The present study is a retrospective study based on the data of 125 patients with pulmonary hypertension who were treated at Shanghai Jiao Tong University School of Medicine affiliated Renji Hospital, between January 2014 and December 2018. 125 PH patients included 114 patients with pulmonary arterial hypertension (PAH, group 1 PH) and 11 patients with chronic thromboembolic PH (CTEPH, group 4 PH). The inclusion criteria for this study were: (1) participants aged 18 years or older; (2) patients were newly diagnosed with PH confirmed by right heart catheterization (mean pulmonary artery pressure ≥ 25 mmHg); (3) availability of relevant clinical data within 1 month before and after right heart catheterization. The exclusion criteria were: (1) participants with group 2, group 3 and group 5 PH; (2) participants with a history of malignancy, lung transplantation, and severe heart failure; (3) participants who were pregnant during the study period; (4) participants with a history of diabetes or inflammatory infection. Informed consent was obtained from all patients included in this study. This study has been approved by the Ethics Committee of Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

This study collected relevant data including patients’ demographics, World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), PH initial therapy, laboratory tests, right heart catheterization data, and echocardiography. Demographic information included age, gender, height, and weight. Laboratory tests included total cholesterol (TC), TG, HDL-C, low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), white blood cell (WBC), and B-type natriuretic peptide (BNP) data. Data of laboratory tests were uniformly assessed before the patients underwent right heart catheterization, at which point their clinical status was relatively stable. Echocardiography mainly collected data on right ventricular internal diameter, estimated pulmonary artery systolic pressure (PASP), and tricuspid annular systolic excursion (TAPSE). Right heart catheterization data included mean pulmonary artery pressure, right atrial pressure (RAP), pulmonary artery wedge pressure (PAWP), cardiac index, cardiac output (CO), mixed venous oxygen saturation (SvO₂), and pulmonary vascular resistance (PVR). The clinical status of PH patients was determined through electronic medical record query or telephone follow-up.

The primary endpoint of this study was the occurrence of clinical worsening outcome, including lung transplantation, rehospitalization, all-cause death. Follow-up time was determined as the time from right heart catheterization to the occurrence of clinical worsening outcomes. Atherogenic index of plasma was defined as the logarithm value of the ratio of triglycerides to high-density lipoprotein cholesterol (log[TG/HDL-C]).

Continuous variables were presented as median (interquartile range). Categorical variables were presented as frequency (percentage). Comparisons between two groups were conducted using Student’s t-test, Mann–Whitney test, Chi-square test, and rank-sum test, depending on the type of data. Multiple imputation was performed to supplement missing variables in this study. Restricted cubic spline and Cox regression analyses were used to assess the correlation between AIP and the risk of clinical worsening events in PH patients. The optimal p-value method was used to determine the best cutoff value of AIP by identifying the point that maximizes the statistical significance of its association with the risk of clinical worsening in PH patients. Kaplan–Meier survival curves were used to compare the difference in survival status between high and low AIP groups in PH patients. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to select potential variables related to PH prognosis. A nomogram was constructed to build a prediction model. Receiver operating characteristic (ROC) curve, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the reliability of the model in predicting clinical worsening events in PH patients. All data analyses in this study were conducted using R 4.41 software and SPSS 27.0 software (IBM Corp). A p-value <0.05 was regarded statistically significant.

The baseline characteristics of PH patients in this study are shown in Table 1. A total of 125 PH patients aged ≥18 years were included in this study. The median age of the 125 PH patients was 38.00 (30.00–51.00) years, with females accounting for 90.4% of the population. The median BMI was 21.50 (19.56–23.34) kg/m², and the median 6MWD was 389.23 (311.60–465.80) meters. IPAH accounted for 21.6% of cases, connective tissue disease-associated PAH accounted for 52.0%, congenital heart disease-associated PAH accounted for 13.6%, portopulmonary hypertension (PoPH) accounted for 4.0%, and CTEPH accounted for 8.8%. The proportion of patients in WHO-FC I/II was 68.0%, while the proportion in class III/IV was 32.0%. The median BNP level was 200.00 (80.00–455.00) pg./mL. Among the clinical variables, there were statistically significant differences in 6MWD, WHO-FC, TC, LDL-C, CRP, and AIP between the two groups of PH patients with and without clinical worsening outcomes (other variables showed no statistically significant differences).

To explore the linear relationship between AIP and the risk of clinical worsening events in PH patients, restricted cubic spline analysis was performed (Figure 1). As shown in Figure 1, there was an inverted U-shaped correlation between AIP and the 1-year and 3-year risk of clinical worsening events in PH patients, with an initial positive correlation followed by a negative correlation. However, there was a significant positive linear correlation between AIP and the 5-year clinical outcome in PH patients.

The optimal cutoff value of AIP for predicting the risk of clinical worsening events in PH patients was estimated using the optimal p-value method, which was 0.144. Cox regression analysis was performed on AIP as a continuous variable and as a categorical variable in relation to the clinical outcome of PH patients (Table 2). As a continuous variable, AIP was not significantly associated with the risk of clinical worsening events in PH patients at 1-year follow-up, but reversed at 3-year and 5-year follow-up. In the crude model, continuous AIP was significantly associated with the risk of clinical worsening events, with hazard ratios (HRs) and 95% confidential intervals (CIs) of 3.399 (1.333–8.664) at 3-year follow-up and 2.829 (1.222–6.548) at 5-year follow-up. After adjusting for age and gender, the above results remained significant, with no change in the HRs and 95% CIs. After further adjusting for BMI, WHO-FC, PH initial therapy, BNP, TC, LDL-C, CRP, WBC, RAP, PAWP, PVR, SvO2, and TAPSE/PASP, the HRs and 95% CIs for continuous AIP were 3.069 (1.180–7.982) at 3-year and 2.426 (1.021–5.763) at 5-year follow-up.

As a categorical variable, AIP was significantly associated with the risk of clinical worsening events in PH patients at 1-year, 3-year, and 5-year follow-up. After adjusting for age and gender, the HRs and 95% CIs for categorical AIP were 3.309 (1.321–8.290) at 1-year, 2.383 (1.368–4.151) at 3-year, and 2.124 (1.298–3.476) at 5-year follow-up. After full adjustment of variables, the HRs and 95% CIs for categorical AIP were 2.805 (1.057–7.444) at 1-year, 2.166 (1.236–3.795) at 3-year, and 1.834 (1.110–3.032) at 5-year follow-up.

The 1-year, 3-year, and 5-year incidence rates of clinical worsening events in PH patients in this study were 20.0, 44.8, and 54.4%, respectively. Kaplan–Meier survival curves were used to compare the survival rate of AIP for the risk of clinical worsening events in PH patients (Figure 2), and the results showed a significantly increased risk of clinical worsening events in the high AIP group (p = 0.002).

LASSO regression was used to select potential variables, with ten-fold cross-validation and the penalty factor lambda selected as lambda.min. When the best lambda.min was 0.121, four prognostic variables (AIP, PH subgroups, 6MWD, and WHO-FC) were selected (Figure 3). Based on these variables, a nomogram was constructed for predicting clinical worsening events in PH patients (Figure 4). The results of the nomogram showed that CTEPH scored 0, connective tissue disease-associated PAH scored 41, IPAH scored 57, congenital heart disease-associated PAH scored 62, and PoPH scored 100. As the 6MWD increased, the score decreased gradually from 56 to 0. The score was 0 for WHO functional class I/II and 33 for class III/IV. With increasing AIP, the score increased gradually from 0 to 54.

To assess the predictive ability of the established model, we plotted the ROC curves for the clinical index model (including PH subtype, WHO functional class, and 6MWD) and the comprehensive model (clinical index model + AIP) for predicting clinical worsening events in PH patients (Figure 5). The 1-year, 3-year, and 5-year areas under the ROC curve (AUC) for the clinical index model alone were 0.671 (0.552–0.789), 0.689 (0.593–0.786), and 0.749 (0.648–0.849), respectively. The 1-year, 3-year, and 5-year AUC for the comprehensive model were 0.743 (0.637–0.849), 0.734 (0.644–0.824), and 0.788 (0.693–0.883), respectively. Although the p-values were not significant (all p > 0.05), the AUC values for 1-year, 3-year, and 5-year all increased. Due to the insensitivity of the ROC curve to the addition of new indices, we further introduced the NRI and IDI to evaluate the changes in the predictive ability of the clinical index model with the addition of AIP for clinical worsening events (Table 3). The NRI for 1-year, 3-year, and 5-year after introducing the model was 0.318 (0.027–0.498) (p = 0.040), 0.306 (0.039–0.459) (p < 0.001), and 0.337 (0.001–0.502) (p = 0.040), respectively, and the IDI was 0.058 (0.001–0.129) (p < 0.001), 0.049 (0.006–0.097) (p = 0.020), and 0.053 (−0.005–0.117) (p = 0.099), respectively. The NRI and IDI results showed a significant improvement in the predictive ability of the clinical index model after the introduction of AIP.

One of the primary limitations of this study is the relatively small sample size of 125 patients, which may limit the generalizability of our findings to the broader population of PH patients. Additionally, the study was conducted at a single center, which may introduce bias related to local patient demographics and treatment protocols. Another limitation is the retrospective design, which inherently carries risks of missing or incomplete data, as well as potential recall bias. Due to the complexity of clinical conditions, the use of anti-inflammatory or immunosuppressive drug during follow-up may introduce some bias into the relationship between AIP and PH prognosis. While the study included a comprehensive collection of clinical and laboratory data, there may be unmeasured confounders that could influence the association between AIP and clinical outcomes in PH patients. Lastly, the conclusion of this study was based on the PH diagnostic standard of 25 mmHg, and whether it could be applicable to the diagnostic standard of 20 mmHg in the latest 2022 PH guidelines (40) remains to be investigated in future research. Future studies should aim to include larger, multi-center cohorts to validate these findings and enhance their applicability to diverse patient populations.