Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive dual pulmonary vascular disorder characterized by organized thrombotic material causing obstruction in the larger pulmonary arteries of elastic type (>0.5 mm) and a secondary vasculopathy in the distal smaller muscular vessels (<0.5 mm).1
The appropriate identification of vascular abnormalities on CT underpins successful surgical outcomes2 3–5 6 3
We performed this retrospective, multi-institutional observational study to (a) assess the presence of PVS in different categories of CTEPH and, in particular, identify if PVS is a feature of distal CTEPH, and (b) evaluate if PVS has any correlation with the right heart catheter (RHC) derived pulmonary hemodynamics
MATERIALS AND METHODS
A retrospective analysis was performed with approval from the Institutional Review Board (IRAS project ID 280472 & IRB:12338) and the need for informed consent was waived. Pulmonary hypertension databases from 2 institutions (nonsurgical centers) were scrutinized between 2010 and 2020, and 93 consecutive cases of CTEPH cases with CTPA and RHC performed within a 3-month of each other were identified. Seventeen cases were excluded due to suboptimal CTPA (poor opacification of the left atrium with HU<160, beam hardening artifacts from dense contrast in the Superior Vena Cava obscuring the proximal pulmonary veins in the right upper lobe).
Clinical data of the patients were retrieved from the Radiology Information System database and age, sex, body mass index, and history of atrial fibrillation were recorded. The CT protocol parameters from both institutions are provided in Table 1 .
TABLE 1 -
CTPA Technical Specifications and Acquisition Parameters
Institution 1
Institution 2
Scanner
Single-source 128-multislice configuration (Somatom Definition AS+; Siemens AG, Germany)
Uses a variety of models from Siemens and GE but majority of the scans in this study were done on Siemens Somatom Force (Siemens AG, Germany)
ECG-gating
No
No
Breath-hold
Single breath-hold (4, 5, 6 s) at end inspiration
No breath-hold necessary as scan is <1 s. But patients are specifically instructed to avoid Valsalva
Coverage
Craniocaudal from lung apices to diaphragm
Craniocaudal from lung apices to diaphragm
Collimation (mm)
0.6
0.6
Table speed (mm per revolution)
61.4
89.2
Pitch
0.7-1.0
1.55
Rotation time (s)
0.5
0.28
Automatic tube current modulation (CARE Dose-4D)
On
On
Automatic tube potential control (CARE kv)
On
On (level 11)
Tube potential (ref) (KVp)
80–120
120
Tube current time product (ref) (mAs)
100–200
174
Length of Z -axis coverage per rotation
38.4
89.2
Reconstruction matrix
512 × 512
512 × 512
Reconstruction interval (mm)
1
1
Contrast medium protocol
Care bolus software (Siemens Medical Solutions, Forchheim, Germany) with ROI in pulmonary artery. As soon as the trigger threshold of 130 HU was reached, the table moved to the cranial start position and scanning was started following a 4 s interval during which time the patient was instructed to take a breath in and hold before imaging (automated verbal breathing command)
Care bolus software (Siemens Medical Solutions, Forchheim, Germany) with ROI in pulmonary artery. Delay is 2/3 of the contrast injection duration. (Default is 10 s interval delay if using 15 s injection duration)
Injection protocol
70-100 Omnipaque 350 (GE Healthcare) @ 5 mL/s followed by 20-mL saline chaser using power injector
ISOVUE 370 (IOPAMIDOL)
Iterative reconstruction
SAFIRE (Sinogram Affirmated Iterative Reconstruction, strength 3)
ADMIRE (Advanced Modeled Iterative Reconstruction, Strength 3)
CTPAs were analyzed for PVS as per the previously described methodology.4–6
Although all the proximal CTEPH cases had undergone pulmonary endarterectomy, only 38 had postop CTPA performed between 3 and 6 months after surgery. A subgroup analysis was done to evaluate the PVS in these 38 subjects before and after endarterectomy.
Statistical Analysis
Data were analyzed using SPSS Statistics (version 25, IBM Corp) and Microsoft Excel. Continuous normal data are presented as mean (±1 SD). Non-normal data are presented as median (interquartile range). Categorical variables are displayed as n (%). Continuous data were compared with the (paired) 2 tailed Student t test. Correlation analysis was performed using the Pearson correlation coefficient. A P -value of<0.05 was considered statistically significant.
RESULTS
The baseline characteristics and RHC data are outlined in Table 2 . There were 52 cases of proximal CTEPH (29 male, 23 female) with a mean age of 55 years and 24 cases of distal CTEPH (11 male, 13 female) with a mean age of 62 years. All patients were in sinus rhythm. The mean body mass index was 29.1 and 27.3, respectively, for the 2 groups. There was no significant difference in the invasive hemodynamic measurements between the proximal and distal CTEPH cases. The mean pulmonary artery pressure (mPAP) was 46±11 and 41±12 mm Hg and pulmonary vascular resistance was 9.4±4.5 and 8.4±4.8 WU, respectively.
TABLE 2 -
Baseline Characteristics of CTEPH Cases
Proximal CTEPH (n=52)
Distal CTEPH (n=24)
Age (y)
55±15
62±14
Sex (%)
29 M (56%), 23 F (44%)
11 M (46%), 13 F (54%)
BMI (kg/m2 )
29.1 (25.4-35.8)
27.3±4.7
mPAP (mm Hg)
46±11
41±12
PVR (WU)
9.4±4.5
8.4±4.8
CO (L/min)
3.9 (3.2-4.8)
4.1±1.2
CI (L/min/m2 )
1.9 (1.7-2.4)
2.1±0.5
BMI indicates body mass index; mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance.
The pulmonary venous flow was abnormal in one or more of the central pulmonary veins in 41/52 (79%) of patients with proximal CTEPH and 7/24 (29%) of patients with distal CTEPH cases (Table 3 ). The majority (71%) of distal CTEPH cases exhibited normal pulmonary venous flow in all the 4 major veins, as compared with 29% of proximal CTEPH cases. Figures 1 and 2 are examples of pulmonary venous flow in proximal and distal CTEPH.
TABLE 3 -
Pulmonary Vein Flow Grading in Proximal and Distal CTEPH
Proximal CTEPH (n=52)
Distal CTEPH (n=24)
P
LA opacification (HU)
250 (198-304)
289 (249-386)
0.034
Patients with normal flow in all 4 pulmonary veins, n (%)
11 (21)
17 (71)
<0.001
Patients with abnormal flow in 1 or more pulmonary veins, n (%)
41 (79)
7 (29)
<0.001
Total pulmonary vein flow score
5 (5-7)
4 (4-5)
<0.001
LA indicates left atrium.
FIGURE 1: Pulmonary venous flow in proximal CTEPH before and after pulmonary endarterectomy with demonstration of the pulmonary vein sign. CTPA images from a 50-year-old male with proximal chronic thromboembolic disease (CTEPH). A–D are before and E–H are after pulmonary endarterectomy. The PVS (A, B) is defined as nonopacification of the pulmonary veins during pulmonary arterial phase imaging and is demonstrated in the right inferior and middle pulmonary vein and left inferior pulmonary veins (arrows). Following endarterectomy, the PVS has resolved as shown by homogenous opacification in the same pulmonary veins (E, F). This is mirrored by clearance of pulmonary arterial obstruction (A, E), decrease in the size of right atrium (RA) and right ventricle (RV) (C, G) and resolution of mosaic attenuation (D, H). LA indicates left atrium.
FIGURE 2: Pulmonary venous flow in distal CTEPH. CTPA images from a 42-year-old male with sickle cell disease and distal chronic thromboembolic disease (CTEPH). All 4 major pulmonary veins show uniform homogenous enhancement (A, C). The proximal pulmonary arteries show normal morphology but vessels in the peripheral one-third of the lungs are sparse (A). Central perfusion is preserved compared with peripheral perfusion (B, D). LA indicates left atrium; RA, right atrium; RV: right ventricle.
In the subgroup analysis of 38 patients with proximal CTEPH before and after endarterectomy, 29/38 (76%) of proximal CTEPH cases had PVS presurgery. Thus, the large majority of cases (33/38, 87%, P <0.001) demonstrated improvement of contrast enhancement in all 4 pulmonary veins following endarterectomy (Table 4 ). There was a concomitant reduction in mean mean pulmonary artery pressure from 46 to 25 mm Hg and pulmonary vascular resistance from 9.2 to 2.6 WU (P <0.001).
TABLE 4 -
Pulmonary Vein Flow Grading in Proximal CTEPH Before and After Surgery
Preoperative proximal CTEPH (n=38)
Postoperative proximal CTEPH (n=38)
P
mPAP (mm Hg)
46±11
25 (20–34)
<0.001
PVR (WU)
9.2±4.3
2.6 (1.7–3.7)
<0.001
CO (L/min)
3.9 (3.4-5.3)
5.5 (4.3-6.7)
0.004
CI (L/min/m2 )
2.0 (1.7-2.5)
2.6 (2.2-3.1)
0.004
Patients with normal flow in all 4 pulmonary veins, n (%)
9 (24)
33 (87)
<0.001
Patients with abnormal flow in 1 or more pulmonary veins, n (%)
29 (76)
4 (11)
<0.001
mPAP indicates mean pulmonary artery pressure; PVR, pulmonary vascular resistance.
DISCUSSION
The principal goals of this investigation were to examine flow disturbances in the central pulmonary veins in different CTEPH categories on CTPA and to correlate the impact of pulmonary hemodynamic parameters on PVS. Our results demonstrated for the first time that a significant majority (71%) of distal CTEPH patients have normal pulmonary venous flow. Only 7 patients in the distal CTEPH category showed PVS. Of these, 5 had a limited degree of proximal disease, mainly in the lower lobes: 4 cases in the right and 1 case in the left lower lobe with PVS in the corresponding inferior pulmonary vein. In the remaining 2 cases, 1 exhibited PVS in the right superior pulmonary vein but there was no proximal disease even on retrospective analysis while the other had an area of peripheral consolidation (possibly an infarct) in the lobe where there was PVS. This underscores the suggestion that compromise of lung perfusion due to proximal vessel chronic thromboembolic disease is the etiology for the presence of PVS as patients with true distal vessel disease did not exhibit this CT finding.
In addition, the histopathologic findings of microvascular disease accompanying distal vessel CTEPH are similar to those seen in idiopathic pulmonary arterial hypertension leading to the hypothesis that these disorders may represent extremes of a disease continuum.7 6 6
While there are pathologic differences between proximal and distal CTEPH,7 8,9
Finally, our finding of PVS resolution in 87% of proximal CTEPH patients who underwent successful surgery is not surprising. Pulmonary endarterectomy provides clearance of the mechanical arterial obstruction and an improvement in regional lung perfusion with an acute reduction in right ventricle afterload and recovery of biventricular cardiac function.10–12
Further weight for the evaluation of the pulmonary vein flow is underscored by the evolving literature on BPA, a catheter-based alternative treatment for patients with inoperable CTEPH. Preprocedural target evaluation by CT includes morphologic classification of arterial lesions as well as identification of limited/delayed venous flow return.13 14,15
It should be emphasized that the identification of PVS on CTPA is dependent on ensuring a balance between good pulmonary vascular opacification and uniform enhancement of the left atrium. In both institutions involved in this study, the CTPAs were acquired with bolus tracking with the use of saline chaser as the latter helps to prolong the plateau-phase of the contrast medium bolus resulting in consistent and homogenous organ and vascular enhancement.
Limitations of this study include the following. This was a subjective analysis of a small cohort of CTEPH cases. The frequency of PVS in proximal CTEPH was similar to the published literature. Even with access to the PH database from 2 institutions, it was challenging to obtain predominantly distal CTEPH cases with matching CTPA and RHC hemodynamics. Nevertheless, the finding that PVS is infrequent in distal CTEPH was statistically significant. It was not possible to blind the readers to the presence of arterial abnormalities during the grading of the pulmonary veins. Inspite of optimization of injection parameters, 7 of the 17 cases that we excluded from analysis had heterogenous and low LA opacification. This may be a reflection of variation in the underlying cardiac function. We acknowledge that CT appearances of the pulmonary veins are dependent on the acquisition phase. A dual-energy–based study to assess lung perfusion in thromboembolic disease demonstrated significant differences in perfusion blood volume in the early and late phases in acute and chronic PE, reflecting the effect of systemic collaterals that could potentially modify the PVS presentation.16
In conclusion, we evaluated pulmonary venous flow abnormalities to seek insights into the pathophysiology of different CTEPH categories. PVS is an infrequent feature of distal CTEPH. There is no correlation between PVS and CTEPH disease severity as both proximal and distal patients exhibited similar baseline pulmonary hemodynamic measurements. The significant improvement in the venous flow after pulmonary endarterectomy as evidenced by the resolution of the PVS can be used as a simple measure of procedural success.
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