Evaluation of pulmonary perfusion and ventilation in suspected chronic thromboembolic pulmonary hypertension via phase-resolved functional lung magnetic resonance imaging: correlations with hemodynamics and cardiopulmonary function

Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious long-term complication and the leading cause of death in patients with pulmonary embolism. It is characterized by perfusion defects resulting from pulmonary vascular obstructions, which cause severe hemodynamic impairment of the lungs, eventually leading to right-sided heart failure and death (1). Ventilation-perfusion (V/Q) scans and computed tomography pulmonary angiography (CTPA) are commonly used to detect perfusion defects and residual clots, while right heart catheterization (RHC) is the gold standard for diagnosing pulmonary hypertension (PH) (2). Although RHC provides the essential hemodynamic parameters, it is an invasive procedure with low—but not ignorable—associated risks for morbidity and mortality (3).

There is increasing interest in the potential application of noninvasive diagnostic methods such as echocardiography and magnetic resonance imaging (MRI) in the assessment of pulmonary hemodynamics. Dynamic contrast-enhanced MRI is a reliable, noninvasive tool for detecting perfusion defects in pulmonary embolism (4). However, it requires breath-holding and the injection of gadolinium-containing contrast agents. In contrast, Fourier decomposition (FD) MRI allows for the quantitative assessment of pulmonary ventilation and perfusion during free breathing and does not require the use of contrast media (5). Phase-resolved functional lung (PREFUL) MRI, an advancement of FD MRI, enables improved temporal resolution and the quantitative evaluation of regional perfusion and ventilation dynamics (6). Since it was first introduced, numerous studies have validated the accuracy and repeatability of PREFUL MRI and demonstrated its utility in evaluating various clinical conditions, such as cystic fibrosis and chronic obstructive pulmonary disease (7-12). There is also an abundance of research indicating that PREFUL MRI has strong repeatability in both healthy individuals and patients, and multicenter studies have demonstrated that is a reliable, noninvasive method for imaging regional lung perfusion in (7,12,13). One study reported that the perfusion defect percentage (QDP) calculated via PREFUL MRI was significantly higher in 18 patients with confirmed CTEPH or chronic thromboembolic pulmonary disease (CTED) than in subgroups with other causes of PH or without PH (14). PREFUL MRI also can detect and quantify changes in perioperative perfusion among patients with CTEPH, and improvements in quantitative lung perfusion can be used to predict changes in 6-minute walk distance (6MWD) (15).

In addition to quantifying perfusion, PREFUL MRI enables the free-breathing assessment of lung ventilation. Studies have demonstrated concordance between PREFUL MRI and ¹²⁹Xe MRI in their measurement of regional ventilation defect percentage (VDP) (16-18). Furthermore, PREFUL MRI can be reliably used to monitor changes in perfusion and ventilation after treatment for conditions such as cystic fibrosis and asthma (19-21). It has even shown the potential utility in assessing VDPs in preterm infants and detecting regional lung function variations in patients with bronchopulmonary dysplasia (22). In patients with CTEPH, microvascular remodeling occurs alongside decreases in pulmonary capillary blood volume and diffusing capacity. Recent reports have indicated that obstructive ventilatory impairment may be etiologically linked to vascular involvement in CTEPH (23). Compared with other imaging modalities, PREFUL MRI may offer advantages in evaluating patients with CTEPH and distinguishing between CTED and CTEPH. In this study, we aimed to evaluate pulmonary perfusion and ventilation in patients with suspected CTEPH using PREFUL MRI and to investigate its correlations with RHC and pulmonary function test results. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2750/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethical Review Board of China-Japan Friendship Hospital, Beijing, China (No. 2017-24). The requirement for individual consent was waived due to the retrospective nature of the analysis.

Patients

This study included all patients with clinically suspected CTEPH who underwent PREFUL MRI and were admitted to the Respiratory Center at China-Japan Friendship Hospital from June 2020 to September 2022. A retrospective analysis of data acquired during a previous prospective cohort study in which PREFUL MRI was applied in patients with suspected CTEPH was conducted (24). Consecutive patients from this cohort who had CTEPH or CTED were included according to the following criteria: (I) persistent shortness of breath or exercise intolerance with follow-up conducted after at least 3 months of standard anticoagulation therapy for acute pulmonary embolism; (II) unexplained PH, defined as elevated systolic pulmonary arterial pressure (>60 mmHg) on transthoracic echocardiography, but not PH due to left-sided heart disease (group 2 PH) or pulmonary disease (group 3 PH); (III) completion of RHC or echocardiography, pulmonary angiography (PA), V/Q lung scan or CTPA, and PREFUL MRI; and (IV) RHC and all imaging examinations completed within 2 weeks of hospital admission. Meanwhile, the exclusion criteria were as follows: (I) absolute contraindications to MRI; (II) severe image artifacts in PREFUL MRI; and (III) the concomitant presence of heart disease, severe interstitial pulmonary disease, or emphysema that could impair cardiac or pulmonary function.

The diagnosis of CTEPH was established through multidisciplinary team discussions based on evidence of chronic pulmonary embolism (CPE) as confirmed by imaging after at least 3 months of standard anticoagulant therapy and a mean pulmonary arterial pressure (mPAP) >20 mmHg (1 mmHg =0.133 kPa) at rest, pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and pulmonary vascular resistance (PVR) >2 Wood units as measured by RHC (2). CTED was diagnosed in patients with CPE who had symptoms such as dyspnea and/or heart failure [World Health Organization (WHO) class II, III, or IV] but who did not exhibit elevated mPAP at rest (2,25). Ultimately, 31 patients with CTEPH and 11 patients with CTED were included in this study.

Clinical data

Clinical information collected for all patients included age, sex, body mass index (BMI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6MWD, and WHO functional class (Table 1).

MRI examinations

All MRI scans were performed with a 1.5T MRI scanner (MAGNETOM Aera, Siemens Healthineers, Erlangen, Germany) with a maximum gradient strength of 45 mT/m and a maximum slew rate of 200 mT/ms. Before scanning, patients were trained to maintain a stable breathing frequency and amplitude. PREFUL MRI was acquired with a two-dimensional balanced steady-state free precession (bSSFP) sequence under free-breathing conditions. Images were acquired across five coronal slices, with the midslice centered on the tracheal bifurcation. The imaging parameters were as follows: echo time, 0.4 ms; repetition time, 1.1 ms; flip angle, 27.5°; acquisition matrix, 104×128; field of view, 500×500 mm²; slice thickness, 15 mm; and generalized autocalibrating partially parallel acquisitions with an acceleration factor of 2. Each slice included 250 images captured over 62 seconds resulting in a total PREFUL protocol acquisition time of ~5 minutes.

PREFUL MRI postprocessing

All bSSFP images were analyzed with stand-alone research software (MRLung 2.2.0; Siemens Healthineers). The postprocessing workflow included image registration, lung segmentation, filtering, and phase resorting, yielding ventilation and perfusion maps across full respiratory and cardiac cycles, along with quantitative parameters for each slice (6,26-29). Additional details of the PREFUL MRI postprocessing are provided in Appendix 1.

A radiologist with 6 years of experience in PREFUL MRI who was blinded to other structure sequences and clinical data reviewed the PREFUL datasets. The mean parameter values for five PREFUL MRI slices were recorded, including normalized perfusion (Q_N), exclusive QDP (QDP_exc), total QDP (QDP_tot), regional ventilation (RV), exclusive VDP (VDP_exc), total VDP (VDP_tot), and V/Q match defect percentage (VQM_def).

RHC and PA

RHC and PA were performed with an Artis Zee III ceiling-mounted angiography system (Siemens Healthineers). The femoral or jugular vein was chosen as the puncture site, and an 8-Fr long sheath (Cook Medical, Bloomington, IN, USA) was introduced via the Seldinger technique. A 6-Fr thermodilution catheter (Bioptimal, Singapore) was then advanced through the sheath. The pressure transducer was placed at the level of the right atrium and zeroed to atmospheric pressure at end expiration. Hemodynamic parameters, including mPAP and PAWP, were recorded. Cardiac output (CO) was calculated via the indirect Fick method, and PVR was calculated as follows: PVR = (mPAP − PAWP)/CO. The cardiac index (CI) was calculated as follows: CI = CO/body surface area. For PA, a 5-Fr/6-Fr pigtail catheter (Cordis, Miami Lakes, FL, USA) was advanced into the main pulmonary artery and both the left and right pulmonary arteries. For selective PA, iodixanol (Ultravist 370; Bayer Schering Pharma AG, Leverkusen, Germany) was injected with a high-pressure injector, with a total volume of 20–40 mL per position and a flow rate of 15–30 mL/s. The main pulmonary angiogram was acquired in the anteroposterior projection, whereas the left and right pulmonary angiograms were obtained in the 45° right-anterior-oblique and 45° left-anterior-oblique views, respectively; image acquisition was conducted at 15 frames/s.

Spirometry

Pulmonary function tests were performed in accordance with the guidelines of the American Thoracic Society (30). All patients underwent assessments of pulmonary ventilation and diffusion capacity. The recorded parameters included percent predicted forced vital capacity (FVC %pred), percent predicted forced expiratory volume in 1 s (FEV₁ %pred), FEV₁/FVC %pred, and percent predicted single-breath diffusing capacity of the lung for carbon monoxide (DLCO SB %pred).

Statistical analysis

Statistical analysis was performed with SPSS version 26.0 (IBM Corp., NY, USA). Continuous variables with a normal distribution are expressed as the mean ± standard deviation, nonnormally distributed continuous variables are expressed as the median and interquartile range, and categorical variables are expressed as frequencies and percentages, with data being compared with the two-tailed Student t-test or the Mann-Whitney test and the χ² or Fisher exact test, respectively. The sensitivity, specificity, and accuracy of the PREFUL MRI parameters in differentiating CTEPH from CTED were calculated. Receiver operating characteristic (ROC) curve analysis was conducted to calculate the area under the curve (AUC), sensitivity, specificity, and accuracy of each PREFUL MRI parameter via MedCalc 22.021 software (MedCalc Software, Ostend, Belgium). The optimal cutoff point corresponding to the largest Youden index was determined. Correlations of PREFUL MRI perfusion with ventilation parameters and hemodynamic parameters, right heart function indicators, and pulmonary function parameters were assessed through Spearman correlation analysis. Correlation coefficients were rated as follows: between 0.6 and 1.0, strong; between 0.3 and 0.6, moderate; and between 0 and 0.3, weak or negligible. P values <0.05 were considered statistically significant.

Results

Clinical characteristics of patients with CTEPH or CTED

The cohort included 26 men and 16 women, with a mean age of 53.5±13.5 years. There were 31 patients in the CTEPH group and 11 patients in the CTED group. No significant differences were observed between the CTEPH and CTED groups in terms of age, sex, or BMI. Thirteen patients with CTEPH and one patient with CTED were classified as WHO functional class III–IV. Additionally, a significant difference in 6MWD was observed between the two groups. All patients with CTEPH and five patients with CTED underwent RHC and PA, while the remaining patients were assessed with echocardiography for the evaluation of mPAP. Patients with CTEPH had a mean mPAP of 41.8±11.7 mmHg. Pulmonary function tests were performed in 27 patients with CTEPH and in 7 patients with CTED. The detailed clinical characteristics for each group are provided in Table 1.

Comparison of PREFUL parameters between CTEPH and CTED

Q_N was significantly higher in the CTED group, while the other two parameters that reflect the extent of perfusion defects, QDP_exc and QDP_tot, were significantly higher in the CTEPH group. Regarding ventilatory parameters, no significant differences were observed in RV or VDP_exc between the two groups. However, VDP_tot was significantly elevated in the CTEPH group and thus so was VQM_def (Figures 1-3 and Table 1).

Figure 1 PREFUL MRI of a 58-year-old man with CTEPH. Five coronal slices, centered at the level of the tracheal bifurcation, are presented from anterior to posterior (displayed from left to right, respectively). The global defect percentages for this patient were as follows: RV =16.7%, Q_N =4.4%, QDP_exc =29.9%, QDP_tot =32.7%, VDP_exc =18.3%, VDP_tot =21.1%, VQM_def =2.8%, and VQM_non-def =49.0%. CTEPH, chronic thromboembolic pulmonary hypertension; MRI, magnetic resonance imaging; PREFUL, phase-resolved functional lung; Q_N, normalized perfusion; QDP_exc, exclusive perfusion defect percentage; QDP_tot, total perfusion defect percentage; RV, regional ventilation; VDP_exc, exclusive ventilation defect percentage; VDP_tot, total ventilation defect percentage; VQM_def, ventilation/perfusion match defect percentage; VQM_non-def, ventilation-perfusion match nondefect percentage.

Figure 2 PREFUL MRI of a 50-year-old man with CTED. The global defect percentages for this patient were as follows: RV =15.9%, Q_N =6.1%, QDP_exc =19.9%, QDP_tot =19.9%, VDP_exc =2.0%, VDP_tot =2.0%, VQM_def =0%, and VQM_non-def =78.1%. CTED, chronic thromboembolic pulmonary disease; MRI, magnetic resonance imaging; PREFUL, phase-resolved functional lung; Q_N, normalized perfusion; QDP_exc, exclusive perfusion defect percentage; QDP_tot, total perfusion defect percentage; RV, regional ventilation; VDP_exc, exclusive ventilation defect percentage; VDP_tot, total ventilation defect percentage; VQM_def, ventilation/perfusion match defect percentage; VQM_non-def, ventilation-perfusion match nondefect percentage.

Figure 3 Other results from the patient in Figure 1 (A,B) and images from the patient in Figure 2 (C,D). (A) Pulmonary angiogram revealed an eccentric filling defect in the main pulmonary artery (arrow). (B) Flow-volume loop indicated mild ventilatory dysfunction and mild diffusion impairment, with a negative bronchodilator test. The premedication pulmonary function test results were as follows: FVC %predicted =86.2%, FEV₁ %predicted =74.5%, FEV₁/FVC %predicted =84.7%, and DLCO SB %predicted =65.6%. (C) Maximum intensity projection of the pulmonary artery indicated filling defects in the right lower lobe pulmonary artery (arrow), with complete occlusion of the lumen. (D) Flow-volume loop demonstrated normal lung function. FVC %predicted, percent predicted forced vital capacity; FEV₁ %predicted, percent predicted forced expiratory volume in 1 s; DLCO SB %predicted, percent predicted single-breath diffusing capacity of the lung for carbon monoxide.

In differentiating CTEPH from CTED, VDP_tot exhibited the highest sensitivity (90%) and lowest specificity (54%) and had an AUC of 0.71. In contrast, Q_N, QDP_exc, QDP_tot, and VQM_def demonstrated better performance, with AUCs of 0.85, 0.87, 0.87, and 0.91, respectively. VQM_def, which combines perfusion and ventilation data from PREFUL MRI, had the best diagnostic performance among all parameters (Figure 4 and Table 2).

Figure 4 ROC curve comparison of various PREFUL MRI parameters. The areas AUCs of Q_N, QDP_exc, QDP_tot, VDP_tot, and VQM_def were 0.85, 0.87, 0.87, 0.71, and 0.91, respectively. AUC, area under the curve; MRI, magnetic resonance imaging; PREFUL, phase-resolved functional lung; Q_N, normalized perfusion; QDP_exc, exclusive perfusion defect percentage; QDP_tot, total perfusion defect percentage; ROC, receiver operating characteristic; VDP_tot, total ventilation defect percentage; VQM_def, ventilation/perfusion match defect percentage.

Correlations of PREFUL MRI perfusion parameters with hemodynamic, right heart function, and pulmonary function parameters

Among the 36 patients who underwent RHC for the measurement of hemodynamic parameters, Q_N, QDP_exc and QDP_tot were significantly correlated with mPAP (r=−0.490, r=0.539, and r=0.534, respectively; P<0.01). Significant associations were observed between QDP_exc and PVR and between QDP_tot and PVR (r=0.369 and r=0.362, respectively; P<0.05). Additionally, Q_N, QDP_exc, and QDP_tot were significantly correlated with clinical indicators of right heart function, including 6MWD, NT-proBNP level, and WHO functional class. No significant correlations were observed between PREFUL MRI perfusion parameters and pulmonary function test results (Table 3).

Correlations of PREFUL MRI ventilation parameters with pulmonary function parameters

RV was negatively correlated with DLCO SB %pred (r=−0.588; P<0.001), and VDP_tot was negatively correlated with FEV₁/FVC %pred (r=−0.379; P=0.027). There were significant correlations between the other pulmonary function parameters and RV, VDP_exc, or VDP_tot (all P values >0.05) (Table 4).

Discussion

In this study, we evaluated a cohort of patients with suspected CTEPH using the recently developed PREFUL MRI technology, focusing on pulmonary perfusion and ventilation. PREFUL MRI revealed significant differences in perfusion parameters between patients with CTEPH and those with CTED, including Q_N, QDP_exc, QDP_tot, and VQM_def. Notably, VQM_def demonstrated the best diagnostic performance in differentiating CTEPH from CTED, with an AUC of 0.91. Additionally, PREFUL MRI parameters were significantly correlated with hemodynamic and right heart function indicators, as well as certain pulmonary function parameters. PREFUL analysis offers considerable advantages in the clinical evaluation of pulmonary embolism because it allows for the global assessment of lung perfusion and ventilation.

Our results showed that patients with CTEPH had more extensive perfusion defects than did those with CTED, as reflected by decreased Q_N and increased QDP_exc and QDP_tot. A recent study also reported that patients with CTEPH or CTED exhibited significantly higher QDP values than did the subgroups with other causes of PH or without PH (14). Another study used PREFUL MRI to monitor changes in perioperative perfusion among 31 patients with CTEPH and found significant improvement in QDP after pulmonary endarterectomy (15). In our study, all perfusion parameters were significantly associated with mPAP. Pöhler et al. reported a significant correlation between the percentage change in mPAP and the percentage change in QDP for the whole lung (Spearman ρ=0.45; P=0.021) (15). In our study, the PREFUL MRI perfusion parameters were also significantly correlated with the clinical indicators of right heart function. These parallels suggest that perfusion parameters derived from PREFUL MRI can effectively characterize the severity of hemodynamic abnormality in patients with CPE.

Although both CTEPH and CTED involve CPE, patients with CTEPH experience more severe hemodynamic abnormalities, which can lead to right-sided heart failure and death. In our study, VQM_def had the best performance in differentiating CTEPH from CTED, suggesting that it could serve as an imaging biomarker for CTEPH progression in patients with CPE. VQM_def reflects regions with coexisting impairment in perfusion and ventilation. The underlying pathophysiological mechanism may be that thrombosis and remodeling of the pulmonary artery in CTEPH generate inflammatory mediators that induce nearby bronchiolar constriction (23). The ability of PREFUL MRI to differentiate between these conditions is highly valuable in managing patients with CPE. Although echocardiography is used to diagnose PH, its accuracy is subject to various factors, including tricuspid regurgitation volume, spectral quality, pulmonary artery pressure levels, right atrial pressure estimates, and operator expertise. Moreover, there is no consensus regarding the cutoff values for a diagnosis of PH (31,32). VQM_def, which integrates both ventilation and perfusion data from a single-acquisition time series, provides an optimal condition for V/Q mapping. Unlike conventional V/Q scans, PREFUL MRI does not require the inhalation or intravenous injection of radiolabeled microparticles.

A number of recent studies have used PREFUL ventilation parameters to evaluate pulmonary function (12,22,33). PREFUL MRI quantifies RV by tracking lung motion during the breathing cycle and identifies ventilation defects through altered signal dynamics between inspiration and expiration. A meta-analysis revealed a pooled correlation coefficient of −0.60 (95% confidence interval: −0.73 to −0.44) between VDP and FEV₁ across seven studies, although significant heterogeneity was present (34). Consistent with previous research (14,34), our study showed that RV was significantly correlated with DLCO SB %pred, whereas VDP_tot was correlated with FEV₁/FVC %pred, with respective correlation coefficients of −0.588 and −0.379. The decline in diffusing capacity in patients with CTEPH may be partly due to a gradual reduction in alveolar-capillary density, along with decreased pulmonary capillary blood volume and increased V/Q mismatch. Our study also identified a significant difference in VDP_tot between patients with CTEPH and those with CTED. However, Moher Alsady et al. suggested that VDP does not significantly differ between patients with confirmed CTEPH or CTED and those in whom these diagnoses were excluded (14). The VDP can reflect reduced ventilation in a given area; in our study, patients with CTEPH exhibited significantly greater airway obstruction (based on FEV₁/FVC) than did those with CTED although the difference in FEV₁ was not significant. This might explain why patients with CTEPH had a significantly higher VDP_tot as compared to patients with CTED. Notably, the determination of thresholds plays a critical role in calculating QDP and VDP, but the sample sizes in studies examining CTEPH and CTED have been limited. Further research is needed to determine whether PREFUL ventilation parameters can reflect the degree of hypoxia in patients with CTEPH.

As an emerging paradigm in functional lung imaging, PREFUL MRI has unique capability to simultaneously quantify RV-perfusion patterns during free breathing. The strong correlation between perfusion parameters and invasive hemodynamic indices establishes PREFUL as a surrogate biomarker system, the use of which may reduce the utilization RHC in patients with CTED. In the future, PREFUL parameters may further provide longitudinal monitoring of therapeutic responses. Moreover, studies with longer follow-up and larger cohorts should focus on the use of PREFUL parameters as a clinical monitoring tool for assessing rehospitalization risk, guiding stratified follow-up strategies and monitoring thrombus progression over time.

There were several limitations in our study which should be acknowledged. First, the cohort included only 11 patients with CTED, and further research with a larger sample size is needed to validate our findings and clarify certain issues, particularly the role of VQM_def in differentiating CTEPH from CTED. Second, the study collected data from only five slices, thereby only providing partial lung coverage that might have led to bias related to the correlations among clinical indicators, hemodynamic parameters, and pulmonary function parameters. Third, a portion of patients with CTED did not undergo RHC for the assessment of hemodynamic changes, introducing the possibility of misdiagnosis that could affect the reliability of comparisons. Fourth, patients with pulmonary arterial hypertension (group 1 PH) were not analyzed because of the small sample size, which limits the generalizability of the findings to all patients with suspected CTEPH. Future studies should evaluate the diagnostic accuracy of PREFUL MRI in patients with group 1 PH through multicenter validation. Finally, the technical limitations of the PREFUL MRI may cause overestimation of perfusion defects. Complex motion of the cardiac wall or markedly thickened pulmonary arteries in severe PH can lead to increases in the perfusion defect parameters in adjacent lung areas.

Conclusions

Quantitative parameters obtained from PREFUL MRI were correlated with hemodynamic status and cardiopulmonary function in patients with CTEPH or CTED. PREFUL MRI is a contrast-free, free-breathing imaging method, and its perfusion parameters demonstrated strong performance in diagnosing CTEPH, supporting its potential for clinical application.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2750/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2750/dss

Funding: This study received funding from the National Natural Science Foundation of China (No. 82272081 to M.L.)

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2750/coif). M.L. reports receiving funding from the National Natural Science Foundation of China (No. 82272081). J.A. is an employee of Siemens Shenzhen Magnetic Resonance Ltd. R.G. is an employee of Siemens Healthineers. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethical Review Board of China-Japan Friendship Hospital, Beijing, China (No. 2017-24). The requirement for individual consent was waived due to the retrospective nature of the analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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