Use of small pulmonary vascular alterations to identify different types of pulmonary hypertension: a quantitative computed tomography analysis

Abstract

BACKGROUND:

The morphological alterations of small pulmonary vessels measured by computed tomography (CT) is increasingly used in evaluation of suspected pulmonary hypertension (PH).

OBJECTIVE:

To investigate the significance alterations of quantitative assessment of small pulmonary vessels on chest CT in distinguishing different types of PH and their severity.

METHODS:

We retrospectively analyzed a dataset of 120 healthy controls (HCs) and 91 PH patients, including 34 patients with connective tissue diseases-related PH (CTD-PH), 26 patients with idiopathic pulmonary arterial hypertension (iPAH), and 31 patients with chronic obstructive pulmonary disease-related PH (COPD-PH). The CTD-PH patients were divided into mild to moderate PH (CTD-LM-PH) group (n = 17) and severe PH (CTD-S-PH) group (n = 17). A total of 53 CTD patients without PH (CTD-nPH) were enrolled for comparison with the CTD-PH. We measured the cross-sectional area of small pulmonary vessels < 5 mm² (%CSA_<5) and between 5–10 mm² (%CSA_5–10) as a percentage of total lung area among the populations included above and compared %CSA in different types of PH groups and HCs group. The mean pulmonary arterial pressure (mPAP) was measured by right heart catheterization.

RESULTS:

The %CSA_5–10 of COPD-PH, CTD-PH, and iPAH patients increased (0.21±0.09, 0.49±0.20 and 0.61±0.20, p < 0.02) sequentially, while the %CSA_<5 of CTD-PH, iPAH, and COPD-PH patients decreased (0.79±0.65, 0.65±0.38 and 0.52±0.27, p < 0.05) sequentially. The %CSA_5–10 was significantly higher in CTD-S-PH patients than CTD-LM-PH patients and CTD-nPH patients (0.51±0.21, 0.31±0.15 and 0.28±0.12, p < 0.01). The %CSA_5–10 was positively correlated with mPAP in the CTD-PH group.

CONCLUSIONS:

The quantitative parameters %CSA_<5 and %CSA_5–10 assessed by chest CT are useful for distinguishing different types of PH. In addition, the %CSA_5–10 can provide information for identification of CTD-PH severity.

Keywords

Small pulmonary vessels pulmonary hypertension (PH)computed tomography (CT)PH severity classification

1 Introduction

Pulmonary hypertension (PH), which is defined as an increase in mean pulmonary arterial pressure (mPAP)≥25 mmHg at rest as assessed by right heart catheterization (RHC), is a progressive disorder of pulmonary circulation characterized by vascular remodeling within precapillary pulmonary arterioles that leads to increased pulmonary vascular resistance and right ventricular failure [1]. The clinical classification of PH is used to categorize multiple clinical conditions into five groups including idiopathic pulmonary arterial hypertension (iPAH), PH associated with diseases such as connective tissue diseases (CTD-PH), PH due to lung diseases and/or hypoxia containing chronic obstructive pulmonary disease with PH (COPD-PH), and other subtypes [1]. Although different types of PH may have similar clinical presentations or hemodynamic characteristics, their treatment strategy and prognosis are different. Thus, accurate and timely diagnosis and classification of PH are crucial for ensuring that patients are treated as early as possible.

RHC is the gold standard for diagnosing PH and echocardiography is the first-line screening tool [2, 3]. However, RHC is an invasive method for diagnosing PH and cannot be performed without appropriate indication; furthermore, it is not feasible as a routine follow-up technique. Echocardiography is described as the “gatekeeper” for diagnosing PH; in addition, it can also be used to identify heart structural abnormalities that may cause PH. However, its use is limited by operator experience and the acoustic window, which substantially affect the accuracy and reproducibility of this diagnostic approach. In light of these limitations, chest CT is increasingly used for routine noninvasive clinical evaluation of patients with suspected PH [3 –5]. Through various methods of quantitative analysis of chest CT data, PH can be evaluated by quantifying pulmonary vascular remodeling. As early as 1984, Kuriyama et al. found that the diameter of the main pulmonary artery (MPA) measured by chest CT can predict the presence of PH and estimate the average pulmonary artery pressure, some later studies have shown that the ratio of MPA to ascending aorta diameter (MPA/AO) derived from chest CT offer higher accuracy for PH diagnosis than using MPA alone [5 –7].

In recent years, more and more studies have focused on CT-derived pulmonary vascular variables for the diagnosis and hemodynamic evaluation of pulmonary hypertension, which include not only large pulmonary vessels, but also small pulmonary vessels [3 , 8–10]. The measurement of the cross-sectional area (CSA) of small pulmonary vessels on CT images has emerged for the quantitative evaluation of the morphologic alterations in small pulmonary vessels [8 –10]. Different types of pulmonary hypertension have different pathogenesis, which may lead to different changes of small pulmonary vessels. However, studies of the relevance of small pulmonary vessel alterations on chest CT for the identification of different types of PH and severity classification of CTD-PH remain scarce. The CSA of small pulmonary vessels as a percentage of total lung area (%CSA), which can reflect the changes of pulmonary small vessels diameter, may be useful for distinguishing PH classification. Therefore, the present study was initiated to investigate the %CSA on chest CT for distinguishing different types of PH and identifying the severity of CTD-PH.

2 Methods

2.1 Study subjects

This retrospective study was approved by our institutional review board and the requirement for informed consent from patients was waived. This study enrolled 1,087 patients with PH diagnosed by RHC between March 2011 and October 2019 (Fig. 1). The inclusion criteria were as follows: (1) a resting mPAP≥25 mmHg and a PAWP ≤15 mmHg on RHC; (2) a confirmed diagnosis of PH according to 2015 guidelines [1]; and (3) CT with/without contrast and RHC performed within 6 months of each other during which time the patient’s condition remained stable. The exclusion criteria were: (1) PH due to heritable, drug-, or toxin-related reasons, HIV infection, portal hypertension, left heart disease, or congenital heart disease; (2) image noise preventing analysis; (3) coexisting pulmonary conditions that affected quantitative CT measurements, such as moderate or severe pulmonary interstitial fibrosis, current pneumonia, and massive pleural effusion.

Fig. 1

Schematic flow-chat inclusion process for patients with PAH. CTD-LM-PAH = connective tissue disease with light to moderate pulmonary arterial hypertension, CTD-S-PAH = connective tissue disease with severe pulmonary arterial hypertension, IPAH = idiopathic pulmonary arterial hypertension, COPD-PH = chronic obstructive pulmonary disease with pulmonary hypertension, RHC = right heart catheterization.

Ultimately, 91 patients with PH (34 patients with CTD-PH, 26 patients with iPAH and 31 patients with COPD-PH) were enrolled in this study. The COPD-PH patients diagnosed by echocardiogram (pulmonary arterial systolic pressure > 36 mmHg) were selected from the consecutive patients who came to our hospital for CT examination due to COPD during the same period. We divided CTD-PH patients into connective tissue disease with light to moderate pulmonary arterial hypertension (CTD-LM-PH) (n = 17) group and connective tissue disease with severe pulmonary arterial hypertension (CTD-S-PH) (n = 17) group according to their mPAP (CTD-LM-PH group: mPAP < 45 mmHg, CTD-S-PH group: mPAP ≥45 mmHg). A total of 53 CTD patients without PH confirmed by echocardiogram (CTD-nPH) were included for comparison with the CTD-LM-PH and CTD-S-PH groups. The CTD-PH group and the CTD-nPH group were matched for age, gender, disease subgroup, and disease duration. Besides, 120 healthy control (HCs) subjects were selected from the patients who came to our hospital for CT physical examination during the same period as PH group. They were matched with PH patients for age and gender and had no history of cardiac, respiratory, or other diseases that might cause PH.

2.2 CT measurement of %CSA

The chest CT was performed with a Siemens Sensation (16-slice) or a Siemens Definition (64-slice) scanner (Siemens Medical Systems, Erlangen, Germany). We used these following acquisition parameters: effective mA of 300, 120 kVp, 0.5 s rotation time, and a pitch of 0.75. CT scans were obtained in supine position with breath-holding at full inspiration. CT scans were reconstructed at contiguous section widths of 1.5 mm using soft-tissue (B31f) and lung (B46f) kernel.

We measured two types of %CSA depending on the size of the cross-sectional area of the vessel: 1. %CSA_<5: the ratio of the sum of the cross-sectional area of the small pulmonary blood vessels with a cross-sectional area < 5 mm² of the total lung cross-sectional area; 2. %CSA_5–10: the ratio of the sum of the cross-sectional area of the small pulmonary vessels with a cross-sectional area between 5–10 mm² of the total lung cross-sectional area.

The %CSA was measured as the average of the following three plain CT axial slices: 1 cm above the upper margin of the aortic arch (upper slice), cm below the carina (middle slice), and 1 cm below the right inferior pulmonary vein (lower slice). Images were then analyzed using semiautomatic quantitative image-processing Image J software (version 1.48; National Institutes of Health, Bethesda, MD, USA). The %CSA was measured as previously described by Matsuoka et al. [11, 12].

For each CT slice, CSA measurements were performed as follows: First, the lung field was segmented using threshold technique with all pixels between –500 and –1024 HU on each CT image. Next, segmented images were converted into binary images with window level of –720 HU, and vessels were then displayed in black on the binary image [13] (Fig. 2). The CSA was obtained using the “Analyze Particles” function in ImageJ to count and measure the objects on binary images, the number of vessels of a specified size, and the CSA of each size range. Notably, vessels that ran obliquely or parallel to the slice were excluded using the “Circularity” function in ImageJ [12]. Vessels that ran at an oblique angle to the axial image were excluded using the “Circularity” function in ImageJ where “circularity” was calculated by the 4π×(area / perimeter2) of the structure of interest. Circularity ranges from 0 (straight line) to 1.0 (circle). The range of circularity was set from 0.9 to 1.0. After these settings only those vessels whose long axis was orthogonal to the scanning plane were included in the CSA measurements.

Fig. 2

Measurement of cross-sectional area of small pulmonary vessels using ImageJ software in CTD-LM-PAH patient (A-D) (mPAP: 31 mmHg, %CSA_<5: 0.731, %CSA₅_–₁₀: 0.302) and CTD-S-PAH patient (F-I) (mPAP: 50 mmHg, %CSA<5 : 0.872, %CSA5-10 : 0.528). (A, F) CT image of a lung field segmented within threshold values of –500 to –1,024 HU. (B, G) Binary image converted with a window level of –720 HU from the segmented image. (C, H) Pulmonary vessels with a cross-sectional area < 5 mm² are indicated in black. (D, I) Pulmonary vessels with a cross-sectional area between 5–10 mm² are indicated in black.

2.3 Statistical analyses

All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) (ver. 25.0, International Business Machines, Inc. Armonk, New York, USA) and Graphpad Prism (version 8.4.0). Qualitative data were expressed as frequency (percentage) and compared among groups using Fisher’s exact test. Quantitative data were expressed as mean±standard deviation and compared among groups using Student’s-test. The correlation between the %CSA and mPAP detected by RHC was assessed using Pearson’s correlation coefficient. One-way analysis of variance (ANOVA), followed by the Tukey post-hoc test, was used to compare the %CSA among groups. Determination of sensitivity, specificity, their 95%confidence intervals and Receiver Operating Characteristic (ROC) curve were performed using GraphPad prism. For analyzing, we used CTD-S-PH cases as “positive” and CTD-LM-PH or CTD-nPH as “negative” cases. The results were expressed in terms of area under the curve (AUC) and 95%confidence interval. All tests are two-sided and a P value smaller than 0.05 is considered as statistically significant.

3 Results

3.1 Demographics and %CSA of COPD-PH, CTD-PH, iPAH, and HC patients

The %CSA_<5 of the CTD-PH, iPAH, and COPD-PH groups decreased sequentially (0.79±0.65, 0.65±0.38 and 0.52±0.27, p < 0.05), while there was no significant difference in %CSA_<5 between CTD-PH patients and HCs (p = 0.508). The %CSA_5–10 of COPD-PH, CTD-PH, and iPAH patients increased (0.21±0.09, 0.49±0.20 and 0.61±0.20, p < 0.02) sequentially, while the %CSA_<5 –10 of COPD-PH patients was significantly lower than that of HCs (0.21±0.09 vs. 0.33±0.16, p = 0.001). (Fig. 3, Table 1).

Fig. 3

Differences in the %CSA between COPD-PH, CTD-PH, iPAH, and HC patient groups. %CSA_<5 = cross-sectional area of small pulmonary vessels < 5 mm² as a percentage of total lung area, %CSA₅_–10 = cross-sectional area of small pulmonary vessels 5–10 mm² as a percentage of total lung area, COPD-PH = chronic obstructive pulmonary disease with pulmonary hypertension, CTD-PH = connective tissue disease-related pulmonary arterial hypertension, iPAH = idiopathic pulmonary arterial hypertension, HC = healthy control subjects.

Table 1

%CSA of patients with CTD-PH, iPAH, COPD-PH and healthy controls

Patients’ characteristics	HCs (n = 120)	CTD-PH (n = 34)	iPAH (n = 26)	COPD-PH (n = 31)	Total (n = 211)
%CSA_<5	0.82±0.14	0.79±0.65	0.65±0.38	0.52±0.27	0.75±0.26
%CSA_5–10	0.33±0.16	0.49±0.20	0.61±0.20	0.21±0.09	0.36±0.20

%CSA_<5, the cross-sectional area of small pulmonary vessels < 5 mm² as a percentage of total lung area; %CSA_5–10, cross-sectional area of small pulmonary vessels 5–10 mm² as a percentage of total lung area; COPD-PH, chronic obstructive pulmonary disease-related pulmonary hypertension; CTD-PH, connective tissue disease-related pulmonary arterial hypertension; iPAH, idiopathic pulmonary arterial hypertension; HCs, healthy control subjects.

3.2 %CSA of CTD-LM-PH, CTD-S-PH, CTD-nPH, and HC patients

There were no differences in demographic characteristics, disease duration, and CTD subgroup between patients with and without PH (Table 2). There were no significant differences in the %CSA_<5 between the four groups. The %CSA_5–10 was significantly higher in CTD-S-PH patients than CTD-LM-PH patients and CTD-nPH patients (0.51±0.21, 0.31±0.15 and 0.28±0.12, p < 0.01) (Table 3). A significant positive correlation was found between %CSA_5–10 and mPAP in the CTD-PH group (r = 0.447, p = 0.008; Fig. 4).

Table 2
The demographic and clinical characteristics in CTD-PAH and CTD-nPAH patients

CTD-PAH (n = 34) CTD-nPAH (n = 53) P

Age(years) 41.2±14.5 38.94±13.3 0.457

Sex 0.965

Female 32 (94%) 50 (94%)

Male 2 (6%) 3 (6%)

Disease duration(months) 65.2±83.1 49.85±61.0 0.324

Subgroup 0.385

MCTD 2 (6%) 1 (2%)

SLE 13 (38%) 29 (55%)

SS 16 (47%) 18 (34%)

SSc 3 (9%) 5 (9%)

	CTD-PAH (n = 34)	CTD-nPAH (n = 53)	P
Age(years)	41.2±14.5	38.94±13.3	0.457
Sex			0.965
Female	32 (94%)	50 (94%)
Male	2 (6%)	3 (6%)
Disease duration(months)	65.2±83.1	49.85±61.0	0.324
Subgroup			0.385
MCTD	2 (6%)	1 (2%)
SLE	13 (38%)	29 (55%)
SS	16 (47%)	18 (34%)
SSc	3 (9%)	5 (9%)

MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus; SS, Sjogren syndrome; SSc, systemic sclerosis.

Table 3

%CSA in patients with CTD-LM-PH, CTD-S-PH, CTD-nPH and HCs

Parameters	CTD-LM-PH (n = 17)	CTD-S-PH (n = 17)	CTD-nPH (n = 53)	HCs (n = 120)	P
%CSA_5 - 10	0.31±0.15	0.51±0.21	0.28±0.12	0.33±0.16	0.000
%CSA_<5	0.78±0.24	0.80±0.40	0.78±0.34	0.81±0.24	0.215

CTD-LM-PH, connective tissue disease with mild to moderate pulmonary arterial hypertension; CTD-S-PH, connective tissue disease with severe pulmonary arterial hypertension; CTD-nPH, connective tissue disease-without pulmonary arterial hypertension; HCs, healthy control subjects; %CSA_<5, the cross-sectional area of small pulmonary vessels < 5 mm² as a percentage of total lung area; %CSA_5–10, cross-sectional area of small pulmonary vessels 5–10 mm² as a percentage of total lung area.

Fig. 4

Correlation between the %CSA_5–10 and mPAP in CTD-PH patients. %CSA₅_–10 = cross-sectional area of small pulmonary vessels 5–10 mm² as a percentage of total lung area, mPAP = mean pulmonary arterial pressure.

3.3 ROC analysis of %CSA5-10 in the CTD-PH group

The area under the curve for %CSA_5–;₁₀ was 0.770 (95%CI, 0.607–0.933). This result indicates that %CSA_5–10 above 0.38 could serve as a threshold for the prognosis of CTD-S-PH with a sensitivity and specificity of 0.824 and 0.706, respectively (Fig. 5).

Fig. 5

ROC analysis of ability of the %CSA_5–10 to predict CTD-S-PH. ROC = receiver operating characteristic curve, CTD-S-PH = connective tissue disease with severe pulmonary arterial hypertension.

4 Discussion

The present study focused on the significance of small pulmonary vessel alterations assessed by chest CT for distinguishing PH classification. Our results demonstrated a significant difference in the %CSA among the COPD-PH, CTD-PH, and iPAH groups. Furthermore, the %CSA_5–10 was observed to play an important role in identification of CTD-PH severity.

Lumen size is an important factor for quantitative evaluation of the CSA of small pulmonary vessels. Pulmonary vessels less than 5 mm² include elastic and muscular vessels. Matsuoka et al. reported that the %CSA_<5 was decreased in a population with severe emphysema and pulmonary hypertension [11]. We observed similar results for patients with COPD-PH and iPAH. The decreased %CSA_<5 in the COPD-PH groups might result from passive vascular compression by emphysema and vasoconstriction/vasodilation imbalance, thrombosis, cell proliferation, and remodeling of the pulmonary arterial walls [12 –14], whereas the decreased %CSA_<5 in the iPAH groups might relate to medial hypertrophy in muscular pulmonary arteries and intimal fibrosis, which may completely occlude the lumen of these vessels [15]. We found no significant difference in the %CSA_<5 between CTD-PH patients and HCs, which might be due to occlusion of muscular vessels and enlargement of elastic vessels.

Pulmonary vessels between 5–10 mm² (%CSA_5–10) were composed of mostly elastic vessels. It is possible that chronic hypoxia and pulmonary emphysema in COPD patients can cause alveolar expansion and thus compress the blood vessels –particularly small terminal vessels in the lungs –and exacerbate vasospasm, eventually leading to the decreased %CSA_5–10 reported in COPD-PH [11, 16]. iPAH and CTD-PH are characterized by vasoconstriction and vascular remodeling [17 –22], which include abnormal muscularization of the distal and medial precapillary arteries, loss of precapillary arteries, thickening of elastic vessels, and neointimal formation [16, 23]. Muscularization is known to occur in both precapillary vascular and post-capillary vessels. The %CSA_5–10 in the iPAH group was higher than that in the CTD-PH group, which reflects the higher severity of iPAH to a certain extent. This result may be because the treatment of primary disease in CTD-PH patients improves the condition of PH in some way.

In this study, we found the %CSA_5–10 was significantly higher in the CTD-S-PH group than that in the CTD-nPH, CTD-LM-PH, and HC groups. This finding suggests that small elastic pulmonary vessel alteration may be secondary to severely elevated pulmonary artery pressure. In patients with CTD-S-PAH, inflammation, autoimmunity, and increased pulmonary artery pressure may contribute to alterations in the %CSA_5–10.

There are several limitations of this study. First, COPD-PH patients were not diagnosed by RHC, which might lead to misdiagnosis of COPD-PH. Second, the study considered three slices for the quantification of vascular area, which may affect vascular counting. Some small vessels that were not perpendicular to the slice (i.e., not round in shape) cannot be accurately measured. Furthermore, CTD-PH patients with light interstitial pneumonia were included, which might reflect the inexact situation of patients with connective tissue disease. Finally, we did not histologically measure the CSA of pulmonary vessels, and there may be differences between CSA measured by CT image and the actual CSA of the pulmonary vessels. Further evaluation is thus necessary.

5 Conclusions

In this study, we found a significant difference in the %CSA_5–10 and %CSA_<5 among different types of PH. The quantitative parameter %CSA on chest CT might serve as a useful tool for distinguishing PH classification. Furthermore, the %CSA_5–10 might reflect PH severity in CTD-PH patients.

Footnotes

Acknowledgments

Not applicable.

Conflict of interests

We certify that we all have participated sufficiently in the work. All authors have read and approved the manuscript. All authors declare that there is no conflict of interest.

Competing interests

All authors also declare that they have no competing interests.

Funding

This work was supported by the National Natural Science Foundation of China [81601464, 81570332, and 81970723], a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and Key Medical Subjects of Jiangsu Province (CN) (ZDRCA2016019).

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