Reduced pulmonary vascular bed volume in cryptogenic stroke patients with patent foramen ovale: a myocardial contrast echocardiography study

Introduction

The foramen ovale is a physiological channel in the atrial septum during embryonic cardiac development, located at the junction of the embryonic septum primum and septum secundum. It typically forms a slit-like abnormal channel covered by the thin lamellar structure of the septum primum, resembling a functional valve. The foramen ovale usually achieves anatomical closure within the first year after birth. When it remains unclosed after 3 years of age, it is termed patent foramen ovale (PFO). PFO manifests as an inferior-right to superior-left-oriented channel between the septum primum and septum secundum, which may present as a functionally adherent potential gap, a persistently open “tunnel-like” structure, or a “stretched” misalignment between the septa (1). At rest, a PFO may exhibit no shunt, left-to-right shunt, right-to-left shunt (RLS), or bidirectional shunt (1). However, all PFO demonstrate transient or persistent RLS when right atrial pressure exceeds left atrial pressure (e.g., during coughing, Valsalva maneuver, volume overload, pulmonary vascular disease, positive end-expiratory pressure, or infant crying), which can lead to a reduction in pulmonary circulation blood flow, thereby potentially impairing normal development and function of the pulmonary vascular bed. The prevalence of PFO in adults ranges from 20% to 34% (2,3); however, its persistent effects on adult pulmonary vasculature remain unclear.

Myocardial contrast echocardiography (MCE) serves as a noninvasive, radiation- and nephrotoxicity-free method for quantitative assessment of pulmonary vascular bed volume (PVBV). Research has validated its utility for rapid bedside diagnosis and differential diagnosis of pulmonary embolism (4). Currently, MCE has been established as a routine examination for critically ill patients in our institutions.

Since its initial discovery by Claudius Galen (5), growing clinical evidence has associated PFO with various clinical syndromes including cryptogenic stroke, transient ischemic attack, migraine, platypnea-orthodeoxia syndrome, sleep apnea syndrome, myocardial infarction with normal coronary arteries, and decompression sickness (1-3,6-8). In the present study, we sought to investigate the changes in PVBV in patients with cryptogenic stroke and further analyzed its determinants, using agitated saline contrast transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) to determine the presence of PFO, and MCE to quantitatively assess PVBV. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-425/rc).

Methods

Study population

This study was approved by the Human Research Ethics Committee of Yangpu Hospital, School of Medicine, Tongji University (No. LL-2020-SHZKKX-001). Written informed consent was provided by all participants prior to enrollment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Between January 2021 and December 2024, consecutive patients with cryptogenic stroke who had suspected PFO and all underwent TTE, agitated saline contrast TTE, TEE, and MCE at Yangpu Hospital, School of Medicine, Tongji University, were enrolled in this study. The exclusion criteria were as follows: pulmonary diseases including pulmonary embolism, interstitial lung disease, chronic obstructive pulmonary disease, pulmonary arteriovenous malformation, intrapulmonary arteriovenous anastomoses, cardiac diseases including coronary artery disease, valvular heart disease, and heart failure, malignancies, the use of chemotherapy and vasoactive drugs, hepatopulmonary syndrome, and standard echo images of inadequate quality.

Conventional TTE

All TTE examinations were performed using a commercially available ultrasound system (EPIQ 7C, Philips, Amsterdam, Netherlands) equipped with an X5-1 PureWave xMATRIX transducer (1–5 MHz). According to the recent European Association of Cardiovascular Imaging (EACVI)/American Society of Echocardiography (ASE) recommendations (9,10), the following parameters were obtained: left ventricular end-diastolic anteroposterior diameter (D_LV), right ventricular end-diastolic anteroposterior diameter (D_RV), left atrial end-systolic transverse diameter (D_LA), right atrial end-systolic transverse diameter (D_RA), left ventricular ejection fraction (LVEF), left ventricular mass index (LVM index), the ratio of the peak early diastolic transmitral filling velocity to the peak early diastolic lateral mitral annulus tissue velocity (E/e’), tricuspid annular plane systolic excursion (TAPSE), the peak tricuspid regurgitation velocity (TR_Vmax), the velocity time integral at right ventricular outflow tract (VTI_RVOT), the velocity time integral at pulmonary artery (VTI_PA), and pulmonary artery diameter (D_PA). The dimensions of the four cardiac chambers were scaled to body surface area (BSA). Finally, estimated pulmonary artery systolic pressure (PASP) was calculated using the formula: PASP (mmHg) = 4TR_Vmax² + right atrial pressure, and pulmonary vascular resistance (PVR) was calculated using the validated formula: PVR (Wood unit) = TR_Vmax/VTI_RVOT × 10 + 0.16 (11).

Agitated saline contrast TTE

Prior to agitated saline contrast TTE, each patient performed three practice attempts of blowing into the pressure gauge. Each attempt was required to generate a pressure exceeding 40 mmHg sustained for at least 5 seconds, followed by normal breathing instructions. This modified Valsalva maneuver demonstrates enhanced reproducibility compared to conventional methods. The agitated saline contrast agent was prepared by vigorously mixing 1 mL of air, 1 mL of autologous blood, and 8 mL of normal saline through rapid exchange between two 10-mL syringes connected via a three-way stopcock for 20 complete passes. Contrast TTE was performed in the standard apical 4-chamber view. Agitated saline contrast was administrated through the left median cubital vein. Gain settings were adjusted individually to optimize the visualization of the microbubbles and the interatrial septum. Patients were encouraged to perform the pressure gauge blowing maneuver as practiced during prior training when complete right atrial opacification was achieved. The presence of RLS-PFO was confirmed when microbubbles shunting into the left atrium and left ventricle originating from the fossa ovalis of the interatrial septum (rather than the pulmonary veins) were observed within ≤3–5 cardiac cycles after right atrial opacification. The RLS level of PFO was classified as grade 0 (no microbubble), grade I (1–9 microbubbles/frame), grade II (10–30 microbubbles/frame), and grade III (>30 microbubbles/frame) (1).

TEE

TEE and contrast TEE were performed using the same system equipped with a 2–8 MHz multi-frequency transesophageal transducer. To enhance test tolerance, pharyngeal surface anesthesia with tetracaine hydrochloride gel was administered 10 minutes prior to the examination. During the examination, two-dimensional and color Doppler images of the interatrial septum at 30–50 degrees midesophageal and in the bicaval window were evaluated, and a fissure located in the fossa ovalis region of the interatrial septum was diagnosed as a PFO. The height of PFO was defined as the maximum separation between the septum primum and septum secundum in the end-systolic frame. The length of PFO was defined as the maximum overlap between the septum primum and septum secundum. Each patient also underwent transesophageal agitated saline contrast imaging. The configuration and administration method of agitated saline contrast were the same as in the above method. The presence of RLS-PFO was confirmed when microbubbles passed through the foramen ovale fissure from the right atrium to the left atrium at rest or during the maintenance stage or release phase of Valsalva maneuver within ≤3–5 cardiac cycles after right atrial opacification.

MCE

MCE was performed using the same system equipped with an X5-1 PureWave xMATRIX transducer (1–5 MHz). A total of 59 mg of Sonovue^® phospholipid-shell sulfur hexafluoride microbubbles (Bracco, Milan, Italy) was diluted in 5 mL of saline according to the manufacturer’s protocol. Examination was performed from the standard apical 4-chamber view. At the beginning, 1 mL of SonoVue^® solution was administered intravenously at an infusion rate of about 0.5 mL/s in order to gain a visible ventricular opacification and myocardial enhancement, quickly followed by the administration of 1.5 mL at an infusion rate of about 0.75 mL/min to assure optimal myocardial enhancement. The whole process (about 120–165 s), specifically, from the gradually visible ventricular opacification to the plateau of myocardial enhancement (mechanical index, 0.07), and then to the peak replenishment of myocardial Sonovue^® microbubbles at consecutive pulsing intervals after a destructive pulse of a mechanical index of 1.35, was stored digitally. Image analysis was performed off-line by this same experienced radiologist. Pulmonary transit time (PTT), the time for the SonoVue^® contrast agent to travel from the peak opacification in RV to the peak opacification in LV, was determined by the time-intensity curves of MCE. To generate the normalize value, the PTT was divided by the mean R-R interval (NPTT = PTT/mRR). The mean R-R interval was calculated from the heart rates that were measured by the electrocardiogram (ECG) during the contrast studies. Finally, PVBV was calculated, according to the formula: PVBV (mL) = right ventricular stroke volume (SV_RV) × NPTT = (D_PA/2)² × π × VTI_PA × NPTT (4,12) (Figure 1). SV_RV and PVBV were also scaled to BSA. In addition, total lung capacity (TLC) was calculated based on the height, weight and sex using Global Lung Initiative calculations.

Figure 1 Conventional transthoracic echocardiography (parasternal short-axis view at the base of the heart) with the measurement of D_PA (A) and the VTI_PA (B) and myocardial contrast echocardiography (apical four-chamber view) with the measurement of PTT (C) in a cryptogenic stroke patients with PFO, illustrating the measurement methodology of PVBV (D). D_PA, pulmonary artery diameter; HR, heart rate; NPTT, normalized PTT by R-R interval; PFO, patent foramen ovale; PTT, pulmonary transit time; PVBV, pulmonary vascular bed volume; SVRV, right ventricular stroke volume; VTI_PA, velocity time integral at pulmonary artery.

All TTE, agitated saline contrast TTE, TEE, agitated saline TEE, and MCE examinations were performed by the same experienced radiologist (with 30 years of clinical experience in echocardiography), who had no knowledge of the patient’s medical history, clinical symptoms, physical signs, or other test results.

Statistical analysis

The normality distribution of continuous data was assessed using Shapiro-Wilk test. Continuous data with normal distribution were presented as mean ± standard deviation (SD) and analyzed using the independent sample t-test. Variables that significantly deviated from normality were assessed by Shapiro-Wilk tests and visual inspection of Q-Q plots. Non-normally distributed variables were reported as median with interquartile range (IQR) and analyzed using the Mann-Whitney U test. Categorical variables were represented by frequencies and percentages and analyzed by the Chi-squared test. Multiple linear regression analysis was conducted to identify the independent determinant of PVBV. All descriptive demographic, clinical, and echocardiographic variables were included in the model. Linearity was confirmed through scatterplots, multicollinearity was evaluated using variance inflation factors (VIFs, <5), and residual normality was tested with Shapiro-Wilk tests. The predictive ability of the optimal model generated from these determinants was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). The optimal cutoff point for the ROC curve was determined by maximizing Youden’s index. Statistical significance was indicated by P values <0.05. Bonferroni method was used for multiple comparisons if multiple tests were performed. The adjusted significance thresholds were calculated based on the number of hypothesis tests performed. All statistical analyses were processed using the software SPSS 19.0 (IBM Corp., Armonk, NY, USA) and MedCalc version 16.8.4 (MedCalc, Ostend, Belgium).

Results

Characteristics of included patients

Between January 2021 and December 2024, two of the 471 patients were excluded due to intolerance to TEE examination, and 469 patients were eventually included in our study. According to the diagnostic criteria for PFO, 423 cryptogenic stroke patients were diagnosed with PFO (PFO group) and 46 were not (control group). A detailed overview on basic characteristics is provided in Table 1. Cryptogenic stroke patients with PFO showed no significant differences compared to the control group in terms of age, gender ratio, height, weight, BSA, or body mass index (BMI) (P>0.05). However, the PFO group demonstrated a significantly higher incidence of stroke [odds ratio (OR) =5.30, 95% confidence interval (CI): 2.81–9.99; P<0.001], whereas no notable differences were observed in the prevalence of hypertension (OR =1.06, 95% CI: 0.43–2.61; P=0.920), renal disease (OR =0.55, 95% CI: 0.03–11.66; P=0.469), and diabetes mellitus (OR =1.31, 95% CI: 0.17–10.34; P=0.832). Compared to controls, PFO patients exhibited larger left ventricular size (Cliff’s δ=0.31, 95% CI: 0.27–0.35), elevated PVR (Cliff’s δ=0.37, 95% CI: 0.27–0.47), and reduced right ventricular systolic function (Cliff’s δ=0.41, 95% CI: 0.31–0.51), whereas PASP, atrial size, LVM index, left cardiac function, and TLC remained comparable between groups (P>0.05). The PFO group showed significantly reduced PVBV relative to the control group (Mann-Whitney U test, Cliff’s δ=0.69, 95% CI: 0.62–0.76) (Table 1).

Multiple linear regression analysis

As shown in Table 2, gender, age, height, weight, BSA, BMI, and the width, length, and RLS level of PFO all showed statistically significant correlations with PVBV in the enter multiple regression analysis (P<0.05). However, only RLS level of PFO, BSA, and gender were independent determinants of PVBV when stepwise multiple regression analysis was conducted (P<0.05). All values of VIF were <5.0 (RLS level of PFO: 1.572; BSA: 3.407; gender: 2.588), confirming the absence of significant multicollinearity (VIF thresholds: <5 acceptable, <10 critical) (Table 3). The regression equation of this optimal model generated from these determinants was PVBV = 623.427 × BSA – 39.559 × RLS level of PFO – 130.929 × gender (females are marked as 0, males are marked as 1) – 622.993 (R=0.668; R²=0.447; R²-adjusted=0.437; k-fold R²=0.413; F=45.454; and P<0.0001). For every 1 m² increase in BSA, PVBV increased by 623.4 mL. Higher RLS levels of PFO reduced PVBV by 39.6 mL per unit increase. Males had 130.9 mL lower PVBV than females; all else was found to be equal.

ROC curve analysis

This model displayed a good ability to predict PVBV less than 250 mL (AUC =0.811, 95% CI: 0.744–0.866; cutoff value, 316.97; sensitivity, 77.22%; specificity, 86.17%, P<0.0001), which was significantly better than the BSA-only model (AUC =0.694). The optimal cutoff value, determined using Youden index J, was 1.70, yielding a sensitivity of 67.86% and specificity of 74.51%. This model has a better ability to predict PVBV less than 200 mL (AUC =0.881, 95% CI: 0.824–0.925; cutoff value, 313.68; sensitivity, 100.00%; specificity, 73.94%, P<0.0001).

Intra-/inter-observer variability

Intraobserver variability: the same observer (Observer A) repeated the PVBV measurements in 30 randomly selected cases at a 4-week interval to minimize recall bias. The results showed excellent agreement, with an intraclass correlation coefficient (ICC) of 0.98 (95% CI: 0.95–0.99) and a coefficient of variation of 2.1%. Interobserver variability: Two independent observers (Observers A and B) analyzed the same set of 30 cases. The agreement between observers was high, with an ICC of 0.95 (95% CI: 0.91–0.97) and a coefficient of variation of 3.5%.

Discussion

To our knowledge, this is the first report on changes in PVBV in cryptogenic stroke patients with PFO. PVBV in these patients was found to be significantly reduced. This finding enriches our understanding of cardiopulmonary interactions in PFO, provides a basis for early screening and treatment of PFO, and offers a reference for the diagnosis and treatment of diseases (such as pulmonary embolism) using PVBV as a reference indicator.

PVBV refers to the total volume of the pulmonary vascular system, including the pulmonary arteries, capillaries, and veins. The reduction in PVBV in PFO may be attributed to the following mechanisms: (I) developmental impairment: Under normal circumstances, PVR decreases after birth, and blood from the right heart primarily flows to the lungs. However, in the presence of PFO, when right atrial pressure exceeds left atrial pressure (e.g., during Valsalva maneuver, forceful coughing, pulmonary hypertension, or right heart dysfunction), some venous blood may bypass the pulmonary circulation by flowing directly into the left atrium through the PFO. In the neonatal period, if PFO is accompanied by other pathological conditions (such as persistent pulmonary hypertension), persistent RLS may occur, further hindering the normal development of the pulmonary vascular bed and leading to hypoplasia (13). During infancy or early childhood, the presence of malnutrition, poor development, or frequent respiratory diseases (e.g., upper respiratory infections, bronchopneumonia), recurrent coughing, wheezing, or forceful crying may delay the closure of the foramen ovale, resulting in intermittent or persistent RLS and subsequent underdevelopment of the vascular bed. (II) RLS: RLS reduces pulmonary blood flow, leading to insufficient filling of the pulmonary vascular bed and a consequent decrease in capacity. (III) Pulmonary vascular remodeling: Long-term reduction in pulmonary blood flow may induce structural changes in the pulmonary vasculature such as vasoconstriction, luminal narrowing, or a decrease in the number of vessels, further reducing pulmonary vascular bed capacity. (IV) Secondary changes: Concomitant pulmonary hypertension increases right heart pressure, exacerbating right-to-left shunting and creating a vicious cycle. Additionally, pulmonary hypertension itself can cause thickening and fibrosis of the pulmonary vascular walls, increasing vascular resistance and reducing capacity. (V) Functional capacity regulation: Reduced pulmonary blood flow may trigger functional capacity regulation through neurohumoral mechanisms (e.g., hypoxic pulmonary vasoconstriction), leading to temporary contraction of the vascular bed (14,15). (VI) Microembolic effects: Paradoxical embolism in PFO patients, in addition to causing cerebral microvascular embolism, can also lead to pulmonary microvascular embolism, directly damaging the pulmonary vascular bed. (VII) Inflammation and endothelial injury: Patients with cryptogenic stroke may exhibit systemic inflammation or hypercoagulability. Inflammatory factors [e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-6] may promote pulmonary vascular endothelial injury and remodeling, further damaging the pulmonary vascular bed (16,17).

MCE is an imaging technique used to evaluate myocardial perfusion and cardiac structural abnormalities. In our study, the contrast agent used in MCE consisted of inert gas (sulfur hexafluoride) microbubbles (5–8 µm in size, similar to red blood cells), which are eventually expelled through the lungs and are non-nephrotoxic with minimal allergenic potential. After intravenous injection, the microbubbles circulate with the blood without extravasation, making them a pure blood-pool contrast agent. They can track blood throughout the circulation, effectively serving as blood tracers. When MCE is performed with the right and left ventricles as observation windows, it allows visualization of the contrast agent-tagged blood as they flow from the right ventricle through the pulmonary vascular bed and return to the left ventricle. The PTT and the number of right ventricular contractions during this period (NPPT) can be calculated. PVBV is then determined by multiplying the right ventricular stroke volume by NPPT. MCE essentially calculates PVBV at the red blood cell level, offering higher accuracy. Compared to computed tomography (CT) and magnetic resonance imaging (MRI), MCE is simpler, faster, more cost-effective, radiation-free, non-nephrotoxic, minimally allergenic, and highly portable, making it a powerful complementary tool for assessing PVBV.

Our study has four limitations: First, the study primarily focused on patients with cryptogenic stroke due to the higher prevalence of PFO in this population, the greater availability of TEE data, and the lower incidence of cardiopulmonary comorbidities. If cardiac patients had been included, although TEE data would also be abundant, the influence of cardiac function on pulmonary vascular bed capacity might have been more pronounced. Second, the study population consisted of adults aged 20–60 years, excluding children, adolescents, and individuals over 60 years of age. This is mainly because children and adolescents often lack obvious symptoms and have fewer medical visits, resulting in limited availability of patients who have undergone both TEE and MCE. Additionally, recruiting elderly volunteers over 60 years old is challenging due to the higher prevalence of systemic diseases (e.g., cardiac, pulmonary, renal) in this age group, which could significantly confound the study of PFO-related changes in PVBV. Third, although PFO is present in approximately 25% of the general population, in the real world, PFO is evaluated only after a stroke/transient ischemic attack, and few ordinary people are willing to undergo semi-invasive and uncomfortable TEE. The imbalanced group sizes (423 PFO vs. 46 controls) of our study may introduce selection bias, despite matching and adjustment. This design limits precision in estimating absolute risk differences between groups. The small control group may underrepresent population variability, though sensitivity analyses excluding outliers showed consistent results. Future studies should prioritize balanced recruitment to validate these findings. Fourth, although our findings suggest a potential association between PFO and reduced PVBV, it is critical to acknowledge that the causal relationship remains speculative. The observed differences could reflect shared underlying mechanisms (e.g., hemodynamic alterations) rather than direct causation. Longitudinal studies or interventional trials (e.g., post-PFO closure hemodynamic assessments) are needed to clarify causality.

Conclusions

To our knowledge, this is the first study to quantitatively evaluate changes in PVBV in cryptogenic stroke patients with PFO using MCE. The results demonstrate a significant reduction in PVBV in these patients, highlighting its potential as a novel hemodynamic biomarker for risk stratification and therapeutic monitoring. Clinically, PVBV assessment could enable individualized management of PFO-related stroke. Patients with both high RLS level and low PVBV may represent a high-risk subgroup warranting aggressive intervention (e.g., PFO closure). PVBV normalization post-closure might serve as an indicator of hemodynamic recovery, supporting its use in monitoring therapeutic efficacy. However, these hypotheses require validation in prospective trials, such as correlating PVBV with embolic load on diffusion-weighted MRI or stroke recurrence rates. Despite these limitations, this study underscores the clinical value of PVBV in optimizing patient selection for PFO closure and advocating for early intervention. Future studies should further define PVBV reference ranges and explore its integration into personalized stroke prevention strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-425/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-425/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-425/coif). The 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 approved by the Human Research Ethics Committee of Yangpu Hospital, School of Medicine, Tongji University (No. LL-2020-SHZKKX-001). Written informed consent was provided by all participants prior to enrollment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

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/.

References

1. Chinese College of Cardiovascular Physicians Structural Cardiology Group. Clinical Study Group on High-risk Prediction Model and treatment Strategy of Cardiogenic Stroke Population. Chinese expert consensus on ultrasound diagnosis of patent foramen ovale. Chin J Intervent Cardiol 2023;31:4-11.
2. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001;38:613-23. [Crossref] [PubMed]
3. Calvert PA, Rana BS, Kydd AC, Shapiro LM. Patent foramen ovale: anatomy, outcomes, and closure. Nat Rev Cardiol 2011;8:148-60. [Crossref] [PubMed]
4. Wang HM, Zheng XZ, Sun F. Differential diagnosis of acute pulmonary embolism using contrast echocardiography. Med Ultrason 2022;24:323-8. [Crossref] [PubMed]
5. May MT. Galen: on the usefulness of the parts of the body. Ithaca, New York: Cornell University Press, 1968.
6. Shah AH, Horlick EM, Kass M, Carroll JD, Krasuski RA. The pathophysiology of patent foramen ovale and its related complications. Am Heart J 2024;277:76-92. [Crossref] [PubMed]
7. Liu XQ, Wang XY, Xie H, Xie XG, Zhang YS, He L. The discovery of in situ thrombus attached to the patent foramen ovale channel in myocardial infarction with normal coronary arteries. Heliyon 2024;10:e35220. [Crossref] [PubMed]
8. Kleber FX, Hauschild T, Schulz A, Winkelmann A, Bruch L. Epidemiology of Myocardial Infarction Caused by Presumed Paradoxical Embolism via a Patent Foramen Ovale. Circ J 2017;81:1484-9. [Crossref] [PubMed]
9. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233-70. [Crossref] [PubMed]
10. Mitchell C, Rahko PS, Blauwet LA, Canaday B, Finstuen JA, Foster MC, Horton K, Ogunyankin KO, Palma RA, Velazquez EJ. Guidelines for Performing a Comprehensive Transthoracic Echocardiographic Examination in Adults: Recommendations from the American Society of Echocardiography. J Am Soc Echocardiogr 2019;32:1-64. [Crossref] [PubMed]
11. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol 2003;41:1021-7. [Crossref] [PubMed]
12. Ait Ali L, Aquaro GD, Peritore G, Ricci F, De Marchi D, Emdin M, Passino C, Festa P. Cardiac Magnetic Resonance Evaluation of Pulmonary Transit Time and Blood Volume in Adult Congenital Heart disease. J Magn Reson Imaging 2019;50:779-86. [Crossref] [PubMed]
13. Mandell E, Kinsella JP, Abman SH. Persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 2021;56:661-9. [Crossref] [PubMed]
14. Duke JW, Beasley KM, Speros JP, Elliott JE, Laurie SS, Goodman RD, Futral E, Hawn JA, Lovering AT. Impaired pulmonary gas exchange efficiency, but normal pulmonary artery pressure increases, with hypoxia in men and women with a patent foramen ovale. Exp Physiol 2020;105:1648-59. [Crossref] [PubMed]
15. Kar S. Cardiovascular implications of obstructive sleep apnea associated with the presence of a patent foramen ovale. Sleep Med Rev 2014;18:399-404. [Crossref] [PubMed]
16. Pan J, Wang R, Pei Y, Wang D, Wu N, Ji Y, Tang Q, Liu L, Cheng K, Liu Q, Sun J, Gong M, Zheng X, Li J, Zhang C, Yuan Y. Sulforaphane alleviated vascular remodeling in hypoxic pulmonary hypertension via inhibiting inflammation and oxidative stress. J Nutr Biochem 2023;111:109182. [Crossref] [PubMed]
17. Shi R, Wei Z, Zhu D, Fu N, Wang C, Yin S, Liang Y, Xing J, Wang X, Wang Y. Baicalein attenuates monocrotaline-induced pulmonary arterial hypertension by inhibiting vascular remodeling in rats. Pulm Pharmacol Ther 2018;48:124-35. [Crossref] [PubMed]