This study was conducted as an ambispective, cross-sectional investigation, having received approval from the institutional ethical review committee of Qilu Hospital of Shandong University (Approval ID: 2019-119). All patients at Qilu Hospital of Shandong University who were suspected of having PH and who underwent RHC from August 2018 to August 2020 were enrolled after obtaining written consent. The diagnosis of pre-capillary PH was established in accordance with current guidelines, characterized by a mean pulmonary arterial pressure (mPAP) > 20 mmHg, pulmonary vascular resistance (PVR) > 2 Wood Units (WU), and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg, as determined by RHC (7). Patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH), heritable PAH, drug-induced and toxin-induced PAH, PAH associated with congenital heart disease (CHD-PAH), portopulmonary hypertension (PoPH), PAH associated with connective tissue disease (CTD-PAH), and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were included in the study.

Patients diagnosed with pre-capillary PH from August 2018 to March 2019, along with 20 healthy volunteers (HC group) exhibiting normal echocardiograms, were included in the discovery cohort. Patients enrolled from April 2019 to August 2020 constituted the validation cohort. Within the validation cohort, patients were categorized into the PAH group and the normal pressure (NP) group based on RHC results. All patients in both the discovery and validation cohorts were monitored periodically over a 41-month period, with the exception of the following: (1) patients with PAH with uncorrected congenital heart disease, including Eisenmenger syndrome; (2) patients with PAH due to lung diseases and/or hypoxia; (3) patients with PAH with unclear or multifactorial mechanisms; and (4) patients with CTEPH who had undergone thromboendarterectomy (PEA) or balloon pulmonary angioplasty (BPA). Only patients in the follow-up cohort underwent risk stratification. The flowchart detailing patient enrollment is presented in Figure 1.

Clinical data, including age, gender, height, weight, type of PAH, and all non-invasive parameters for risk stratification, were collected. These parameters encompass the World Health Organization functional class (WHO FC), 6 min walking distance (6MWD), N-terminal pro B-type natriuretic peptide (NT-proBNP), right atrial area (RAA) as assessed by echocardiography, right atrial pressure (RAP), mixed venous oxygen saturation (SvO₂), and cardiac index (CI). Risk groups were categorized as low, intermediate, and high, corresponding to estimated 1-year mortality risks of <5%, 5%–20%, and >20%, respectively (7). The risk stratification model was proven to be usable in all patients with Group 1 PAH and CTEPH (8, 9).

A 7-Fr Swan-Ganz catheter (Edwards Lifesciences, California) was used for RHC. RAP, PAP, PAWP, SvO₂, and CO by the thermodilution technique were recorded (10). PVR was calculated as (mPAP-PAWP)/CO. CI was calculated as CO/body surface area (BSA).

ICG measurements were carried out at rest before RHC by the same operator using a CSM3100 monitor (Shenzhen Qianfan Electronics Co. Ltd, China). ICG uses variations in the transthoracic impedance to a high-frequency (1,600 kHz), low-amperage (7 μA) alternating current across the thorax during cardiac ejection to calculate stroke volume. The left ventricular stroke work index (LSWI) calculation formula is as follows: LSWI = 0.0144 × (MAP − LAP) × SVI (11). Mean arterial pressure (MAP) was determined using the formula: MAP = (SAP + 2 × DAP)/3, where SAP represents systolic aortic pressure, and DAP denotes diastolic aortic pressure. The left arterial pressure (LAP) is a fixed value set at 7 Torr by the ICG system. The stroke volume index (SVI) was calculated as SV divided by BSA.

During the 41-month follow-up period, clinical worsening events were recorded and adjudicated by independent experts in PH. These events were defined as follows: (1) all-cause mortality, (2) hospitalization due to worsening PAH, which includes non-elective hospitalization due to PAH or the initiation of parenteral prostanoid therapy, or (3) disease progression, characterized by a decrease in the 6MWD of ≥15% on two separate occasions, accompanied by either a deterioration in the WHO functional class, the necessity for new PAH-targeted medication, or the occurrence of decompensated right heart failure.

The normally distributed continuous variables are presented as mean ± standard deviation (SD), otherwise as median and interquartile (25%, 75%) ranges [M (Q1, Q3)]. Student’s t-test and the Mann–Whitney test were used for group comparison, as appropriate. The relationship between left ventricular stroke work (LSW)/LSWI and PAH was further analyzed by univariate and multivariate logistic regression. In multivariate logistic regression, we showed (1) unadjusted models and (2) model I, adjusted for covariates including age, sex, body weight index (BMI), and heart rate. Receiver operator characteristic (ROC) curves were used to determine the optimal diagnostic cut-off values of ICG parameters for PAH risk stratification. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of PAH clinical worsening risk in relation to LSW and LSWI. In the time-to-event analyses, end points were estimated with the use of the Kaplan–Meier method and were analyzed with the use of the log-rank test. Hazard ratios with 95% confidence intervals were estimated with the use of proportional-hazard models. The cut-off date of follow-up was 30 June 2023. A p-value < 0.05 was considered statistically significant. All analyses were performed using the statistical software packages R (http://www.R-project.org, The R Foundation) and EmpowerStats (http://www.empowerstats.com, X&Y Solutions, Inc., Boston, MA).

In the discovery cohort, there were 26 patients with PAH, comprising 11 with IPAH, 6 with CHD-PAH, 2 with CTD-PAH, 6 with CTEPH, and 1 with PoPH. Additionally, 20 healthy controls were included. The median age of the participants was 29 years (interquartile range: 24–35 years), with 12 (60%) being female. The validation cohort consisted of 100 patients, among whom 10 subjects with mPAP ≤ 20 mmHg were categorized into the NP group. The remaining 90 subjects were classified into the PAH group, which included 24 (26.7%) with IPAH, 33 (36.6%) with CHD-PAH, 9 (10%) with CTD-PAH, and 20 (22.2%) with CTEPH, as detailed in Table 1.

As shown in Table 2, compared to health controls, patients with PAH had decreased LSW [58.7 (44.6, 71.6) vs. 81.2 (69.5, 100.9) g·m/beat, p < 0.001] and shorter left ventricular ejection time (LVET) [275 (240, 293) vs. 408 (333, 472) ms, p < 0.001]. A significant difference was also observed between the NP group and the PAH group in the validation cohort. LSW was 51.5 (41.8–67.2) g·m/beat in the PAH group compared to 69.7 (68.1–72.3) g·m/beat in the NP group (p = 0.014) and LSWI was 30.9 (26.5–40.9) vs. 41.7 (40.8–43.8) g·m/beat/m² (p = 0.026).

Patients were categorized into a low-risk group and an intermediate/high-risk group based on a comprehensive risk assessment for pulmonary arterial hypertension, as recommended by the 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. As indicated in Table 3, patients classified as low risk at baseline demonstrated significantly higher LSW [57.1 (45.8, 73.1) vs. 45.8 (35.1, 57.4) g·m/beat, p = 0.002] and LSWI [35.1 (28.4, 43.7) vs. 27.2 (20.4, 36.3) g·m/beat/m², p < 0.001] values than those at intermediate/high risk.

The ROC curve depicted in Figure 2 demonstrates that the areas for LSW and LSWI were significant in predicting low-risk status for PAH. The area under the curve (AUC) was 0.692 (95% CI 0.584–0.799) for LSW and 0.718 (95% CI 0.613–0.823) for LSWI. The cut-off points for predicting low-risk status for PAH, determined using the Youden index, were 57.85 g·m/beat for LSW (sensitivity 59% and specificity 63%) and 36.75 g·m/beat/m² for LSWI (sensitivity 61% and specificity 79%), as illustrated in Figure 2.

The primary endpoint was a composite of clinical worsening events, encompassing all-cause mortality, hospitalization due to worsening PAH, or disease progression. A cohort of 62 patients was monitored over a median duration of 41 months, during which one participant passed away, and 14 patients experienced disease progression. A one-unit increase in the natural log-transformed LSW was associated with an 11.5% reduction in the risk of PAH clinical worsening (HR = 0.885, 95% CI: 0.839–0.933). Additionally, there was a 21.1% reduction in PAH clinical worsening for such an increase in LSWI (HR = 0.789, 95% CI: 0.712–0.875). Following multivariable adjustment, elevated LSW (HR = 0.859, 95% CI: 0.797–0.926) and LSWI (HR = 0.795, 95% CI: 0.713–0.886) remained significantly associated with a reduced incidence of PAH clinical worsening events (Table 4).

In total, 34 patients exhibited an LSW of less than 58 g·m/beat, among whom 15 patients (44.1%) experienced a clinical worsening event during the follow-up period. In contrast, no clinical worsening events were observed in patients with an LSW of 58 g·m/beat/m² or greater. Similarly, 36 patients had an LSWI of less than 37 g·m/beat/m², with 15 patients (41.7%) experiencing a clinical worsening event during follow-up, compared to none in the cohort with an LSWI of 37 g·m/beat/m² or greater. The hazard ratio for a clinical worsening event in the group with LSW less than 58 g·m/beat was 8.80 (95% CI: 3.16–24.54; p = 0.0001), which is consistent with the LSWI less than 37 g·m/beat/m² group (HR = 7.36, 95% CI: 2.65–20.44; p = 0.0001) (Figure 3).