in a single centre and it is likely to represent a selected cohort of patients, as all these patients were referred for pulmonary endarterectomy being highly symptomatic. As a matter of fact, we lack population studies assessing the prevalence and the characteristics of symptomatic and asymptomatic patients with CTEPD and in which characteristics of such patients may differ from those who are referred to expert centres because of disabling symptoms.
We therefore acknowledge that validation in larger (and if possible unselected) series of patients is necessary, standardising the technical approach to the quantification of vascular obstruction and of lung perfusion.
Another limitation is that CT protocols in CTEPD patients are not uniform, but the enrollment period lasted for several years since CTEPD is not a common condition and technical advances occurred during this period.
In conclusion, CTEPD patients show a vascular obstruction burden similar to CTEPH patients, but without CT signs of pulmonary hypertension and mosaic hyperaemia and with a smaller extension of perfusion defects in the iodine map; these findings could be useful to distinguish CTEPD from CTEPH patients. Eventually, identification of CTEPD population with DECT might in the future avoid performing an invasive procedure like right heart catheterisation.
Most importantly, these data suggest that the absence of peripheral microvascular disease, even in presence of an important thrombotic burden, might be the reason for the absence of pulmonary hypertension at rest in CTEPD.
Acknowledgements
AV, SG and AMD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. CC, AV, SLS, CK, AC, MP, RD, AGC, SG and AMD contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. All authors reviewed the final manuscript.
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