Application of platelet-derived growth factor PDGF-D in the evaluation of right heart failure

Abstract

The present invention discloses the use of platelet-derived growth factor (PDGF-D) in the assessment of right heart failure. Specifically, it provides the use of a substance for detecting PDGF-D in the preparation of a product for assessing or monitoring the prognosis of right heart failure; the right heart failure is caused by pulmonary hypertension. The introduction of PDGF-D can significantly improve the accuracy and sensitivity of right heart failure assessment, helping clinicians better understand changes in a patient's condition and improving the effectiveness of long-term treatment.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to the application of platelet-derived growth factor (PDGF-D) in the assessment of right heart failure. Specifically, it relates to the use of PDGF-D as a new biomarker to specifically improve the accuracy of long-term treatment assessment of clinical right heart failure. Background Art

[0002] Pulmonary hypertension (PH) is a serious cardiovascular disease that imposes a heavy global health burden. It is particularly common in patients with underlying conditions such as chronic obstructive pulmonary disease and left heart disease.

[0003] Pulmonary hypertension is one of the main causes of right heart failure. Studies have shown that 30% to 50% of patients with pulmonary hypertension eventually develop right heart failure (data from the Journal of the European Respiratory Society), especially those with other cardiopulmonary diseases, whose incidence of right heart failure is even higher.

[0004] Pulmonary hypertension predisposes to right heart failure because of increased pulmonary vascular resistance and a significant rise in right ventricular afterload. Long-term high afterload can lead to right ventricular remodeling, including myocardial fibrosis and right ventricular hypertrophy. Early on, the right ventricle compensates by hypertrophy and dilation to maintain normal blood flow. However, this compensation only provides short-term symptom relief. As the disease progresses, the right ventricle gradually loses its compensatory capacity, leading to right ventricular failure.

[0005] Currently, research on platelet-derived growth factor D (PDGF-D) in heart failure is extremely limited. Existing research primarily focuses on the role of PDGF-D in angiogenesis, but its specific application in right heart failure has not been fully explored and utilized.

[0006] Existing clinical testing methods, such as N-terminal pro-brain natriuretic peptide (NT-proBNP), have limitations in assessing right heart failure. Although widely used as a marker for heart failure, NT-proBNP primarily reflects overall cardiac function and lacks specificity and sensitivity for right heart failure. This means that relying solely on NT-proBNP cannot fully reflect right heart function. Therefore, there is an urgent need to develop new biomarkers to enhance the assessment of right heart failure and improve long-term clinical treatment outcomes. Summary of the Invention

[0007] This invention aims to address the existing lack of specific and sensitive detection indicators for right heart failure. Through in-depth research on platelet-derived growth factor D (PDGF-D), the present invention has discovered its unique expression pattern and clinical detection value in patients with right heart failure. This provides a new, sensitive, and specific biomarker, overcoming the shortcomings of existing technologies and providing strong clinical support for prognostic assessment and personalized treatment of right heart failure.

[0008] This study used right heart tissue from patients with clinical right heart failure, a rare and valuable resource. Procuring these samples is extremely challenging, providing the inventors with a rare opportunity to further explore the potential application of PDGF-D in right heart failure.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] On one hand, the present invention provides an application of a substance for detecting PDGF-D in the preparation of a product for evaluating or monitoring the prognosis of right heart failure; the right heart failure is right heart failure caused by pulmonary hypertension.

[0011] In some embodiments, the substance for detecting PDGF-D is selected from one or more of the following:

[0012] 1) Antibodies or antigen-binding fragments that specifically bind to PDGF-D;

[0013] 2) protein microarray; and,

[0014] 3) siRNA or shRNA targeting PDGF-D.

[0015] In some embodiments, the antibody or antigen-binding fragment that specifically binds to PDGF-D is, for example, Thermo Fisher Scientific PA5-114143 or H00080310-D01P.

[0016] In some embodiments, the antibody or antigen-binding fragment that specifically binds to PDGF-D can be prepared into a detection kit, such as a PDGF-D enzyme-linked immunosorbent assay (ELISA) kit (biotechwell, Cat #EH10901M).

[0017] In some embodiments, the substance for detecting PDGF-D is used to detect the molecular level of PDGF-D.

[0018] In some embodiments, the product includes a kit and a chip.

[0019] When the product for assessing right heart function or monitoring prognosis of right heart failure is a kit, it comprises an antibody or antigen-binding fragment that specifically binds to PDGF-D.

[0020] When the product for right heart function assessment or prognosis monitoring of right heart failure is a chip, microspheres of a specific color are used, each of which is bound to a different antibody or nucleic acid probe. The microspheres labeled with different antibodies are mixed with the sample. If the sample contains PDGF-D, it will bind to the antibody on the corresponding microsphere. A second fluorescent-labeled antibody is added, and the Luminex instrument is used to detect the fluorescent signal on the microsphere to determine the concentration of PDGF-D.

[0021] In some embodiments, the molecular level is selected from protein expression level or mRNA level.

[0022] Another aspect of the present invention provides a use of a substance for detecting PDGF-D in preparing a product for evaluating right ventricular function associated with pulmonary hypertension.

[0023] In some embodiments, the right heart function associated with pulmonary hypertension includes one or more of right ventricular end-diastolic volume, right ventricular end-systolic volume, right ventricular fractional area change, tricuspid annular systolic excursion, and right heart ejection fraction.

[0024] In some embodiments, the substance for detecting PDGF-D is used to detect the molecular level of PDGF-D.

[0025] In some embodiments, the molecular level is selected from protein expression level or mRNA level.

[0026] In some embodiments, the substance for detecting PDGF-D is selected from one or more of the following:

[0027] 1) Antibodies or antigen-binding fragments that specifically bind to PDGF-D;

[0028] 2) protein microarray; and,

[0029] 3) siRNA or shRNA targeting PDGF-D.

[0030] In some embodiments, PDGF-D was compared with a range of clinical indicators, including plasma and cardiac catheterization tests, in patients with pulmonary hypertension and right heart failure. The P value for PDGF-D was 0.013, with a hazard ratio of 1.002 (95% CI: 1.001-1.005), indicating that PDGF-D was statistically significant in predicting risk in patients with pulmonary hypertension and right heart failure. In contrast, the P values for other parameters, such as mPAP (mean pulmonary artery pressure), mRAP (mean right atrial pressure), PVRi (pulmonary vascular resistance index), and NT-proBNP (N-terminal pro-B-type natriuretic peptide), did not reach significance.

[0031] Currently, mPAP (mean pulmonary artery pressure), mRAP (mean right atrial pressure), PVRi (pulmonary vascular resistance index) and NT-proBNP are important markers for assessing the severity of pulmonary hypertension and right heart failure.

[0032] Mean pulmonary artery pressure (mPAP) refers to the average pressure within the pulmonary arteries during systole and diastole. Elevated mPAP can lead to remodeling of the pulmonary microvasculature and cause pulmonary hypertension. Pulmonary hypertension increases right ventricular afterload, which can lead to right ventricular hypertrophy and dysfunction in the long term. Therefore, elevated mPAP is an important indicator of pulmonary hypertension, reflecting right ventricular overload. This indicator is typically measured via right cardiac catheterization.

[0033] mRAP (mean right atrial pressure) refers to the average pressure within the right atrium. When right heart failure occurs, the right ventricle's pumping function decreases, causing blood to stagnate within the right atrium, thereby increasing mRAP. Measuring mRAP helps assess right ventricular preload and is an indirect indicator of right heart failure. It can be assessed using cardiac ultrasound or Doppler echocardiography.

[0034] The pulmonary vascular resistance index (PVRi) is a measure of pulmonary vascular resistance, representing the ratio of pulmonary artery pressure to cardiac output. In the setting of right heart failure, pulmonary vascular resistance increases, further increasing right ventricular afterload and worsening right heart failure. Therefore, an elevated PVRi is a key indicator of pulmonary hypertension and right heart failure. This index can be measured and calculated using right heart catheterization.

[0035] NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a hormone released by ventricular myocytes in response to pressure and volume overload. In right heart failure, increased ventricular wall tension leads to increased secretion of NT-proBNP. NT-proBNP is a biomarker for assessing the severity of heart failure, with its levels positively correlated with the severity of heart failure. This indicator can be measured through blood tests.

[0036] When PDGF-D is used as a clinical evaluation indicator, its long-term sensitivity can show higher specificity and sensitivity as the disease progresses.

[0037] Another aspect of the present invention provides an application of a substance for detecting PDGF-D in the screening and development of drugs for right heart failure; the right heart failure is right heart failure caused by pulmonary hypertension.

[0038] In some embodiments, the substance for detecting PDGF-D is used to detect the molecular level of PDGF-D.

[0039] In some embodiments, the substance for detecting PDGF-D is used to evaluate the therapeutic effect of a test drug on right heart failure.

[0040] In some embodiments, the substance for detecting PDGF-D is used to identify the target of the drug to be tested.

[0041] In some embodiments, the molecular level is selected from protein expression level or mRNA level.

[0042] In some embodiments, the substance for detecting PDGF-D is selected from one or more of the following:

[0043] 1) Antibodies or antigen-binding fragments that specifically bind to PDGF-D;

[0044] 2) protein microarray; and,

[0045] 3) siRNA or shRNA targeting PDGF-D.

[0046] In some embodiments, substances that detect PDGF-D are used to assess and stratify right heart failure and help determine the progression of right heart failure in patients.

[0047] In addition, PDGF-D can also play a key role in efficacy evaluation and safety monitoring. It can be used to evaluate the efficacy of drug treatment. For example, a decrease in PDGF-D levels after using the test drug may indicate that the test drug is effective in improving heart failure symptoms and slowing disease progression, thereby serving as an intermediate endpoint to evaluate the short-term effect of the drug.

[0048] For example, a new drug for the treatment of right heart failure is being developed. In the early stages of clinical trials, PDGF-D could be used as the primary endpoint to assess the drug's initial efficacy. If the drug is found to significantly reduce PDGF-D levels and this change is associated with improvement in clinical symptoms, the drug might be tested in a larger clinical trial.

[0049] Another aspect of the present invention provides a substance for detecting PDGF-D for use in the development of biomarkers related to right heart failure, or in the study of the pathophysiological mechanism of right heart failure; the right heart failure is right heart failure caused by pulmonary hypertension.

[0050] In some embodiments, the substance for detecting PDGF-D is used to detect the molecular level of PDGF-D.

[0051] In some embodiments, the substance for detecting PDGF-D is used to validate a newly discovered potential biomarker.

[0052] In some embodiments, the molecular level is selected from protein expression level or mRNA level.

[0053] In some embodiments, the substance for detecting PDGF-D is selected from one or more of the following:

[0054] 1) Antibodies or antigen-binding fragments that specifically bind to PDGF-D;

[0055] 2) protein microarray; and,

[0056] 3) siRNA or shRNA targeting PDGF-D.

[0057] Therefore, the present invention demonstrates that PDGF-D can serve as a benchmark to aid in the development of new biomarkers associated with right heart failure. For example, mPAP, mRAP, PVRi, and NT-proBNP are known to be closely associated with the pathophysiological mechanisms of right heart failure. In the present invention, these indicators were used to demonstrate that PDGF-D of the present invention has a good correlation with right heart failure, demonstrating its potential as a biomarker.

[0058] Another aspect of the present invention provides a method for detecting PDGF-D and its use as a biomarker in the preparation of a product having the following functions:

[0059] 1) Prognostic assessment of right heart failure; and / or,

[0060] 2) Right heart failure prognosis monitoring;

[0061] The right heart failure is right heart failure caused by pulmonary hypertension.

[0062] In some embodiments, the substance for detecting PDGF-D is used to detect the molecular level of PDGF-D.

[0063] In some embodiments, the molecular level is selected from protein expression level or mRNA level.

[0064] In some embodiments, the substance for detecting PDGF-D is selected from one or more of the following:

[0065] 1) Antibodies or antigen-binding fragments that specifically bind to PDGF-D;

[0066] 2) protein microarray; and,

[0067] 3) siRNA or shRNA targeting PDGF-D.

[0068] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0069] The reagents and raw materials used in the present invention are commercially available.

[0070] The positive progress effect of the present invention is:

[0071] Enhanced prognostic assessment capabilities: Studies have shown that PDGF-D levels are closely related to patient prognosis. Monitoring PDGF-D can provide clinicians with a more comprehensive disease assessment tool, helping to optimize treatment strategies and improve patient outcomes.

[0072] Promote personalized treatment: PDGF-D, as a new biomarker for right heart failure, will provide a scientific basis for the formulation of personalized treatment plans, enabling patients to receive more precise treatment and reduce hospitalization and mortality rates.

[0073] Support multidisciplinary collaboration: The clinical application of PDGF-D will promote interdisciplinary cooperation in cardiology, molecular biology and related disciplines, and promote the comprehensive development of heart failure research and clinical practice.

[0074] Discovery of a new biomarker: The first systematic study of the expression characteristics of PDGF-D in patients with right heart failure has opened up a new direction for the clinical detection of right heart failure.

[0075] Multi-level validation mechanism: This study verified the clinical application potential of PDGF-D through multiple approaches, including patient plasma samples, right heart tissue from rare right heart failure patients, animal models, corresponding control sample testing, and in vitro experiments, providing sufficient experimental data to support its rationality and effectiveness as a biomarker.

[0076] Highly targeted application value: PDGF-D has strong specificity and sensitivity in predicting clinical deterioration events. It can target the specific pathophysiological characteristics of right heart failure and significantly improve the applicability of existing detection methods in clinical practice.

[0077] Promoting clinical standardization: The implementation of the present invention helps to promote the standardized treatment of right heart failure, improve the overall level of clinical practice, and conform to the trend of modern medical development. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 : Statistical analysis of the correlation between PDGF-D and NT-proBNP;

[0079] The figure shows a significant positive correlation between PDGF-D and NT-proBNP levels, providing a theoretical basis for using PDGF-D as a biomarker for evaluating right heart failure.

[0080] Figure 2 : Kaplan-Meier curves of patients with pulmonary hypertension and right heart failure based on PDGF-D levels;

[0081] The figure shows that the probability of no clinical worsening events in patients with low PDGF-D levels is significantly higher than that in patients with high PDGF-D levels, indicating a close correlation between PDGF-D levels and patient prognosis.

[0082] Figure 3 : Comparison of plasma PDGF-D concentrations before and after Potts procedure in patients with right heart failure due to pulmonary hypertension. ** indicates p value less than or equal to 0.01.

[0083] The figure shows that after patients with pulmonary hypertension underwent Potts surgery, right heart failure was significantly improved. The plasma PDGF-D concentration of these patients with pulmonary hypertension was lower after surgery than before surgery, and the difference was statistically significant, indicating that PDGF-D levels are closely correlated with the patient's right heart function.

[0084] Figure 4 :COX proportional hazards model for prognosis evaluation in patients with pulmonary hypertension and right heart failure;

[0085] This figure shows that PDGF-D is statistically significant in predicting the risk of right heart failure in patients with pulmonary hypertension. In contrast, the P values for other pulmonary hemodynamic parameters (mPAP, mRAP, PVRi) and right heart function parameters (NT-proBNP) did not reach the significance level.

[0086] Figure 5 : ROC curves of PDGF-D and NT-ProBNP as prognostic indicators;

[0087] This figure evaluates the performance of PDGF-D and NT-proBNP as prognostic markers for right heart failure. NT-proBNP is currently a commonly used clinical marker for predicting right heart function in pulmonary hypertension. Due to limited sample size, the AUCs for NT-proBNP as a 1-year, 3-year, and 5-year prognostic marker in this study cohort were 0.5, 0.61, and 0.54, respectively. In contrast, the AUCs for PDGF-D as a prognostic marker for right heart failure were 0.64, 0.87, and 0.88, respectively, over 1-year, 3-year, and 5-year periods. This suggests that the accuracy of PDGF-D as a clinical prognostic marker increases with the long-term course of the disease and is higher than that of NT-proBNP. DETAILED DESCRIPTION

[0088] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0089] The embodiments of the present invention have discovered and verified the key role of PDGF-D in right heart remodeling in pulmonary hypertension through multi-level research.

[0090] Single-cell nuclear transcriptome sequencing of right heart tissue from patients with pulmonary hypertension and controls revealed a significant increase in the proportion of fibroblasts in the right heart of patients with pulmonary hypertension, with significant differences in their proliferation capacity. Further analysis revealed a subpopulation of fibroblasts with high proliferative activity that specifically overexpressed PDGF-D. The significance of PDGF-D was confirmed across both cell subpopulations and patient samples, suggesting that it may play a key role in the pathological development of right heart remodeling in pulmonary hypertension.

[0091] Establishment and validation of a right heart failure mouse model

[0092] Model establishment: 8-week-old male C57BL / 6J mice (Beijing Vital River Laboratory Animal Technology Co., Ltd.) were placed in a hypoxia chamber (Shanghai Tawang Intelligent Technology Co., Ltd.) and continuously fed with hypoxia (oxygen concentration of 10% O2) for 4 weeks to simulate right heart failure caused by pulmonary hypertension.

[0093] Verification: Right ventricular systolic pressure was measured in mice using a Millar catheter thoracotomy to confirm successful establishment of the pulmonary hypertension model. WGA and H&E staining were then used to assess right ventricular remodeling phenotypes. Real-time quantitative polymerase chain reaction was used to measure Nppa and Nppb mRNA levels in right ventricular tissue, confirming successful establishment of the right heart failure model. The heart was then removed, and the right ventricular tissue was isolated, snap-frozen in liquid nitrogen, and stored at -80°C.

[0094] During the preparation of a single nucleus suspension, frozen right ventricular tissue was minced in a cell lysis buffer consisting of 0.1% NP40, 10 mM Tris-HCl, 146 mM NaCl, 1 mM CaCl2, 21 mM MgCl2, and 1 U / μL RNase inhibitor. After confirming complete cell lysis using trypan blue staining, 1 mL of ST Wash buffer (10 mM Tris-HCl, 146 mM NaCl, 1 mM CaCl2, 21 mM MgCl2, 0.01% BSA (NEB B9000S), and 40 U / mL RNase inhibitor) was added. The suspension was filtered through a 40 µm cell sieve, and the filtrate was transferred to a 15 mL centrifuge tube. The cell sieve was rinsed with an appropriate amount of ST Wash buffer, and the rinse buffer and the nucleus filtrate were combined. The suspension was then centrifuged at 500 g for 5 min at 4°C in a swing-out rotor. Resuspend the nuclei in 5 mL of PBS (containing 1% BSA), wash, centrifuge, and resuspend the nuclei in 100 µL of PBS (containing 1% BSA). Stain with trypan blue and count under a microscope.

[0095] Cell nuclei were diluted to a concentration of 1000 / µL. For single-cell nucleus sequencing, the 10× Genomics Chromium Next GEM Single Cell 3' Reagent Kits v3.1 (1000268) were used for sequencing and cDNA library amplification. DNA libraries were constructed using the Chromium™ Single Cell 3' / 5' Library Construction Kit (1000020). The constructed libraries were sequenced using the Illumina sequencing platform using the PE150 sequencing mode. Sequencing data were processed using Cell Ranger software and R packages (such as Seurat) for quality control, alignment, quantification, dimensionality reduction, and cluster analysis to identify specific genes altered during right heart failure. These genes were then compared with marker genes and biological functions in clinical samples.

[0096] Similar findings from human studies were observed in a mouse model of right heart failure caused by pulmonary hypertension: fibroblast proliferation and gene expression signatures of specific subpopulations were closely associated with PDGF-D. Further gene screening and enrichment analysis revealed that PDGF-D also has significant expression and functional properties during mouse right heart remodeling.

[0097] Finally, in vitro experiments confirmed the PDGF-D-promoting effects on fibroblast proliferation, migration, and cell cycle in mouse cardiac fibroblasts cultured and treated with recombinant PDGF-D protein (rmPDGF-DD). These results further support the potential pathogenic mechanism of PDGF-D in right heart remodeling in pulmonary hypertension.

[0098] In summary, the core role of PDGF-D in right heart remodeling in pulmonary hypertension has been verified at multiple levels from clinical samples, animal models and cell experiments, and its potential as a prognostic monitoring indicator has been demonstrated.

[0099] Example 1 Statistical Analysis of the Correlation between PDGF-D and NT-proBNP

[0100] Venous blood samples were collected from 65 patients with pulmonary hypertension and right heart failure. PDGF-D concentrations were measured using ELISA. NT-proBNP concentrations were determined by immunoassay in the laboratory department and obtained through the clinical record system of Shanghai Children's Medical Center.

[0101] Sample Preparation: 3 mL of venous blood was collected from patients with pulmonary hypertension and right heart failure. The blood was placed in an EDTA-containing anticoagulant tube and centrifuged at 3000 rpm for 10 minutes at 4°C. Plasma was separated and stored frozen at -80°C until testing. For testing, plasma samples were thawed and equilibrated at room temperature for 10 minutes.

[0102] PDGF-D concentration was measured using a PDGF-D enzyme-linked immunosorbent assay (ELISA) kit (biotechwell, Cat #EH10901M). A standard curve was prepared according to the kit instructions. After diluting the sample with 0.1 M PBS, 100 μL of the sample was added to a 96-well ELISA plate and incubated at room temperature for 1 hour. After incubation, the reaction was stopped, the plate was washed, and the secondary antibody was added. The plate was incubated again at room temperature for 30 minutes. After washing, a colorimetric reagent was added for the reaction. The absorbance of the sample was read at 450 nm, and the PDGF-D concentration was calculated using the standard curve.

[0103] All samples follow uniform sampling guidelines and are processed as described above to ensure data accuracy.

[0104] After data collection, correlation analysis was performed using SPSS or R statistical software. First, data normality and the influence of outliers were confirmed, and necessary transformations or corrections were performed on the raw data. Scatter plots were then created using the "ggplot2" and "stats" packages in R software, and the Pearson correlation coefficient was used to calculate the correlation between PDGF-D and NT-proBNP. The correlation coefficient and confidence interval generated by R software were used to evaluate the efficacy of PDGF-D as a test indicator. During data processing and analysis, all data points were included in the analysis, and outliers and missing values were removed.

[0105] like Figure 1 The results showed a significant positive correlation between PDGF-D and NT-proBNP, a well-established marker for right heart failure, and this consistency was statistically significant (p=0.025). This establishes a theoretical foundation for the clinical application of PDGF-D as a sensitive plasma marker in patients with right heart failure. Therefore, PDGF-D has the potential to become a new marker for right heart failure assessment, with significant clinical application value.

[0106] Example 2 Determination of Kaplan-Meier survival curves for patients with pulmonary hypertension and right heart failure based on PDGF-D levels

[0107] To evaluate the correlation between PDGF-D levels and survival in patients with pulmonary hypertension and right heart failure, venous blood samples were collected from 55 patients with right heart failure, and plasma PDGF-D concentrations were measured by ELISA according to the method in Example 1. Patients were divided into a low PDGF-D group (27 patients) and a high PDGF-D group (28 patients) based on their median PDGF-D concentration. All samples were normalized before the experiment. Clinical deterioration events, including death, heart transplantation, lung transplantation, and Potts surgery, were subsequently recorded and followed up for a long period of time. The Kaplan-Meier method was then used to calculate the probability of clinical deterioration-free survival in the low and high PDGF-D groups. Survival differences between the two groups were assessed using the Log-rank test. All data were processed in SPSS or R statistical software. Kaplan-Meier survival curves were constructed in R software using the "survival" package, and the curves were calculated based on the survival data of each group. During data analysis, all patient data were normalized to ensure the accuracy of the results. Appropriate confidence intervals and statistical tests were used to validate the curves.

[0108] The inventors found in a clinical cohort that Figure 2 As shown in the Kaplan-Meier survival curve, patients with low PDGF-D levels had a significantly higher probability of survival without clinical worsening events than those with high PDGF-D levels, with a statistically significant difference (p=0.019). This indicates that PDGF-D levels are closely associated with patients' long-term survival, with low PDGF-D levels predicting a better prognosis. This also suggests that PDGF-D can serve as a potential clinical prognostic indicator to predict patient survival and help develop personalized treatment plans.

[0109] Example 3 Comparison of Plasma PDGF-D Concentrations in Patients with Pulmonary Hypertension and Right Heart Failure Before and After Potts Surgery

[0110] Venous blood samples were collected from 10 patients with pulmonary hypertension and right heart failure who underwent Potts surgery before and after surgery. The PDGF-D concentration was determined by ELISA according to the method described in Example 1. The experimental results showed that the clinical symptoms of patients with right heart failure were improved after Potts surgery. Figure 3 As shown in the results, the plasma PDGF-D concentration decreased significantly after surgery, suggesting the potential of PDGF-D as a detection indicator in the clinical prognosis of patients with right heart failure.

[0111] Example 4 COX hazard ratio model for prognosis assessment in patients with pulmonary hypertension and right heart failure

[0112] A total of 49 patients with pulmonary hypertension and right heart failure were enrolled. PDGF-D was compared with established plasma markers of pulmonary hypertension and right heart failure, including NT-proBNP and cardiac catheterization-based risk factors. Mean pulmonary artery pressure (mPAP) and mean right atrial pressure (mRAP) were obtained through right cardiac catheterization. Pulmonary vascular resistance index (PVRi) was calculated from mPAP and cardiac output. Cardiac output was calculated using oxygen consumption, aortic oxygen saturation, superior vena cava oxygen saturation, and hemoglobin level. Data were obtained from the clinical record system of Shanghai Children's Medical Center.

[0113] Figure 4 The study showed that PDGF-D had a P value of 0.013 and a hazard ratio of 1.002 (95% CI: 1.001-1.005), indicating that PDGF-D significantly predicted the risk of right heart failure in patients with pulmonary hypertension. In contrast, the P values for other parameters, such as mPAP, mRAP, PVRi, and NT-proBNP, did not reach significance. These results support the clinical potential of PDGF-D as a new marker for the prognosis of right heart failure and demonstrate its superiority in assessment accuracy.

[0114] Example 5 ROC curves of PDGF-D and NT-ProBNP as prognostic indicators

[0115] To compare the predictive abilities of PDGF-D and NT-proBNP at different time points, long-term follow-up data were collected from 49 patients. PDGF-D concentrations were measured by ELISA according to the method in Example 1, and NT-proBNP concentrations and related clinical indicators were obtained from the clinical record system. Curve plotting and data analysis were performed using R software, using the "pROC" package to generate receiver operating characteristic (ROC) curves. Based on PDGF-D and NT-proBNP concentrations at different time points and the patient's clinical exacerbation events, curves were generated and corresponding area under the curves (AUCs) were calculated. The red line represents the one-year AUC, the green line represents the three-year AUC, and the blue line represents the five-year AUC. The dashed line represents the random prediction baseline (AUC = 0.5). The closer the curve is to the upper left corner, the higher the model's predictive accuracy. The final data were normalized to ensure the accuracy of the curves.

[0116] The inventors used PDGF-D and NT-proBNP as prognostic evaluation indicators for right heart failure, and evaluated their prognostic prediction performance using ROC curves. Figure 5As shown, the AUCs for NT-proBNP as a 1-year, 3-year, and 5-year prognostic marker were 0.5, 0.61, and 0.54, respectively. In contrast, the AUCs for PDGF-D as a prognostic marker for right heart failure were 0.64, 0.87, and 0.88, respectively, over 1-year, 3-year, and 5-year periods. This suggests that when used as a clinical prognostic marker, PDGF-D's predictive accuracy increases with disease progression, exhibiting high specificity and sensitivity, exceeding those of NT-proBNP. These results suggest that PDGF-D has significant clinical value and promise in the long-term treatment assessment and monitoring of patients with right heart failure.

Claims

1. Use of a substance for detecting PDGF-D in the preparation of a product for evaluating or monitoring the prognosis of right heart failure; the right heart failure is right heart failure caused by pulmonary hypertension.

2. The use according to claim 1, characterized in that The substance for detecting PDGF-D is selected from one or more of the following: 1) Antibodies or antigen-binding fragments that specifically bind to PDGF-D; 2) protein microarray; and, 3) siRNA or shRNA targeting PDGF-D; And / or, the substance for detecting PDGF-D is used to detect the molecular level of PDGF-D; And / or, the product includes a kit and a chip.

3. The use according to claim 2, characterized in that The molecular level is selected from protein expression level or mRNA level.

4. Use of a substance for detecting PDGF-D as a biomarker in the preparation of a product having the following functions: 1) Prognostic assessment of right heart failure; and / or, 2) Right heart failure prognosis monitoring; The right heart failure is right heart failure caused by pulmonary hypertension.

5. The use according to claim 4, characterized in that The substance for detecting PDGF-D is used to detect the molecular level of PDGF-D.

6. The use according to claim 5, characterized in that The molecular level is selected from protein expression level or mRNA level.

7. The use according to any one of claims 4 to 6, characterized in that The substance for detecting PDGF-D is selected from one or more of the following: 1) Antibodies or antigen-binding fragments that specifically bind to PDGF-D; 2) protein microarray; and, 3) siRNA or shRNA targeting PDGF-D.

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