Association of Anxiety and Depressive Symptoms with Short-Term Functional Recovery in Pulmonary Arterial Hypertension: A Longitudinal Cohort Study

Association of Anxiety and Depressive Symptoms with Short-Term Functional Recovery in Pulmonary Arterial Hypertension: A Longitudinal Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of Anxiety and Depressive Symptoms with Short-Term Functional Recovery in Pulmonary Arterial Hypertension: A Longitudinal Cohort Study Yan cheng, Xinxin Wang, Sailan Li, Jiancong Zheng, Xiaorong Jiang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9341136/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background and Objective: The prevalence of anxiety and depression is significantly elevated in patients with pulmonary arterial hypertension (PAH). It remains unclear whether baseline psychological status predicts subsequent trajectories of functional recovery and whether changes in psychological status are dynamically associated with changes in physiological function. This study aimed to investigate whether baseline anxiety and depressive symptoms are independently associated with changes in exercise capacity and ventilatory efficiency over a 3-month follow-up period in patients with PAH. Methods: This longitudinal observational study included 105 patients diagnosed with type 1 PAH who were recruited from Fujian Medical University Union Hospital between January and May 2025. All patients completed the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) at baseline (T0) and at the 3-month follow-up (T1) and underwent the 6-minute walk test (6MWT), cardiopulmonary exercise testing (CPET), and pulmonary function tests (PFTs). Multivariable linear regression and linear mixed-effects models were used to examine the associations between baseline SAS/SDS scores and changes in functional outcomes, as well as the concurrent associations between changes in psychological status (ΔSAS/ΔSDS) and corresponding changes in functional parameters. Results: This study included 105 patients with PAH (mean age 56.2 ± 15.7 years, 57% female). At baseline, patients exhibited mild to moderate anxiety and depression symptoms, with SAS scores of 56.6 ± 4.3 and SDS scores of 53.1 ± 5.4; they also exhibited impaired exercise capacity, with a 6-minute walking distance (6MWD) of 349.1 ± 45.4 meters and a peak oxygen uptake (VO2peak) of 12.9 ± 3.2 mL/kg/min. Multivariate analysis showed that higher baseline SAS scores were significantly associated with a reduced magnitude of improvement in Δ6MWD (β = -1.804, p = 0.016) and ΔVO2peak (β = 0.-092, p = 0.024). Higher baseline SDS scores significantly predicted more pronounced deterioration in predicted FEV1% and the FEV1/FVC ratio (both p < 0.05). Changes in psychological state (ΔSAS, ΔSDS) were significantly correlated with concurrent changes in nearly all functional outcome measures (all p < 0.001). Conclusion: Baseline anxiety and depressive symptoms are independent predictors of poor short-term functional rehabilitation in patients with PAH, and dynamic changes in psychological state are strongly correlated with changes in physiological function. Incorporating psychological screening into routine clinical assessment may help identify patients at risk of poor functional rehabilitation outcomes.Limplementing comprehensive psychological rehabilitation interventions can improve patient prognosis. Pulmonary arterial hypertension Anxiety Depression Exercise capacity Cardiopulmonary exercise testing Functional recovery Figures Figure 1 Introduction Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by pulmonary vascular remodeling and progressive elevation of pulmonary vascular resistance, ultimately leading to right heart failure and even death [ 1 – 3 ] . In recent years, advances in targeted drug therapy have significantly improved the survival prognosis of patients with PAH, but most patients still exhibit progressive decline in exercise tolerance and quality of life, which is lower than the predicted values for individuals of the same age and gender [ 2 , 4 ] . Cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT), as core indicators for assessing cardiopulmonary endurance in patients with PAH, can not only be used for risk stratification of these patients but also serve as independent predictors of prognosis [ 5 , 6 ] . Therefore, early identification of risk factors affecting cardiopulmonary function in patients with PAH is crucial for optimizing individualized treatment strategies and improving long-term outcomes. In recent years, the issue of psychological comorbidities in patients with PAH has received increasing attention. Epidemiological statistics show that 25%–40% of patients with PAH exhibit symptoms of anxiety and depression [ 7 , 8 ] , a prevalence significantly higher than rates observed in the general population and among patients with other chronic diseases. Existing research indicates that anxiety and depression status can reduce cardiopulmonary endurance and quality of life in patients with PAH and lead to worse cardiac function classification [ 7 ] . Mechanistically, persistent anxiety and depression activate the "hypothalamic-pituitary-adrenal axis," causing sympathetic nervous system activation, thereby increasing cardiovascular burden and impairing cardiopulmonary functional reserve [ 9 , 10 ] . Psychological distress can make patients fearful of activities, keeping the body in a state of "high alert," amplifying their perception of physical symptoms such as dyspnea and palpitations, ultimately leading to reduced activity and decreased cardiopulmonary endurance [ 11 ] . Most existing studies treat psychological distress as a "concomitant phenomenon" or "outcome indicator" of the disease, with few studies exploring whether baseline anxiety and depression levels can independently predict dynamic changes in cardiopulmonary function during follow-up in patients with PAH. Therefore, this study aims to conduct a 3-month longitudinal observation to investigate whether baseline anxiety and depression are independently associated with the magnitude of improvement in cardiopulmonary function during follow-up; whether there are differences in the impact of anxiety and depression on cardiopulmonary function recovery; and whether changes in psychological status are concordant with changes in cardiopulmonary function indicators. If the study finds that baseline psychological status affects the trajectory of cardiopulmonary function recovery in patients with PAH, then incorporating psychological status screening into routine clinical assessments will help early identification of high-risk patients with limited improvement in cardiopulmonary function. Timely intervention for abnormal psychological status can not only alleviate psychological symptoms but also break the vicious cycle of psychological effects on physiology, thereby enhancing rehabilitation benefits. Methods Study Design and Participants This longitudinal observational study enrolled 105 patients with type 1 PAH diagnosed at Fujian Medical University Union Hospital between January and May 2025. Inclusion criteria were: (1) age ≥ 18 years; (2) clinically stable condition and receiving optimized PAH-targeted drug therapy for at least 3 months prior to enrollment; (3) ability to undergo CPET and complete the 6MWT; (4) completion of assessments at both baseline (T0) and the 3-month follow-up (T1); (5) signed informed consent. Exclusion criteria included: (1) significant comorbidities affecting exercise capacity (e.g., uncontrolled left heart disease, severe chronic obstructive pulmonary disease (COPD), musculoskeletal disorders); (2) pregnancy; (3) cognitive or language impairments preventing completion of self-reported questionnaires; (4) untreated severe psychiatric illness at diagnosis. During T1, patients received standardized education on physical activity but did not undergo structured exercise intervention, reflecting real-world clinical practice. The study was approved by the Institutional Ethics Committee of Fujian Medical University Union Hospital (approval number 2025KY751), and all participants provided written informed consent in accordance with the Declaration of Helsinki. Measurements Demographic and Clinical Characteristics Demographic data including age, sex, height, weight, and body mass index (BMI) were collected at T0. Disease severity was assessed using the World Health Organization functional class (WHO-FC). Right heart catheterization (RHC) was performed to obtain hemodynamic parameters, including mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), pulmonary arterial wedge pressure (PAWP), right atrial pressure (RAP), cardiac output (CO), and cardiac index (CI). All procedures adhered to standardized protocols. Psychological Assessment Anxiety and depressive symptoms were assessed at T0 and T1 using the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS), respectively. Both scales consist of 20 items rated on a 4-point Likert scale (1 = none or a little of the time to 4 = most or all of the time), with total scores ranging from 20 to 80. The raw scores were converted to standard scores. Standard scores of ≥ 50 on the SAS and ≥ 53 on the SDS were classified as indicative of clinically significant symptoms, where higher scores reflect greater severity of anxiety or depression [ 12 , 13 ] . These instruments have been widely validated and used in patients with cardiovascular and chronic respiratory diseases, including pulmonary hypertension. Exercise Capacity and Cardiopulmonary Function At both T0 and T1, all patients underwent the following assessments: 6MWT: The 6MWT was performed according to American Thoracic Society guidelines. Patients were instructed to walk as far as possible in 6 minutes along a marked corridor, and the 6-minute walk distance(6MWD) was recorded. Standardized verbal encouragement was provided at regular intervals [ 14 ] . CPET: The patient underwent a symptom-limited exercise test using the Ramp protocol. Calibrated gas analyzers measured respiratory gas exchange during exercise [ 15 ] . Cardiorespiratory function data were recorded [ 16 ] . All tests were supervised by both experienced cardiologists and cardiac rehabilitation therapists. pulmonary function tests (PFTs): At T0 and T1, static pulmonary function parameters were recorded according to standardized procedures using a Pulmometer. Statistical Analysis Data were analyzed using R (version 4.5.1). Longitudinal changes (Δ) were calculated as the difference between T1 and T0 values. Multivariable linear regression was used to examine: (1) cross-sectional associations between psychological status (SAS/SDS) and functional parameters at T0 and T1, adjusted for age, sex, and BMI; (2) predictive associations between baseline psychological status and changes in functional outcomes (Δ), adjusting for the baseline values of the respective outcomes; and (3) associations between changes in psychological status (ΔSAS/ΔSDS) and Δfunctional outcomes, using linear mixed models with adjustment for baseline functional values. Model assumptions were assessed via Shapiro–Wilk tests for residual normality, Breusch–Pagan tests for heteroscedasticity, and variance inflation factors for multicollinearity. Results are presented as unstandardized β coefficients, accompanied by 95% confidence intervals and two-sided p-values. Statistical significance was set at p < 0.05, with false discovery rate (FDR) correction applied for multiple comparisons. Results 1. Participant Characteristics This longitudinal study enrolled 105 patients with PAH (mean age 56.2 ± 15.7 years; 57% female). Most patients were classified as WHO-FC III (80%), with the remainder as class II (20%). Hemodynamic assessment indicated moderate disease severity (mPAP 35.5 ± 11.7 mmHg; PVR 6.7 ± 3.6 Wood units). At baseline, patients exhibited impaired exercise capacity (6MWD: 349.1 ± 45.4 m; VO2 peak: 12.9 ± 3.2 mL/kg/min) and mild to moderate anxiety and depressive symptoms (SAS: 56.6 ± 4.3; SDS: 53.1 ± 5.4), as shown in Table 1. Follow-up assessments were completed for all patients. 2. Cross-Sectional Associations at Baseline and Follow-Up At T0, higher SAS and SDS scores were significantly associated with lower VO2 at AT, peak VO2, and PETCO2, and with higher VE/VCO2 at AT and the VE/VCO2 slope (all p < 0.05). SAS demonstrated stronger associations with ventilatory inefficiency, while SDS was correlated with both OUES and VO2/WR (p < 0.05). No significant associations were observed with 6MWD or pulmonary function parameters at T0 (Table 2). At T1, these associations strengthened. Both SAS and SDS were significantly associated with nearly all functional parameters, including 6MWD, VO2 at AT, VO2 peak, VE/VCO2, PETCO2, VO2/WR, and OUES (all p < 0.05). SDS exhibited more robust and widespread associations than SAS, particularly with VO2/WR and OUES (Table 3). Baseline Psychological Status Predicts Functional Changes After correction for baseline functional values, higher baseline SAS scores significantly predicted attenuated improvements in Δ6MWD (β= -1.804, p = 0.016) and ΔVO2 peak (β=-0.092, p=0.024). Baseline SDS scores showed a trend in predicting smaller gains in ΔVO2 peak (β=-0.054, p=0.091) and significantly predicted deterioration in ΔFEV1% and ΔFEV1/FVC% (both p< 0.05). Baseline SAS/SDS showed no significant associations with changes in VE/VCO2 slope or PETCO2 (Table 4).These results suggest that a poorer mental state at baseline, particularly an anxiety status, may predict a greater decline in cardiopulmonary function in the future. Concurrent Changes in Psychological and Functional Status Changes in psychological status (ΔSAS and ΔSDS) were strongly and consistently associated with concurrent changes in all functional parameters (all p < 0.001), including 6MWD, VO2 at AT, VO2 peak, VE/VCO2 at AT, PETCO2, VO2/WR, OUES, and all pulmonary function indices. These associations remained robust after adjustment for the baseline functional values, it indicates a synchronous relationship between mental health and functional improvement. (Table 5). Model Diagnostics Residual normality was not met in approximately half of the models, and heteroscedasticity was observed in a subset of models. However, variance inflation factors were low (all VIF<2.0), indicating no multicollinearity concerns. FDR correction did not alter the statistical significance of key findings (Table 6). Discussion This study shows that baseline anxiety and depression are independent predictors of poor short-term cardiopulmonary function recovery in patients with PAH. Patients with higher baseline anxiety levels showed significantly limited improvements in 6MWD and VO2peak during the 3-month follow-up period, patients with more severe baseline depressive symptoms exhibited an attenuated improvement in cardiopulmonary endurance and experienced a significant decline in lung function.The study found a high degree of synchrony between changes in mental state and physical performance: during the follow-up period, failure to improve or worsening in anxiety and depression levels was closely associated with concurrent declines across almost all functional domains. This indicates a dynamic, bidirectional interaction between mental health and physical function in the course of PAH. These findings move beyond the limitations of earlier cross‑sectional studies, suggesting that psychological factors are not just tied to immediate symptom burden they may also shape the course of functional rehabilitation. The predictive role of baseline anxiety and depression highlights the core prognostic value of mental health in PAH management. Patients with greater psychological distress may derive limited benefit from standard rehabilitation, with potential mechanisms including behavioral factors, such as reduced physical activity, fear and avoidance of exercise-induced symptoms, and decreased compliance. Psychophysiological mechanisms, including autonomic nervous system dysregulation (e.g., excessive sympathetic activation), heightened chemosensitivity, and chronic low-grade systemic inflammation, may directly lead to exercise intolerance and reduced ventilatory efficiency. This study advocates for incorporating early psychological assessment and intervention as part of the standard treatment for PAH to optimize overall rehabilitation outcomes. Anxiety and Depression Exert Differential Effects on Functional Recovery This study found that anxiety and depression have distinct physiological characteristics and may exert their effects through different dominant pathways. The study showed that anxiety symptoms showed a stronger and more stable association with ventilatory efficiency (VE/VCO2 slope). Anxiety state may activate the locus coeruleus-sympathetic nervous system [ 17 ] , potentiating the already elevated exercise-induced hyperventilation response in patients with PAH, thereby exacerbating dyspnea. This state heightens patient sensitivity and vigilance toward internal and external stimuli, creating a vicious cycle of dyspnea and fear. Depressive symptoms exhibited a broader and more persistent negative correlation with indicators reflecting peripheral oxygen uptake and utilization efficiency (such as VO2/WR, OUES). This finding aligns with the "skeletal muscle myopathy" hypothesis posited in depression research. It suggests that depressive symptoms are associated with a chronic low-grade inflammatory state, where elevated levels of circulating inflammatory cytokines (such as interleukin-6 (IL-6), tumor necrosis factor-alpha ༈TNF-α༉) can directly damage skeletal muscle [ 18 ] . These cytokines collectively lead to muscle atrophy, decreased strength, and reduced metabolic efficiency by promoting protein breakdown, inhibiting protein synthesis, and inducing mitochondrial dysfunction and oxidative stress [ 19 ] . Peripheral muscle dysfunction (such as muscle atrophy, hypoperfusion, and metabolic abnormalities) in PAH patients is itself one of the core factors limiting their exercise capacity [ 20 , 21 ] . This study found that comorbid depression may not be an independent psychological issue but rather a critical synergistic exacerbating factor. Through the aforementioned inflammatory pathway, it superimposes on the existing muscle pathology in PAH, further impairing the muscle's ability to extract and utilize oxygen. Overall, patients with anxiety may benefit from interventions targeting dyspnea-related fear, while patients with depression may require strategies to alleviate fatigue and improve peripheral muscle function. The Synchrony of Psychological and Functional Decline Suggests Shared Mechanisms Changes in mental state (ΔSAS/ΔSDS) exhibit a strong concordance with concurrent changes in almost all functional outcomes(Fig. 1 ). This synchronicity has two important implications. It suggests that psychological disturbances and functional decline may share common underlying drivers, such as systemic inflammation or autonomic imbalance, rather than a merely unidirectional causal relationship. This marked synchronicity suggests bidirectional therapeutic potential: interventions targeting mental health may simultaneously promote improvements in physical function, while effective exercise training can alleviate anxiety and depressive symptoms by enhancing self-efficacy, modulating inflammatory pathways, or improving autonomic balance [ 22 ] . Evidence indicates that exercise training, while improving cardiopulmonary function, can indirectly alleviate depression by enhancing patients' sense of self-efficacy and reducing systemic inflammation levels [ 23 , 24 ] , successful anxiety management may optimize ventilatory efficiency and exercise tolerance by reducing sympathetic nervous system tone [ 25 ] . This bidirectional influence highlights the importance of "dual-heart medicine" in the management of pulmonary arterial hypertension, addressing both psychological and physiological domains simultaneously to optimize therapeutic outcomes. Depression may lead to long-term adverse prognosis Depressive symptoms show a strong and sustained association with the peak VO2/WR and OUES,indicating that depression is a stable predictor of poor prognosis. This phenomenon may stem from the multifaceted mechanisms of depression: it affects physiological pathways like inflammatory response and autonomic nervous function and shows up as symptoms such as anhedonia, fatigue and lack of motivation [ 26 ] , thereby reducing patient adherence to exercise training and treatment. Consequently, this perpetuates a vicious cycle of reduced cardiopulmonary function and worsening mood. Depressive symptoms can independently predict decline in pulmonary function indicators (such as ΔFEV1% and ΔFEV1/FVC%), an effect not observed with anxiety symptoms. This further suggests that in patients with PAH, depression may have a broader impact on overall health status. Clinical Implications In the initial assessment of patients with PAH, psychological screening should be routinely incorporated to identify patients at higher risk of poor functional recovery. Patients with higher baseline levels of anxiety or depression may benefit more from early psychological interventions (such as cognitive behavioral therapy or pharmacotherapy), so psychological assessment and intervention should be integrated into comprehensive rehabilitation. Special attention should be paid to these patients' fear and avoidance of exercise during the recovery process, along with their dyspnea-related anxiety. Implementing an individualized, supervised, and progressive exercise regimen may improve adherence and optimize outcomes in this vulnerable subgroup. Limitations and Future Directions This study has certain limitations. The three-month follow-up period is relatively short, and future studies should employ extended follow-up periods to assess the sustainability of the effects. Psychological status was assessed via self-reported measures, which may introduce some bias. As a single-center study, the restricted sample enrollment source limits the generalizability of the results. Furthermore, although FDR correction and low multicollinearity support the robustness of the findings, some models violated the normality assumption. Future research should explore mechanistic pathways, such as autonomic nervous system, inflammatory responses, and behavioral factors, and validate the efficacy of integrated psychosocial-exercise interventions in randomized controlled trials. Conclusion Baseline anxiety and depressive symptoms are independent predictors of poor short-term functional rehabilitation outcomes in patients with PAH. Higher levels of anxiety and depression are associated with smaller improvements in exercise capacity and ventilatory efficiency; the failure to improve or the worsening of anxiety and depression during treatment is significantly correlated with functional decline. These findings emphasize the necessity of incorporating psychological assessment into the routine comprehensive treatment of patients with PAH and provide support for developing early, targeted psychosocial interventions to optimize rehabilitation outcomes. Adopting a comprehensive, patient-centered approach that simultaneously addresses both mental and physical health is crucial for optimizing long-term functional outcomes in this population. Declarations Author Contributions YC made substantial contributions to the conception, design, interpretation of data, and drafted the study. XXW made substantial contributions to the conception, design, interpretation of data, and substantively revised the study. SLL JCZ XRJ made substantial contributions to the conception, acquisition, interpretation of data, and revised the study. HBL made substantial contributions to the acquisition, analysis, and interpretation of data. FHQ made substantial contributions to the conception, interpretation of data, and substantively revised the study. YQL made substantial contributions to the conception and revised the study.All authors have approved the submitted version and have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work. Funding This work was supported by the Fujian Provincial Key Discipline Construction Project in Traditional Chinese Medicine (Document No. Min Wei Zhong Yi Han [2023] 2718). The funding body played no role in the design of the study, the collection, analysis, or interpretation of data, or in writing the manuscript. Ethics approval and consent to participate This study was approved by the Ethics Committee of Fujian Medical University Union Hospital (Approval No. 2025KY751). Written informed consent was obtained from all individual participants included in the study. Acknowledgments The authors thank Sumei Lin and Shiwei Hong for their contributions to data collection. Competing interests The authors declare that they have no competing interests. Clinical trial number Not applicable. Data Availability Declaration All data supporting the findings of this study are available from the corresponding author upon reasonable request. Consent to Publish declaration Not applicable. References Zheng D, Guo Y. Targeting the Hippo pathway in pulmonary arterial hypertension: emerging pharmacological strategies. J Hypertens. 2026 . Dang K, Zhang J, Yu K, et al. Natural terpenoids with therapeutic potential against pulmonary arterial hypertension. Front Pharmacol. 2025. 16: 1713745. Wu F, Chen X, Chen K, Wei J, Gong C, Wu W. Association of Immunoglobulin E With Right Ventricular Dysfunction in Pulmonary Arterial Hypertension. Pulm Circ. 2026. 16(1): e70263. Rong C, Zhang L, Li B, et al. 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Tables Tables 1 to 6 are available in the supplementary files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 13 May, 2026 Reviews received at journal 10 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers invited by journal 06 May, 2026 Editor invited by journal 10 Apr, 2026 Editor assigned by journal 09 Apr, 2026 Submission checks completed at journal 09 Apr, 2026 First submitted to journal 07 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9341136","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":640352971,"identity":"b7261b70-5362-4cf0-af99-520d56ceef15","order_by":0,"name":"Yan cheng","email":"","orcid":"","institution":"Union Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"cheng","suffix":""},{"id":640352973,"identity":"f7f8e0ae-73c6-43be-8bfa-d4e34e99898d","order_by":1,"name":"Xinxin Wang","email":"","orcid":"","institution":"Union Hospital, Fujian Medical 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09:40:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":148475,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9341136/v1/46248127b76b22f6b6952113.png"},{"id":109405619,"identity":"55af2079-681a-434e-83a4-1906fe86c9c6","added_by":"auto","created_at":"2026-05-17 13:19:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":293023,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9341136/v1/e6c1a09f-afe5-4017-a480-76ae3ce40e46.pdf"},{"id":109303451,"identity":"19f725a9-5513-4de4-8f99-5e338ce39b57","added_by":"auto","created_at":"2026-05-15 09:40:14","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":48911,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9341136/v1/edc859d4d34aa80ba18ef44f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of Anxiety and Depressive Symptoms with Short-Term Functional Recovery in Pulmonary Arterial Hypertension: A Longitudinal Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by pulmonary vascular remodeling and progressive elevation of pulmonary vascular resistance, ultimately leading to right heart failure and even death\u003csup\u003e[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In recent years, advances in targeted drug therapy have significantly improved the survival prognosis of patients with PAH, but most patients still exhibit progressive decline in exercise tolerance and quality of life, which is lower than the predicted values for individuals of the same age and gender\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT), as core indicators for assessing cardiopulmonary endurance in patients with PAH, can not only be used for risk stratification of these patients but also serve as independent predictors of prognosis\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Therefore, early identification of risk factors affecting cardiopulmonary function in patients with PAH is crucial for optimizing individualized treatment strategies and improving long-term outcomes.\u003c/p\u003e \u003cp\u003eIn recent years, the issue of psychological comorbidities in patients with PAH has received increasing attention. Epidemiological statistics show that 25%\u0026ndash;40% of patients with PAH exhibit symptoms of anxiety and depression\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, a prevalence significantly higher than rates observed in the general population and among patients with other chronic diseases. Existing research indicates that anxiety and depression status can reduce cardiopulmonary endurance and quality of life in patients with PAH and lead to worse cardiac function classification\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Mechanistically, persistent anxiety and depression activate the \"hypothalamic-pituitary-adrenal axis,\" causing sympathetic nervous system activation, thereby increasing cardiovascular burden and impairing cardiopulmonary functional reserve\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Psychological distress can make patients fearful of activities, keeping the body in a state of \"high alert,\" amplifying their perception of physical symptoms such as dyspnea and palpitations, ultimately leading to reduced activity and decreased cardiopulmonary endurance\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Most existing studies treat psychological distress as a \"concomitant phenomenon\" or \"outcome indicator\" of the disease, with few studies exploring whether baseline anxiety and depression levels can independently predict dynamic changes in cardiopulmonary function during follow-up in patients with PAH.\u003c/p\u003e \u003cp\u003eTherefore, this study aims to conduct a 3-month longitudinal observation to investigate whether baseline anxiety and depression are independently associated with the magnitude of improvement in cardiopulmonary function during follow-up; whether there are differences in the impact of anxiety and depression on cardiopulmonary function recovery; and whether changes in psychological status are concordant with changes in cardiopulmonary function indicators. If the study finds that baseline psychological status affects the trajectory of cardiopulmonary function recovery in patients with PAH, then incorporating psychological status screening into routine clinical assessments will help early identification of high-risk patients with limited improvement in cardiopulmonary function. Timely intervention for abnormal psychological status can not only alleviate psychological symptoms but also break the vicious cycle of psychological effects on physiology, thereby enhancing rehabilitation benefits.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eThis longitudinal observational study enrolled 105 patients with type 1 PAH diagnosed at Fujian Medical University Union Hospital between January and May 2025. Inclusion criteria were: (1) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (2) clinically stable condition and receiving optimized PAH-targeted drug therapy for at least 3 months prior to enrollment; (3) ability to undergo CPET and complete the 6MWT; (4) completion of assessments at both baseline (T0) and the 3-month follow-up (T1); (5) signed informed consent. Exclusion criteria included: (1) significant comorbidities affecting exercise capacity (e.g., uncontrolled left heart disease, severe chronic obstructive pulmonary disease (COPD), musculoskeletal disorders); (2) pregnancy; (3) cognitive or language impairments preventing completion of self-reported questionnaires; (4) untreated severe psychiatric illness at diagnosis. During T1, patients received standardized education on physical activity but did not undergo structured exercise intervention, reflecting real-world clinical practice. The study was approved by the Institutional Ethics Committee of Fujian Medical University Union Hospital (approval number 2025KY751), and all participants provided written informed consent in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMeasurements\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDemographic and Clinical Characteristics\u003c/h2\u003e \u003cp\u003eDemographic data including age, sex, height, weight, and body mass index (BMI) were collected at T0. Disease severity was assessed using the World Health Organization functional class (WHO-FC). Right heart catheterization (RHC) was performed to obtain hemodynamic parameters, including mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), pulmonary arterial wedge pressure (PAWP), right atrial pressure (RAP), cardiac output (CO), and cardiac index (CI). All procedures adhered to standardized protocols.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePsychological Assessment\u003c/h3\u003e\n\u003cp\u003eAnxiety and depressive symptoms were assessed at T0 and T1 using the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS), respectively. Both scales consist of 20 items rated on a 4-point Likert scale (1\u0026thinsp;=\u0026thinsp;none or a little of the time to 4\u0026thinsp;=\u0026thinsp;most or all of the time), with total scores ranging from 20 to 80. The raw scores were converted to standard scores. Standard scores of \u0026ge;\u0026thinsp;50 on the SAS and \u0026ge;\u0026thinsp;53 on the SDS were classified as indicative of clinically significant symptoms, where higher scores reflect greater severity of anxiety or depression\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. These instruments have been widely validated and used in patients with cardiovascular and chronic respiratory diseases, including pulmonary hypertension.\u003c/p\u003e\n\u003ch3\u003eExercise Capacity and Cardiopulmonary Function\u003c/h3\u003e\n\u003cp\u003eAt both T0 and T1, all patients underwent the following assessments:\u003c/p\u003e \u003cp\u003e 6MWT: The 6MWT was performed according to American Thoracic Society guidelines. Patients were instructed to walk as far as possible in 6 minutes along a marked corridor, and the 6-minute walk distance(6MWD) was recorded. Standardized verbal encouragement was provided at regular intervals\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCPET: The patient underwent a symptom-limited exercise test using the Ramp protocol. Calibrated gas analyzers measured respiratory gas exchange during exercise\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Cardiorespiratory function data were recorded\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. All tests were supervised by both experienced cardiologists and cardiac rehabilitation therapists.\u003c/p\u003e \u003cp\u003epulmonary function tests (PFTs): At T0 and T1, static pulmonary function parameters were recorded according to standardized procedures using a Pulmometer.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using R (version 4.5.1). Longitudinal changes (Δ) were calculated as the difference between T1 and T0 values. Multivariable linear regression was used to examine: (1) cross-sectional associations between psychological status (SAS/SDS) and functional parameters at T0 and T1, adjusted for age, sex, and BMI; (2) predictive associations between baseline psychological status and changes in functional outcomes (Δ), adjusting for the baseline values of the respective outcomes; and (3) associations between changes in psychological status (ΔSAS/ΔSDS) and Δfunctional outcomes, using linear mixed models with adjustment for baseline functional values. Model assumptions were assessed via Shapiro\u0026ndash;Wilk tests for residual normality, Breusch\u0026ndash;Pagan tests for heteroscedasticity, and variance inflation factors for multicollinearity. Results are presented as unstandardized β coefficients, accompanied by 95% confidence intervals and two-sided p-values. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, with false discovery rate (FDR) correction applied for multiple comparisons.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e1. Participant Characteristics\u003c/p\u003e\n\u003cp\u003eThis longitudinal study enrolled 105 patients with PAH (mean age 56.2 \u0026plusmn; 15.7 years; 57% female). Most patients were classified as WHO-FC III (80%), with the remainder as class II (20%). Hemodynamic assessment indicated moderate disease severity (mPAP 35.5 \u0026plusmn; 11.7 mmHg; PVR 6.7 \u0026plusmn; 3.6 Wood units). At baseline, patients exhibited impaired exercise capacity (6MWD: 349.1 \u0026plusmn; 45.4 m; VO2 peak: 12.9 \u0026plusmn; 3.2 mL/kg/min) and mild to moderate anxiety and depressive symptoms (SAS: 56.6 \u0026plusmn; 4.3; SDS: 53.1 \u0026plusmn; 5.4), as shown in Table 1. Follow-up assessments were completed for all patients.\u003c/p\u003e\n\u003cp\u003e2. Cross-Sectional Associations at Baseline and Follow-Up\u003c/p\u003e\n\u003cp\u003eAt T0, higher SAS and SDS scores were significantly associated with lower VO2 at AT, peak VO2, and PETCO2, and with higher VE/VCO2 at AT and the VE/VCO2 slope (all p \u0026lt; 0.05). SAS demonstrated stronger associations with ventilatory inefficiency, while SDS was correlated with both OUES and VO2/WR (p \u0026lt; 0.05). No significant associations were observed with 6MWD or pulmonary function parameters at T0 (Table 2).\u003c/p\u003e\n\u003cp\u003eAt T1, these associations strengthened. Both SAS and SDS were significantly associated with nearly all functional parameters, including 6MWD, VO2 at AT, VO2 peak, VE/VCO2, PETCO2, VO2/WR, and OUES (all p \u0026lt; 0.05). SDS exhibited more robust and widespread associations than SAS, particularly with VO2/WR and OUES (Table 3).\u003c/p\u003e\n\u003cp\u003eBaseline Psychological Status Predicts Functional Changes\u003c/p\u003e\n\u003cp\u003eAfter correction for baseline functional values, higher baseline SAS scores significantly predicted attenuated improvements in \u0026Delta;6MWD (\u0026beta;= -1.804, p = 0.016) and \u0026Delta;VO2 peak (\u0026beta;=-0.092, p=0.024). Baseline SDS scores showed a trend in predicting smaller gains in \u0026Delta;VO2 peak (\u0026beta;=-0.054, p=0.091) and significantly predicted deterioration in \u0026Delta;FEV1% and \u0026Delta;FEV1/FVC% (both p\u0026lt; 0.05). Baseline SAS/SDS showed no significant associations with changes in VE/VCO2 slope or PETCO2 (Table 4).These results suggest that a poorer mental state at baseline, particularly an anxiety status, may predict a greater decline in \u0026nbsp;cardiopulmonary function in the future.\u003c/p\u003e\n\u003cp\u003eConcurrent Changes in Psychological and Functional Status\u003c/p\u003e\n\u003cp\u003eChanges in psychological status (\u0026Delta;SAS and \u0026Delta;SDS) were strongly and consistently associated with concurrent changes in all functional parameters (all p \u0026lt; 0.001), including 6MWD, VO2 at AT, VO2 peak, VE/VCO2 at AT, PETCO2, VO2/WR, OUES, and all pulmonary function indices. These associations remained robust after adjustment for the baseline functional values, it indicates a synchronous relationship between mental health and functional improvement. (Table 5).\u003c/p\u003e\n\u003cp\u003eModel Diagnostics\u003c/p\u003e\n\u003cp\u003eResidual normality was not met in approximately half of the models, and heteroscedasticity was observed in a subset of models. However, variance inflation factors were low (all VIF\u0026lt;2.0), indicating no multicollinearity concerns. FDR correction did not alter the statistical significance of key findings (Table 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study shows that baseline anxiety and depression are independent predictors of poor short-term cardiopulmonary function recovery in patients with PAH. Patients with higher baseline anxiety levels showed significantly limited improvements in 6MWD and VO2peak during the 3-month follow-up period, patients with more severe baseline depressive symptoms exhibited an attenuated improvement in cardiopulmonary endurance and experienced a significant decline in lung function.The study found a high degree of synchrony between changes in mental state and physical performance: during the follow-up period, failure to improve or worsening in anxiety and depression levels was closely associated with concurrent declines across almost all functional domains. This indicates a dynamic, bidirectional interaction between mental health and physical function in the course of PAH. These findings move beyond the limitations of earlier cross‑sectional studies, suggesting that psychological factors are not just tied to immediate symptom burden they may also shape the course of functional rehabilitation. The predictive role of baseline anxiety and depression highlights the core prognostic value of mental health in PAH management. Patients with greater psychological distress may derive limited benefit from standard rehabilitation, with potential mechanisms including behavioral factors, such as reduced physical activity, fear and avoidance of exercise-induced symptoms, and decreased compliance. Psychophysiological mechanisms, including autonomic nervous system dysregulation (e.g., excessive sympathetic activation), heightened chemosensitivity, and chronic low-grade systemic inflammation, may directly lead to exercise intolerance and reduced ventilatory efficiency. This study advocates for incorporating early psychological assessment and intervention as part of the standard treatment for PAH to optimize overall rehabilitation outcomes.\u003c/p\u003e \u003cp\u003eAnxiety and Depression Exert Differential Effects on Functional Recovery\u003c/p\u003e \u003cp\u003eThis study found that anxiety and depression have distinct physiological characteristics and may exert their effects through different dominant pathways. The study showed that anxiety symptoms showed a stronger and more stable association with ventilatory efficiency (VE/VCO2 slope). Anxiety state may activate the locus coeruleus-sympathetic nervous system\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, potentiating the already elevated exercise-induced hyperventilation response in patients with PAH, thereby exacerbating dyspnea. This state heightens patient sensitivity and vigilance toward internal and external stimuli, creating a vicious cycle of dyspnea and fear.\u003c/p\u003e \u003cp\u003eDepressive symptoms exhibited a broader and more persistent negative correlation with indicators reflecting peripheral oxygen uptake and utilization efficiency (such as VO2/WR, OUES). This finding aligns with the \"skeletal muscle myopathy\" hypothesis posited in depression research. It suggests that depressive symptoms are associated with a chronic low-grade inflammatory state, where elevated levels of circulating inflammatory cytokines (such as interleukin-6 (IL-6), tumor necrosis factor-alpha ༈TNF-α༉) can directly damage skeletal muscle\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. These cytokines collectively lead to muscle atrophy, decreased strength, and reduced metabolic efficiency by promoting protein breakdown, inhibiting protein synthesis, and inducing mitochondrial dysfunction and oxidative stress\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Peripheral muscle dysfunction (such as muscle atrophy, hypoperfusion, and metabolic abnormalities) in PAH patients is itself one of the core factors limiting their exercise capacity\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. This study found that comorbid depression may not be an independent psychological issue but rather a critical synergistic exacerbating factor. Through the aforementioned inflammatory pathway, it superimposes on the existing muscle pathology in PAH, further impairing the muscle's ability to extract and utilize oxygen. Overall, patients with anxiety may benefit from interventions targeting dyspnea-related fear, while patients with depression may require strategies to alleviate fatigue and improve peripheral muscle function.\u003c/p\u003e \u003cp\u003eThe Synchrony of Psychological and Functional Decline Suggests Shared Mechanisms\u003c/p\u003e \u003cp\u003eChanges in mental state (ΔSAS/ΔSDS) exhibit a strong concordance with concurrent changes in almost all functional outcomes(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This synchronicity has two important implications. It suggests that psychological disturbances and functional decline may share common underlying drivers, such as systemic inflammation or autonomic imbalance, rather than a merely unidirectional causal relationship. This marked synchronicity suggests bidirectional therapeutic potential: interventions targeting mental health may simultaneously promote improvements in physical function, while effective exercise training can alleviate anxiety and depressive symptoms by enhancing self-efficacy, modulating inflammatory pathways, or improving autonomic balance\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Evidence indicates that exercise training, while improving cardiopulmonary function, can indirectly alleviate depression by enhancing patients' sense of self-efficacy and reducing systemic inflammation levels\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, successful anxiety management may optimize ventilatory efficiency and exercise tolerance by reducing sympathetic nervous system tone\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. This bidirectional influence highlights the importance of \"dual-heart medicine\" in the management of pulmonary arterial hypertension, addressing both psychological and physiological domains simultaneously to optimize therapeutic outcomes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003cdiv class=\"Heading\"\u003eDepression may lead to long-term adverse prognosis\u003c/div\u003e \u003cp\u003eDepressive symptoms show a strong and sustained association with the peak VO2/WR and OUES,indicating that depression is a stable predictor of poor prognosis. This phenomenon may stem from the multifaceted mechanisms of depression: it affects physiological pathways like inflammatory response and autonomic nervous function and shows up as symptoms such as anhedonia, fatigue and lack of motivation\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e, thereby reducing patient adherence to exercise training and treatment. Consequently, this perpetuates a vicious cycle of reduced cardiopulmonary function and worsening mood. Depressive symptoms can independently predict decline in pulmonary function indicators (such as ΔFEV1% and ΔFEV1/FVC%), an effect not observed with anxiety symptoms. This further suggests that in patients with PAH, depression may have a broader impact on overall health status.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eClinical Implications\u003c/h2\u003e \u003cp\u003eIn the initial assessment of patients with PAH, psychological screening should be routinely incorporated to identify patients at higher risk of poor functional recovery. Patients with higher baseline levels of anxiety or depression may benefit more from early psychological interventions (such as cognitive behavioral therapy or pharmacotherapy), so psychological assessment and intervention should be integrated into comprehensive rehabilitation. Special attention should be paid to these patients' fear and avoidance of exercise during the recovery process, along with their dyspnea-related anxiety. Implementing an individualized, supervised, and progressive exercise regimen may improve adherence and optimize outcomes in this vulnerable subgroup.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eLimitations and Future Directions\u003c/h2\u003e \u003cp\u003eThis study has certain limitations. The three-month follow-up period is relatively short, and future studies should employ extended follow-up periods to assess the sustainability of the effects. Psychological status was assessed via self-reported measures, which may introduce some bias. As a single-center study, the restricted sample enrollment source limits the generalizability of the results. Furthermore, although FDR correction and low multicollinearity support the robustness of the findings, some models violated the normality assumption. Future research should explore mechanistic pathways, such as autonomic nervous system, inflammatory responses, and behavioral factors, and validate the efficacy of integrated psychosocial-exercise interventions in randomized controlled trials.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBaseline anxiety and depressive symptoms are independent predictors of poor short-term functional rehabilitation outcomes in patients with PAH. Higher levels of anxiety and depression are associated with smaller improvements in exercise capacity and ventilatory efficiency; the failure to improve or the worsening of anxiety and depression during treatment is significantly correlated with functional decline. These findings emphasize the necessity of incorporating psychological assessment into the routine comprehensive treatment of patients with PAH and provide support for developing early, targeted psychosocial interventions to optimize rehabilitation outcomes. Adopting a comprehensive, patient-centered approach that simultaneously addresses both mental and physical health is crucial for optimizing long-term functional outcomes in this population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYC made substantial contributions to the conception, design, interpretation of data, and drafted the study. XXW made substantial contributions to the conception, design, interpretation of data, and substantively revised the study. SLL JCZ XRJ made substantial contributions to the conception, acquisition, interpretation of data, and revised the study. HBL made substantial contributions to the acquisition, analysis, and interpretation of data. FHQ made substantial contributions to the conception, interpretation of data, and substantively revised the study. YQL made substantial contributions to the conception and revised the study.All authors have approved the submitted version and have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Fujian Provincial Key Discipline Construction Project in Traditional Chinese Medicine (Document No. Min Wei Zhong Yi Han [2023] 2718). The funding body played no role in the design of the study, the collection, analysis, or interpretation of data, or in writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Fujian Medical University Union Hospital (Approval No. 2025KY751). Written informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Sumei Lin and Shiwei Hong for their contributions to data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data supporting the findings of this study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZheng D, Guo Y. Targeting the Hippo pathway in pulmonary arterial hypertension: emerging pharmacological strategies. J Hypertens. 2026 .\u003c/li\u003e\n\u003cli\u003eDang K, Zhang J, Yu K, et al. Natural terpenoids with therapeutic potential against pulmonary arterial hypertension. Front Pharmacol. 2025. 16: 1713745.\u003c/li\u003e\n\u003cli\u003eWu F, Chen X, Chen K, Wei J, Gong C, Wu W. Association of Immunoglobulin E With Right Ventricular Dysfunction in Pulmonary Arterial Hypertension. Pulm Circ. 2026. 16(1): e70263.\u003c/li\u003e\n\u003cli\u003eRong C, Zhang L, Li B, et al. Efficacy and safety of specific treatment combined with SGLT2-i in pulmonary hypertension. Front Cardiovasc Med. 2025. 12: 1684394.\u003c/li\u003e\n\u003cli\u003eBridi G, Freire da Silva B, Sobral-Alves JB, et al. Mechanisms of exercise limitation and prevalence of pulmonary hypertension in hypersensitivity pneumonitis. ERJ Open Res. 2026. 12(1).\u003c/li\u003e\n\u003cli\u003eResqueti V, Torres-Castro R, Gimeno-Santos E, et al. Limitations of 6-minute walk test-based equations in predicting peak oxygen uptake and risk assessment in patients with pulmonary hypertension and COPD. Respir Med. 2026. 254: 108738.\u003c/li\u003e\n\u003cli\u003eTakita Y, Morishita J, Park S, et al. Mindfulness-Based Self-Management Program Using a Mobile App for Patients With Pulmonary Hypertension: Single-Arm Feasibility Study. JMIR Cardio. 2026. 10: e79639.\u003c/li\u003e\n\u003cli\u003eZhou J, Yang Y, Zou H, et al. A carrier-free nanomedicine targeting vascular remodeling and oxidative stress for enhanced pulmonary arterial hypertension therapy. J Colloid Interface Sci. 2026. 708: 139821.\u003c/li\u003e\n\u003cli\u003eYang H, Narayan S, Bordes J, et al. Mineralocorticoid Receptor in Glutamatergic Neurons Modulates Anxiety Exclusively in Male Mice Via Regulation of the Actin-Bundling Factor Fam107a. Biol Psychiatry Glob Open Sci. 2026. 6(2): 100651.\u003c/li\u003e\n\u003cli\u003eMarazziti D, Russomanno G, Gambini M, Digiuseppe FR, Fazio E, Gurrieri R. Sensory Deprivation and the Brain: Neurobiological Mechanisms, Psychological Effects, and Clinical Implications. Brain Sci. 2026. 16(2).\u003c/li\u003e\n\u003cli\u003eVon Visger TT, Chang YP. Mindfulness meditation for pulmonary hypertension program development: Acceptability and feasibility of technology-assisted complementary health intervention for symptom self-management. Heart Lung. 2026. 78: 102759.\u003c/li\u003e\n\u003cli\u003eLiu X, Zhang X, Liu Y. How Anxiety Shapes Students\u0026apos; Self-Rated Health at Elite Universities: A Longitudinal Study. Behav Sci (Basel). 2026. 16(2).\u003c/li\u003e\n\u003cli\u003eZhu A, Xue D, Yang H, Ren Y. Personality traits and psychological distress in Chinese adolescents: the mediating roles of anxiety and depression. Front Psychol. 2025. 16: 1748370.\u003c/li\u003e\n\u003cli\u003eS S, Devarajan A, Lakshmi VS. Functional Recovery Patterns and Exercise Tolerance in Children With Persistent Asthma: An Observational Study Using Spirometry and the Six-Minute Walk Test (6MWT). Cureus. 2026. 18(2): e103012.\u003c/li\u003e\n\u003cli\u003eReddy Y, Frantz RP, Miranda WR, Harada T, Kazui S, Borlaug BA. Sotatercept in Pulmonary Arterial Hypertension: Central, Hematologic, and Peripheral Mechanisms of Benefit. J Am Coll Cardiol. 2026 .\u003c/li\u003e\n\u003cli\u003eVan Hooren B, Souren T, Miqueu F, Bongers BC. Technological and Biological Reliability, and Validity of Five Different CPET Systems During Simulated and Human Exercise. Scand J Med Sci Sports. 2026. 36(1): e70184.\u003c/li\u003e\n\u003cli\u003eTyler WJ. Transcutaneous Auricular Vagus Nerve Stimulation for Treating Emotional Dysregulation and Inflammation in Common Neuropsychiatric Disorders. Brain Sci. 2025. 16(1).\u003c/li\u003e\n\u003cli\u003eTero-Vescan A, Ștefănescu R, Pușcaș A, Buț M, Ősz BE, Slevin M. Kynurenine Pathway Metabolites as Mediators of Exercise-Induced Mood Enhancement, Fatigue Resistance, and Neuroprotection. Int J Mol Sci. 2025. 27(1).\u003c/li\u003e\n\u003cli\u003eShemer S. Mechanisms of protein degradation in atrophying muscles: What have we learned during the past decade. J Biol Chem. 2026. 302(3): 111229.\u003c/li\u003e\n\u003cli\u003eChen X, Wang X, Xu R, Gao S, Han J. Beyond the Vasculature: The Emerging Role of Systemic Metabolism and Immunometabolism in Pulmonary Arterial Hypertension. Int J Mol Sci. 2026. 27(6).\u003c/li\u003e\n\u003cli\u003eMitsuyoshi K, Kubota K, Miyanaga S, Akao M, Ohishi M. Association of peak expiratory flow rate with clinical outcomes in pulmonary arterial hypertension. Hypertens Res. 2026 .\u003c/li\u003e\n\u003cli\u003eGe B, Liao X, Lai F, Luo J, Wang Z. Effects of Traditional Chinese Exercise on Mental Health and Physical Function With Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis. Physiother Res Int. 2026. 31(2): e70193.\u003c/li\u003e\n\u003cli\u003eStark C, Beck J, Oswald A, et al. Lifestyle physical activity coaching in outpatients with major depressive disorder (PACOUTPAT): study protocol for a randomized controlled trial on physical activity, depression, and quality of life. Trials. 2026 .\u003c/li\u003e\n\u003cli\u003eKreppke JN, Brupbacher G, Rupf K, et al. Association Between Physical Activity, Heart Rate Variability and Major Depressive Disorders: An Umbrella Review. Sports Med. 2026 .\u003c/li\u003e\n\u003cli\u003eGanesh A, Mishra S, Hwang GW, Dinkha S, Chan E. Improving Psychological Well-Being and Quality of Life in Rheumatoid Arthritis-Associated Interstitial Lung Disease Through Exercise and Pulmonary Rehabilitation: A Narrative Review. Healthcare (Basel). 2026. 14(5).\u003c/li\u003e\n\u003cli\u003eIannotta F, Iasevoli F, Caiazza C, Fornaro M, Nolano M, de Bartolomeis A. Autonomic dysfunctions in psychotic disorders, interaction with antipsychotic intervention and treatment resistance: a comprehensive systematic review and meta-analysis. J Psychiatr Res. 2026. 194: 123-135.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the supplementary files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pulmonary arterial hypertension, Anxiety, Depression, Exercise capacity, Cardiopulmonary exercise testing, Functional recovery","lastPublishedDoi":"10.21203/rs.3.rs-9341136/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9341136/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and Objective: \u003c/strong\u003eThe prevalence of anxiety and depression is significantly elevated in patients with pulmonary arterial hypertension (PAH). It remains unclear whether baseline psychological status predicts subsequent trajectories of functional recovery and whether changes in psychological status are dynamically associated with changes in physiological function. This study aimed to investigate whether baseline anxiety and depressive symptoms are independently associated with changes in exercise capacity and ventilatory efficiency over a 3-month follow-up period in patients with PAH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis longitudinal observational study included 105 patients diagnosed with type 1 PAH who were recruited from Fujian Medical University Union Hospital between January and May 2025. All patients completed the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) at baseline (T0) and at the 3-month follow-up (T1) and underwent the 6-minute walk test (6MWT), cardiopulmonary exercise testing (CPET), and pulmonary function tests (PFTs). Multivariable linear regression and linear mixed-effects models were used to examine the associations between baseline SAS/SDS scores and changes in functional outcomes, as well as the concurrent associations between changes in psychological status (ΔSAS/ΔSDS) and corresponding changes in functional parameters.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThis study included 105 patients with PAH (mean age 56.2 ± 15.7 years, 57% female). At baseline, patients exhibited mild to moderate anxiety and depression symptoms, with SAS scores of 56.6 ± 4.3 and SDS scores of 53.1 ± 5.4; they also exhibited impaired exercise capacity, with a 6-minute walking distance (6MWD) of 349.1 ± 45.4 meters and a peak oxygen uptake (VO2peak) of 12.9 ± 3.2 mL/kg/min. Multivariate analysis showed that higher baseline SAS scores were significantly associated with a reduced magnitude of improvement in Δ6MWD (β = -1.804, p = 0.016) and ΔVO2peak (β = 0.-092, p = 0.024). Higher baseline SDS scores significantly predicted more pronounced deterioration in predicted FEV1% and the FEV1/FVC ratio (both p \u0026lt; 0.05). Changes in psychological state (ΔSAS, ΔSDS) were significantly correlated with concurrent changes in nearly all functional outcome measures (all p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eBaseline anxiety and depressive symptoms are independent predictors of poor short-term functional rehabilitation in patients with PAH, and dynamic changes in psychological state are strongly correlated with changes in physiological function. Incorporating psychological screening into routine clinical assessment may help identify patients at risk of poor functional rehabilitation outcomes.Limplementing comprehensive psychological rehabilitation interventions can improve patient prognosis.\u003c/p\u003e","manuscriptTitle":"Association of Anxiety and Depressive Symptoms with Short-Term Functional Recovery in Pulmonary Arterial Hypertension: A Longitudinal Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-15 09:38:43","doi":"10.21203/rs.3.rs-9341136/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"220631740258154590679522478101969871539","date":"2026-05-13T16:50:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-10T19:25:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35554427066422695253439708742154618719","date":"2026-05-06T09:32:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-06T07:32:54+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-10T07:08:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-09T18:52:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-09T18:51:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-04-07T07:18:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"348db94e-0399-418a-a75d-adefba643481","owner":[],"postedDate":"May 15th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"220631740258154590679522478101969871539","date":"2026-05-13T16:50:32+00:00","index":58,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-10T19:25:51+00:00","index":40,"fulltext":""},{"type":"reviewerAgreed","content":"35554427066422695253439708742154618719","date":"2026-05-06T09:32:45+00:00","index":35,"fulltext":""},{"type":"reviewersInvited","content":"30","date":"2026-05-06T07:32:54+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T09:38:43+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-15 09:38:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9341136","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9341136","identity":"rs-9341136","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}