Minimising postoperative pulmonary complications (PPCs) after thoracic surgery is of utmost importance. A major factor contributing to PPCs is the driving pressure, which is determined by the ratio of tidal volume to lung compliance. Inhalation and intravenous administration of penehyclidine can improve lung compliance during intraoperative mechanical ventilation. Therefore, our study aimed to compare the efficacy of inhaled vs. intravenous penehyclidine during one-lung ventilation (OLV) in mitigating driving pressure and mechanical power among patients undergoing thoracic surgery.1 (5 min after OLV), T2 (15 min after OLV), T3 (30 min after OLV), and T4 (45 min after OLV) in both groups. The primary outcome of this study was the composite measure of driving pressure during OLV. The area under the curve (AUC) of driving pressure from T1 to T4 was computed. Additionally, the secondary outcomes included mechanical power, lung compliance and the incidence of PPCs.A double-blind, prospective, randomised study involving 176 patients scheduled for elective thoracic surgery was conducted. These patients were randomly divided into two groups, namely the penehyclidine inhalation group and the intravenous group before their surgery. Driving pressure was assessed at TP = 0.138). The incidence of PPCs within 7 days after surgery was 27.7% in the intravenous group and 23.8% in the inhalation group (P = 0.564). No significant differences were observed in any of the other secondary outcomes between the two groups .All 167 participants, 83 from the intravenous group and 84 from the inhalation group, completed the trial. The AUC of driving pressure for the intravenous group was 39.50 ± 9.42, while the inhalation group showed a value of 41.50 ± 8.03 (Our study found that among patients undergoing thoracoscopic surgery, no significant differences were observed in the driving pressure and mechanical power during OLV between those who received an intravenous injection of penehyclidine and those who inhaled it. Moreover, no significant difference was observed in the incidence of PPCs between the two groups. Postoperative pulmonary complications (PPCs) are commonly observed during the first postoperative week and have been associated with a prolonged hospital stay , increasStrategies aimed at decreasing the incidence of PPCs include preoperative functional exercise , intraopAirway driving pressure and mechanical power are two widely used parameters in pulmonary protective ventilation. Airway driving pressure represents the pressure generated by mechanically ventilated patients during inhalation and is expressed as the ratio of tidal volume to lung compliance. It can also be calculated at the bedside by subtracting positive end-expiratory pressure (PEEP) from platform pressure . A recenThis clinical trial evaluated the specific roles of driving pressure and mechanical power as mediators in reducing PPCs. A randomised, prospective, and double-blind study was conducted to determine whether inhaled penehyclidine could effectively decrease the incidence of PPCs by reducing individualised drive pressure and mechanical power when compared with intravenous penehyclidine.www.chictr.org.cn, ChiCTR2200063427; 06/09/2022). Written informed consent was obtained from all participants before their inclusion in the study.This prospective trial was conducted at affiliated hospital of Jiaxing University, China, from September 2022 to April 2023. The Institutional Review Board approved this study (2022-LY-164), and it was registered with the Chinese Clinical Trial Registry  inability to cooperate during inhalation therapy, (2) moderate-to-severe symptomatic prostatic hypertrophy or narrow-angle glaucoma, (3) history of a previous myocardial infarction, severe heart dysfunction (New York Heart Association classification > 3), or tachyarrhythmia within the past 3 months, (4) presence of severe respiratory tract infections with low and thick sputum, (5) severe renal insufficiency requiring renal replacement therapy, (6) severe liver dysfunction (Child–Pugh class C), (7) recent use of anticholinergic drugs on the day before surgery, (8) prohibition from using PEEP, and (9) refused to participate in the trial. Additionally, patients taking other intraoperative anticholinergic drugs, those whose surgeries were cancelled, and patients who experienced serious allergies during surgery were considered as dropout criteria.2) of 5–8 mL/kg within 15–20 min before surgery, and 5 mL of normal saline was injected before anaesthesia induction. On the other hand, patients in group B inhaled 5 mL of normal saline with a FiO2 of 5–8 mL/kg approximately 15–20 min before surgery, and 5 mL of penehyclidine was injected before the anaesthesia induction.The anaesthesia was administered by an anaesthesiologist who was blinded to the patient grouping, and the postoperative assessment was conducted by a researcher who was also blinded to the patient grouping. All patients received a combination of inhalation and intravenous therapy. In both groups, the study drug, 0.5 mg penehyclidine, was diluted and mixed with 5 mL of normal saline. In group A, patients inhaled penehyclidine with a fraction of inspired oxygen , rocuronium (0.6–0.8 mg/kg) and sufentanil (0.2–0.5 µg/kg). During the maintenance phase of anaesthesia, sevoflurane, remifentanil, and propofol were used. An appropriate double-lumen tracheal tube was selected based on the patient’s sex . The positioning of the double-lumen endotracheal tube and bronchi was determined using fibreoptic bronchoscopy. Additional medications, such as rocuronium, were administered as required during the surgery. The target entropy index was maintained between 40 and 60 during the maintenance phase of general anaesthesia. Anaesthesiologists were given discretion in the use of analgesic pumps or peripheral nerve blocks when possible. Lactated Ringer’s solution was administered as the maintenance fluid at a rate of 3–5 mL/kg/h. Intraoperative vasoactive drugs were administered based on the mean arterial pressure, and routine postoperative antiemetic medications, such as glasnost, were administered.2O. Each level of PEEP was consistently maintained for eight respiratory cycles, and the driving pressure was recorded during the final cycle of each PEEP level for better accuracy. The PEEP level that resulted in the lowest driving pressure was selected to maintain a consistent PEEP level during OLV. Prior to the incision, a lateral position trial was conducted to determine the PEEP level associated with the lowest driving pressure.In this study, a standardised ventilation strategy was implemented for each patient. Tidal volume and respiratory rate were set at 6 mL/kg of predicted body weight and 13 breaths per minute, respectively, during OLV. Volume-controlled ventilation was employed with a 30% inspiratory pause and a 1:2 inspiratory to expiratory ratio. The inspired oxygen level was maintained at ≥ 60% and mixed with air. Predicted body weight (PBW) was calculated based on the patient’s sex, with PBW for men calculated as 50 + 0.91 × (height [cm] − 152.4) and PBW for women calculated as 45.5 + 0.91 × (height [cm] − 152.4). Oxygen concentration was increased as required to ensure adequate oxygenation during OLV and maintain a saturation level of at least 95%. After 5 min of OLV, the lowest driving pressure was determined, and PEEP was gradually increased from 0 to 10 cmH1] ≥ 80% of the predicted value, 2) moderate , 3) severe , 4) very severe .For data collection, a standardised form was used, sourced from the clinical charts to obtain baseline characteristics. Baseline data included demographic and morphometric characteristics, preoperative comorbidities, and smoking and alcohol history, along with pulmonary function test results. These pulmonary function test results were categorised based on clinical diagnosis and their reported values: 1) mild , the surgery type and duration, and the surgical site.1 (5 min after OLV), T2 (15 min after OLV), T3 (30 min after OLV), and T4 (45 min after OLV). The driving pressure was calculated using the following equation: driving pressure (cmH2O) = plateau pressure − PEEP. The area under the curve (AUC) of driving pressure from T1 to T4 for the participant was calculated. The composite secondary outcome was the occurrence of major PPCs within 7 days after surgery, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and hypoxaemia ) ) .1-T4 intervals was evaluated to increase the accuracy of our sample size calculation. The AUC of driving pressure was determined during the procedure for both groups, resulting in values of 41.40 ± 8.14 for the inhalation group and 37.48 ± 9.22 for the intravenous group. A total of 158 patients were recruited for this study to achieve a two-sided alpha level of 5% and a statistical power of 80%. Considering a dropout rate of 10%, the target enrolment was established at 176 patients, with each group comprising 88 participants.During the preliminary study, the driving pressure of 60 patients across TCategorical variables are presented as numbers and percentages. Continuous variables are presented as the mean ± standard deviation or median (interquartile). The chi-square test or Fisher’s exact test was used to compare categorical variables and Student’s t-test or Mann–Whitney U test was used for continuous variables, based on the normality of the data. Generalised estimating equations were used for repeated measures. Statistical analyses were performed using SPSS version 25 and GraphPad Prism 9, with a significance level set at 0.05 (two-tailed).From September 2022 to April 2023, 201 patients were initially assessed for eligibility, of which 176 patients were randomised. Nine patients were excluded after randomisation, resulting in 167 patients for per-protocol analysis. The final analysis encompassed 83 patients in the intravenous group and 84 patients in the inhalation group  (Table 1 to T4 was detected between the two groups (P = 0.144). At each time point, there was no significant difference in driving pressure within the inhalation group compared with the intravenous group. In terms of intragroup analysis, the intravenous and inhalation groups exhibited statistically significant differences in driving pressure at T1, T2, T3, and T4 (both P < 0.001) .The AUC for driving pressure did not reveal any significant differences between the inhalation and intravenous groups  (Table 1 to T4 was observed between the two groups during the intergroup comparison (P = 0.545). Furthermore, when comparing the inhalation and intravenous groups at each time point, the differences in mechanical power were not statistically significant. In terms of intragroup comparisons, the inhalation group exhibited a significant overall difference in mechanical power (P < 0.001) .No significant differences were observed between the inhalation and intravenous groups in terms of the AUC of mechanical power  Table . Similar01) Fig. . SimilarP = 0.564) (Table P = 0.626). Respiratory failure and hypoxaemia were rare in both groups, with a singular instance of respiratory failure in the intravenous group. Hypoxaemia was observed in both groups, while bronchospasm or severe atelectasis were not reported in either group.Within 7 days postoperatively, PPCs, categorised according to the Clavien–Dindo classification were observed in 20 of the 84 patients 23.8%) in the inhalation group and 23 of the 83 (27.7%) patients in the intravenous group (.8% in thP = 0.413). Similarly, no statistically significant distinctions were found between the inhalation and intravenous groups at each specific time point. In terms of the intragroup comparison, no significant differences were observed in the overall lung compliance  .According to generalised estimating equations, the comparison of lung compliance between the two groups was not significantly different in the intergroup comparison (No significant differences were observed in terms of the adverse reactions associated with penehyclidine, and no serious adverse outcomes were attributed to the study drug Table .In this randomised clinical trial involving adults undergoing thoracoscopic surgery, preoperative prophylactic inhalation of penehyclidine did not significantly reduce the driving pressure and mechanical power during OLV compared with intravenous administration. Moreover, there was no observed reduction in PPCs within the first 7 days postoperatively.Preliminary studies have established an association between increased driving pressure and an augmented risk of complications and mortality , 30. OurPrevious retrospective studies have drawn attention to a concerning connection between the excessive application of mechanical power during surgery and an increased risk of postoperative complications , 27. MecPenehyclidine, a novel anticholinergic drug, specifically targets M1 and M3 receptors and achieves peak plasma concentration around 0.56 h after administration . A prospNebulised drug inhalation delivers the drug directly to the airway, resulting in a higher local concentration and faster onset of action, with fewer systemic adverse effects. However, the absence of a significant difference between the inhaled and intravenous groups in our study might be attributed to the inhalation technique employed and the drug’s blood concentration. Further research should focus on determining the optimal dosage and inhalation method for nebulised drugs.There are several limitations to this study. First, the absence of a placebo-controlled trial to demonstrate the effectiveness of penehyclidine on driving pressure and mechanical power is notable. This limitation stems from the requirement of routine anticholinergic administration during thoracic surgery to manage secretions. Second, our inability to determine the blood concentration and peak time after penehyclidine inhalation posed challenges in aligning the duration of action with intravenous administration. Third, this study concentrated on determining the driving pressure and mechanical power during OLV, however, it did not factor in the respiratory mechanics during two-lung ventilation, which could influence the reliability of the research results. Fourth, wedge resection has been found to have a low rate of PPCs in thoracic surgery . The intThe study revealed no significant differences in terms of driving pressure and mechanical power during OLV between intravenous injection and those receiving inhaled penehyclidine in the context of thoracoscopic surgery. Furthermore, there existed no difference in the incidence of PPCs between the two methods. Future research might explore the relationship between penehyclidine, driving pressure, and mechanical power in individuals with pre-existing pulmonary conditions or those at high risk of developing PPCs.


Patient involvement in health research is rarely driven solely by patients, who could be considered to have the highest degree of investment in such research. In the Kidney Connect project, the patients have been the driving force. This commentary considers the following questions: How did we, as patients, lead the work as the driving force in the project? What went well and what did not go so well from our perspective? How did the project compare with work driven by researchers? We argue that projects driven solely by either patients or researchers each have their own limitations. Projects driven solely by patients have some limitations in their robustness, rigour, and likelihood of publication. Nevertheless, a project driven solely by patients has been able to produce findings that are broadly comparable to a project driven solely by researchers that employed methods ensuring robustness and rigour. We suggest collaboration between patients and researchers also for projects driven by patients. Health research often uses patients as either participants or partners. Patients running the research is less common, even though the outcomes might be more important to patients than to anyone else. A medical company started the Kidney Connect project, but invited patients to drive it. The main driving role was planning and conducting data collection and analysis of data for the project. In this commentary, patient representatives describe how they led the project’s work, what went well and what did not go so well for patients. It then compares the project’s results with those from similar work that involved patients as partners but had only researchers in charge. We found that certain things can limit research that is run only by patients, but it has similar results to a project with only researchers in charge. How did we, as patients, lead the work as the driving force in the project?What went well and what did not go so well from our perspective?How did the project compare with work driven by researchers?In 2015, Novo Nordisk, a large Danish medical company, decided to enhance its research approach by asking the Danish Kidney Association to lead a project investigating patients’ perspectives on better diabetic kidney care. The initiative came from the company, but the project was driven by the patient representatives from the Danish Kidney Association. The project was named Kidney Connect. Novo Nordisk involves patients in medical research and development in six different roles: research subjects, insight providers, advisors, reviewers, co-researchers, and driving force. In the Kidney Connect project, Novo Nordisk wanted the patients to take the role of the driving force [Two patient representatives from the Danish Kidney Association were in charge of the entire project, including design, data collection, and data analysis . We were recruited by the Danish Kidney Association, having conducted other projects for the association, although not research. Both of us hold master’s degrees (in psychology and law respectively). We had support for data collection and data analysis from researchers at Novo Nordisk. The scope of the project was decided by Novo Nordisk, which aimed to determine a future-oriented patient vision for diabetes and kidney care and treatment, backed by survey data and voice-of-patient qualitative data. The project used four different methods in pursuit of its aim: 1) a question lab to determine mutually interesting areas of enquiry, 2) a survey to identify overall trends in attitudes and behaviours among patients and to recruit patient participants, 3) in-home semi-structured interviews to gather rich descriptive data to understand underlying motivations, and 4) a future co-visioning workshop to describe and define an ideal future for care and treatment.Figure The initiative for the project came from Novo Nordisk, but as the patients in charge of the project, we had a great deal of freedom to act as its driving force. Novo Nordisk decided on the project’s scope and design, including data collection methods. However, we chose our own questions for the survey, developed the interview guide for the interviews, conducted the individual interviews, and did the data analysis both for the survey and the individual interviews. We perceived ourselves as principal investigators during the project, supported by a co-researcher from Novo Nordisk during data collection and analysis. In our role as the driving force, we experienced only a few minor limitations to our freedom to choose a direction for our research. These were most evident during the process of recruiting participants. We wished to recruit participants with only chronic kidney disease or with diabetes and kidney failure . Novo Nordisk, however, wanted less restrictive inclusion criteria regarding participants with diabetes and we therefore agreed to include participants with diabetes and reduced kidney function. Recruitment of participants with both chronic kidney disease and diabetes was consistent with the scope of the project, and the same methods chosen for data collection could be used. Patients with both diabetes and kidney disease were of great interest to the Danish Kidney Association because this group was not represented in our association. An additional goal was to focus more on how to prevent progression of kidney disease, and we wanted to gain knowledge about living with two chronic conditions.As patients, we elaborated on the purpose of the study in alignment with our understanding of quality of life. Thus, we included five research questions: 1) How do we live a fulfilling life with two diseases? 2) How do we juggle managing our everyday life and our conditions? 3) What do we want to hold on to in life? 4) What can we let go of? and 5) Who decides what interventions are acceptable? The project was regarded as a win-win by both Novo Nordisk and the Danish Kidney Association because it was designed to achieve goals linked to the respective activities and capabilities of both organisations. To be a win-win, a project also needs to have an output. However, at the time of writing, no documentation of the output from the project is available on either organisation’s website. The study had some implicit gains as the results came to characterize and shape the foundation of the Danish Kidney Association's Kidney School Program. This indirect output has not been disseminated in a written format and thus begs the questions: Did neither Novo Nordisk nor the Danish Kidney Association win? Did the organisations achieve sufficient value for their efforts?We were invited to various conferences and meetings that focused on either diabetes or kidney disease in Denmark and internationally to disseminate our findings. Some of the meetings were held by Novo Nordisk for its own international guests. Between March 2016 and March 2019, we gave a total of eight presentations (four each). One output goal was to write a paper reporting the project results—a short report for either the Danish Kidney Association website or newsletter—but we also wished to publish a paper on the results in a scientific journal. Due to illness and the effects of suffering from a chronic disease, especially fatigue, we did not succeed in this goal. In 2020, a collaboration with a professor in patient involvement (author KL) resulted in a draft of a comment article that we planned to submit to a Danish newspaper. However, again, we did not have the energy at that time to work collaboratively with the researcher to complete the final draft for publication. To finally share our experiences, this article’s team of authors was established in autumn 2022, comprising a mixed group of patients and researchers. The previous lack of a formal scientific paper as an output was not only due to a lack of energy, but also because the study was not conducted with sufficient robustness and rigour. The survey was self-developed without tests of its reliability and validity  . AnotherFigure This commentary reports on how patients have been the driving force in a research project using surveys, interviews, and workshops for data collection. Furthermore, patients carried out the data analysis and presented the findings at national and international conferences and meetings. The four main findings in the Kidney Connect revealing the patients' perspective to diabetic and kidney care is claiming ownership of my health, maintaining relationships, taking responsibility and physical health. Projects driven solely by patients have some limitations in their robustness, rigour, and likelihood of publication. Nevertheless, a project driven solely by patients has been able to report findings that are broadly comparable to those of projects driven solely by researchers and that employed methods ensuring robustness and rigour. We suggest, that health research projects driven solely by patients should be transformed to partnerships with researchers, just as projects driven solely by researchers should seek collaboration with patient partners. We suggest to consider the number of patient partners to ensure a robust group of patient partners through the whole project.


A significant inverse correlation between renin activity and supine and orthostatic blood pressure levels was observed in healthy individuals , but not in POTS patients. Conclusions: Renin activity, but not aldosterone concentration, is downregulated in patients with POTS. Moreover, renin activity in POTS is dissociated from supine and standing blood pressure levels in contrast to healthy individuals. These findings suggest impaired renin function in POTS, which may direct future therapeutic approaches.Background: Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous condition predominantly affecting autonomic control of the cardiovascular system. Its extensive symptom diversity implies multi-organ involvement that interacts in ways still requiring full exploration. Current understanding of POTS pathophysiology suggests alterations in the renin–angiotensin–aldosterone system as a possible contributing factor. Therefore, we investigated the relationship between the activity of the renin–angiotensin–aldosterone system and hemodynamic parameters in a cohort of POTS patients and controls recruited at a tertiary referral center. Methods: The case-control study included 46 patients with POTS (27 ± 9 years), and 48 healthy controls (30 ± 9 years) without orthostatic intolerance. Plasma renin activity, expressed as angiotensin I generation, and plasma aldosterone were measured by enzyme-linked immunosorbent assay and were correlated with hemodynamic parameters obtained during active standing tests. Results: Renin activity was significantly downregulated in POTS patients compared to healthy individuals (median, 3406 ng/mL vs. 9949 ng/mL,  Postural orthostatic tachycardia syndrome (POTS) is a dysautonomic disorder characterized by an excessive increase in heart rate when upright, accompanied by a broad spectrum of cardiovascular and non-cardiovascular symptoms ,2,3. POTThe renin–angiotensin–aldosterone system (RAAS) is a major neuroendocrine mechanism that regulates plasma sodium concentration, arterial blood pressure, and extracellular volume ,11. IntePrevious studies have suggested that lower renin activity, lower estimated angiotensin-converting enzyme-2 activity  and lowePatients were not involved in the design, conduct, reporting, or dissemination plans of our research. We included 46 patients with confirmed POTS recruited from a tertiary referral center at the Department of Cardiology, Skåne University Hospital in Malmö, Sweden, and 48 hospital staff members or volunteers that participated as controls. The controls had neither orthostatic intolerance symptoms nor history of syncope and were age-and-sex matched as closely as possible with POTS patients. Patients with POTS fulfilled predefined diagnostic POTS criteria, including symptoms of orthostatic intolerance for at least 6 months and a positive head-up tilt test (HUT), confirming heart rate (HR) increase > 30 beats per minute (bpm), or HR exceeding 120 bpm when tilted from supine to upright position, according to international consensus ,20. PrioAll study participants underwent a standardized active standing test, as described below, at their blood sample collection visit to the Clinical Research Unit at Skåne University in Malmö between September 2017 and June 2019 . Particig within 4 h. Centrifuged samples were then poured into a new tube and kept for 15 h at room temperature and up to 2 days refrigeration. Frozen samples were transported to the laboratory. Blood samples were collected into EDTA vacutubes and centrifuged for 10 min at 2000× EDTA plasma from POTS patients and controls was stored on ice. A plasma pool was created for normalization. Samples were diluted in three steps to 1:4000 . Enzyme-linked immunosorbent assay (ELISA) of human intact angiotensinogen and total angiotensinogen  was carried out according to the manufacturer’s instructions. Absorbance was measured with the Magellan instrument at OD450nm. Concentrations were obtained using the standard curve OD450nm, and a nonlinear quadratic curve fitted regression according to the manufacturer’s instructions. Angiotensin I generation was calculated as total angiotensinogen − intact angiotensinogen . AngioteThe analytical method for determining aldosterone concentration in serum is based on extraction with supported liquid extraction technology, followed by online extraction and analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS system was equipped with a Nexera LC system  and a Q-TRAP 5500 mass spectrometer . Quantification of serum aldosterone concentration was performed using a deuterated internal standard. On the LC system, an additional purification step for the samples was first performed with an on-line extraction on a nitrile extraction column , with an alternately coupled double pump system. Final separation was performed on an analysis column . Aldosterone concentration was determined using calibration curves based on the ratio between signals for analyzed samples and an internal standard. t-test for normally distributed variables and a non-parametric test (Mann–Whitney) for non-normally distributed continuous variables. Spearman’s rank correlation coefficients were used to examine relationships among continuous variables. IBM SPSS Statistics for Macintosh, Version 27.0  was used for statistical analyses. Group characteristics were reported as mean and standard deviation or median and interquartile range, as appropriate, for continuous variables and as counts and percentages for categorical variables. Group comparison was performed using an independent samples p = 0.006) and diastolic blood pressure  were observed in POTS when supine. Likewise, during active standing, both heart rate and DBP were higher in POTS at 1, 3, and 5 min  , 2275–4767) when compared to healthy controls  .p < 0.05), but not in subjects with POTS, except for DBP after 5 min standing. A weak correlation was observed between aldosterone and supine heart rate in POTS  when compared to healthy controls. In contrast, plasma aldosterone levels in controls and POTS did not differ. Moreover, an inverse correlation between renin activity and both supine and orthostatic blood pressure values was observed in healthy controls but was clearly absent in POTS. The renin–angiotensin–aldosterone system regulates plasma sodium concentration, arterial blood pressure, and extracellular volume ,11. The When the autonomic control of the cardiovascular system is intact, the blood pressure increases when upright due to peripheral vasoconstriction as a compensatory response to preserve adequate blood perfusion to the brain. Paradoxically, renin release decreases due to increased perfusion of blood. As observed in this study, renin activity was inversely correlated with BP in the control group, both supine and during active standing, which can be explained by this compensatory mechanism. However, in POTS, this correlation was absent. These results may be explained by disruption in the feedback loop of the renin–angiotensin–aldosterone system resulting in disturbed regulation of renin activity. Alternatively, this may be a consequence of inappropriate activation or blockade of angiotensin II, type I receptor by autoantibodies, as suggested by a recent study . PreviouPatients with POTS had a higher supine and standing heart rate and diastolic blood pressure. Increased heart rate is a typical feature of POTS pathophysiology and is explained by different possible mechanisms such as increased sympathetic activity, reflex tachycardia due to hypovolemia, and autoimmunity against adrenergic receptors . IncreasPrevious studies have not been unanimous regarding RAAS activity in POTS. Raj et al. reported paradoxically unchanged renin activity and lower aldosterone in patients with POTS despite their lower plasma volume . In contThis is a single-center study with all the limitations that are thus imposed. All participants were asked to stop cardiovascular medications and salt tablets for 48 h prior to testing, but they were not on a low sodium diet. Increased salt diet, which some POTS patients pursue, may lead to altered hormonal activity in the renin–angiotensin–aldosterone cascade.Another important aspect is the relatively small cohort size. A larger study sample with independent populations may offer confirmation of these findings. Furthermore, angiotensinogen and aldosterone levels were not sampled at each BP measurement. The sampling occurred once and served as baseline levels. For a more accurate assessment, it would be ideal for blood sampling to occur at 0 (supine), 1, 3, and 5 min (upright). Renin activity, but not aldosterone concentration, is downregulated in patients with POTS. Moreover, renin activity in POTS is dissociated from supine and standing blood pressure levels in contrast to healthy individuals. These findings suggest impaired renin function in POTS, which may direct future therapeutic approaches.


Chronic heart failure (CHF) is regarded as common clinical heart disease. This study aims to investigate the clinical diagnostic value of echocardiography (Echo) and serum C-reactive protein (CRP) levels in patients with CHF.A total of 75 patients with CHF  were enrolled as study subjects, with 70 non-CHF subjects  as controls. The left ventricular ejection fraction (LVEF), fraction shortening rate of the left ventricle (FS), and early to late diastolic filling (E/A) were determined by Echo, followed by an examination of the expression of serum CRP by ELISA. In addition, the Pearson method was used to analyze the correlation between echocardiographic quantitative parameters (EQPs)  and serum CRP levels. Receiver operating characteristic (ROC) curve was adopted to evaluate the diagnostic efficacy of EQPs and serum CRP levels for CHF. The independent risk factors for CHF patients were measured by logistics regression analysis.The serum CRP level of CHF patients was elevated, the values of LVEF and FS decreased, and the E/A values increased. ROC curve revealed that the EQPs  combined with serum CRP had high diagnostic values for CHF patients. Logistic regression analysis showed that the EQPs  and serum CRP levels were independent risk factors for CHF patients.Echo combined with serum CRP level has high clinical diagnostic values for CHF patients. Chronic heart failure (CHF) is a clinical syndrome of ventricular filling dysfunction and ejection dysfunction due to cardiac structural damage and functional disturbances caused by various factors, including ischemic heart disease, hypertension, and cardiomyopathy , 2. AlthEchocardiography (Echo) is a diagnostic method for assessing the systolic and diastolic function of the heart to diagnose and manage HF . In paraC-reactive protein (CRP) has been established as a classic marker of systemic inflammation . It is pThis study was ratified by the Ethics Committee of The Third Affiliated Hospital of Guangzhou Medical University, and each subject signed the informed consent. All procedures were strictly implemented according to the Declaration of Helsinki.A total of 75 CHF patients  diagnosed and treated in The Third Affiliated Hospital of Guangzhou Medical University from June 2018 to June 2020, were assigned to the study group (CHF group). During the same period, 70 non-CHF subjects  matching the age and sex of the study group were enrolled as the control group.Inclusion criteria : (1) AllCardiac function was graded according to the New York Heart Association (NYHA) grading system revised in 1928 and 1994 . Class IAge, sex, body mass index (BMI), smoking history, drinking history, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), uric acid (UA), left ventricle ejection fraction (LVEF), complications  and other clinical baseline data of the enrolled subjects were recorded, as well as NYHA cardiac function classification of the patients. The 3 mL of elbow venous blood was extracted from the enrolled CHF patients on an empty stomach on the morning of the second day after admission. Similarly, blood samples were collected from control subjects and centrifuged at 2800 × g for 10 min. The supernatant was collected and stored in a refrigerator at − 80 °C for centralized detection.The serum CRP level of the subjects was examined using a double antibody sandwich ELISA kit , and the specific operation was carried out under the kit instructions. In short, CRP was measured by ELISA using a 100-fold diluted serum sample at a final volume of 50 μL. Samples were added to a 96-well micro-titration plate precoated with CRP-specific monoclonal antibody and incubated for 2 h. After four times of washing, the serum was incubated with an anti-CRP antibody conjugated with horseradish peroxidase for 2 h for detection. The titration plate was washed four times and incubated with the substrate solution for 30 min. Eventually, 50 μL of stop solution was supplemented to each well, and the color altered from blue to yellow. Optical density (OD) values of each well were determined at 450 nm using a microplate reader . The results were linearized by plotting the logarithm (log) of the CRP concentration versus the log of the OD value, and the best fitting line was measured by regression analysis. Since the samples were diluted previously, the concentrations read from the standard curve were corrected by the dilution factor.Cardiac function was evaluated in subjects in both groups, and Philips Affiniti 70W  Doppler echocardiography was used for cardiac ultrasound examination, with the frequency parameters of the instrument probe set to 2 ~ 4 MHz. Detailed operation methods were as follows: the patient was in a left lateral decubitus position; after the probe was smeared with the coupling agent, the probe was placed in the chest apex of the patient and the inspection screen was observed; according to the cardiac structure of the patient, the inspectors need to move the position of the inspection probe back and forth, and switch the direction of the probe to observe the cardiac valve structure of the patient in detail and obtain clear images. Inspectors also need to switch the function of the ultrasound examination instrument to test the left ventricular ejection fraction (LVEF), fraction shortening rate of the left ventricle (FS), and early to late diastolic filling (E/A), to obtain more accurate test results.t test; counting data were represented as the number of cases, and the chi-square test was used for data comparison between groups. ROC curve was used to evaluate the diagnostic efficiency of the parameters, and the optimal ROC curve threshold was found by using the Youden index. Logistic model was used for multivariate regression analysis. P was obtained from the bilateral tests. A value of P < 0.05 meant statistical significance.SPSS21.0 statistical software , GraphPad Prism 6.0 software , and MedCalc 19.0 Software  were used for statistical analysis and plotting of data. Shapiro–Wilk test was used for the normal distribution test, measurement data in normal distribution was expressed as mean ± standard deviation (SD), and data comparison between groups was performed by the P > 0.05). Meanwhile, compared with the control group, LVEF (%) and FS (%) values in the CHF group were substantially reduced, while E/A values were enhanced .A total of 75 CHF patients and 70 matched non-CHF subjects were recruited. Their basic clinical information is shown in Table P < 0.01).Subsequently, we identified CRP expression in the serum of CHF patients and non-CHF subjects by ELISA, which manifested that the serum CRP level of CHF patients 3.7 ± 1.4 mg/L) was higher than that of non-CHF subjects (2.8 ± 1.2 mg/L)    and serum CRP levels. The results revealed that serum CRP level in CHF patients was negatively correlated with LVEF and FS  Fig. A/B, wher01) Fig. C.Fig. 2CP < 0.05). These results indicate that EQPs combined with serum CRP levels had high diagnostic efficacy for CHF.To further clarify the clinical diagnostic significance of EQPs and serum CRP levels in patients with CHF, we analyzed the diagnostic efficacy of LVEF, FS, E/A, CRP level, and EQPs combined with serum CRP levels on CHF by ROC curve. The results uncovered that LVEF, FS, E/A, and CRP levels all had certain diagnostic efficacy for CHF Table . MedCalcP < 0.1) and serum CRP level as independent variables. Logistic multifactor regression showed that after adjusting smoking history, TC, LDL-C, and UA, the EQPs  and serum CRP level were independent correlation factors for CHF and closely correlated with CHF  in Table HF Table .Table 3LCHF is an end-stage of multiple cardiac diseases, and its diagnosis and prognosis remain a challenge . With efPatients with CHF (N = 75) and matched non-CHF subjects (N = 70) were enrolled in the study. CHF is a complex syndrome, and myocardial injury causes abnormal activation of the neuroendocrine regulatory system, resulting in sodium retention, circulatory congestion, and cardiac and vascular remodeling , 30. HenHF is characterized by systemic inflammation that worsens as the disease progresses . The preAll imaging techniques can provide an ejection fraction, but the versatility of Echo makes it unique in providing volumes, diastolic function, right ventricular function, hemodynamics, and valvular regurgitation . ElevateSerum CRP level is an independent factor for HF after acute myocardial infarction . MeanwhiIn conclusion, as a prospective study, this paper clarified the role of EQPs  combined with serum CRP level in the diagnosis of CHF, providing a new entry point for clinical diagnosis and classification of CHF. However, the time span of sample collection was small and the patients were older, which may affect the determination of CRP levels. In addition, few cases and EQPs were included in this study. In the future, we need to carry out multi-center prospective studies to expand the sample size and match the control, to increase the credibility of the results. Moreover, EQPs and CRP levels can be measured in the early or middle stage of CHF to study its diagnostic and prognostic values.


Multiple studies have reported a link between mental health and high blood pressure with mixed or even contradictory findings. Here, we resolve those contradictions and further dissect the cross-sectional and longitudinal relationship between mental health, systolic blood pressure, and hypertension using extensive psychological, medical and neuroimaging data from the UK Biobank. We show that higher systolic blood pressure is associated with fewer depressive symptoms, greater well-being, and lower emotion-related brain activity. Interestingly, impending hypertension is associated with poorer mental health years before HTN is diagnosed. In addition, a stronger baseline association between systolic blood pressure and better mental health was observed in individuals who develop hypertension until follow-up. Overall, our findings offer insights on the complex relationship between mental health, blood pressure, and hypertension, suggesting that—via baroreceptor mechanisms and reinforcement learning—the association of higher blood pressure with better mental health may ultimately contribute to the development of hypertension. Mental and cardiovascular health interact in complex ways. Here, the authors demonstrate an association of blood pressure with depressive symptoms, well-being, and emotion-related brain activity that may be relevant to the development of hypertension. An increased risk of HTN has been described in patients with affective disorders10. The burden of vascular risk factors, including HTN, has further been suggested to drive depressive symptoms in ageing through microvascular brain damage11.Both hypertension (HTN) and affective disorders, such as depression, frequently co-occur and have been identified as single16 and clinical populations19. Baroreceptor mechanisms have been suggested to explain these effects, as their intrinsic and experimentally-induced signalling has been shown to phasicly adjust pain sensitivity thresholds, alter sensory and emotional processing, decrease cortical excitability, and inhibit central nervous system activity26. These observations have been proposed as a critical neuro-behavioural component in the development of essential HTN. Momentary relief from an adverse state might positively reinforce blood pressure-elevating behaviours and thus, via baroreceptor-mediated neural circuits, insidiously increase blood pressure over time, resulting in ‘learned hypertension’29. However, it remains unclear if blood pressure elevations and HTN development relate to mental health and if such an association reflects in brain function.In contrast to these findings, some studies showed that higher blood pressure relates to better mood, higher well-being, and lower distress in healthy18, we capitalized on the unique study design offered by the UK Biobank. The UK Biobank combines a deeply phenotyped longitudinal cohort with high statistical power of more than 500,000 participants30 which enables the detection of robust small effects. In addition, it includes two follow-up timepoints for longitudinal analyses in two sub-samples of the baseline cohort: an online mental health follow-up at around 5 years and a follow-up at around 10 years. We hypothesized for cross-sectional and longitudinal analyses that increased blood pressure relates to fewer depressive symptoms and greater well-being (preregistration: https://osf.io/638jg/).The first goal of the present study was to systematically describe the relationship of blood pressure with depressive symptoms and well-being, while accounting for potential confounding effects of medication intake and chronic illness, such as CVD and clinical depression. Due to small effect sizes reported in previous research related to our studyThe second goal of this study was to explore the relevance of blood pressure-mental health associations in relation to HTN development. If a systematic relationship between mental health and blood pressure exists, this could positively reinforce long-term blood pressure elevations via baroreceptor mechanisms. Hence, we explored if the relationship between mental health and blood pressure differed between participants who developed hypertension compared to those who stayed normotensive.32.The third goal of this study was to explore the prospective effects of blood pressure-mental health associations in emotion-related brain function using UK Biobank’s imaging assessment . Due to the previously established baroreceptor effects on central nervous processing, blood pressure elevations and the development of HTN might relate to more general affective processes in brain function. We therefore investigated the effect of blood pressure variations on emotional task-based functional MRI activationOverall, there were data of 502,494 participants  at initial assessment visit of whom 47,933  participants attended the follow-up visit.  and well-being in a mean score of 4.46 (SD = 0.58). At follow-up, depressive symptoms were reported with mean score of 1.30 (SD = 0.44) and well-being with a mean score of 4.63 (SD = 0.54).N = 47,933), correlation analyses revealed positive associations between baseline and follow-up measures for both depressive symptoms  and well-being , respectively. Thus, test-retest reliability of mood assessments was high, indicating stability over assessment timepoints.Among participants who completed both initial and follow-up assessments  and positively associated with well-being . Inversely, HTN was related to more depressive symptoms  and poorer well-being . Restricting the analyses to participants with HTN only , yielded similar associations of higher SBP with fewer depressive symptoms  and greater well-being , respectively . Furthermore, our analyses yielded a small negative relationship between the number of antihypertensive medications taken and depressive symptoms , and a positive trend with well-being . In the analyses of participants with HTN, higher numbers of antihypertensive medications were similarly associated with fewer depressive symptoms  and with greater well-being .For the multiple linear regression testing cross-sectional associations of SBP, HTN, and number of antihypertensive medications with depressive symptoms 303,771 participants could be included in the model, while 129,876 could be included for the multiple linear regression model with well-being as outcome. At baseline .Overall, the model for depressive symptoms including all participants yielded a model fit of adj. β = −0.042; 95% CI ; p < 0.001) and to higher follow-up well-being scores . Similar to the cross-sectional results, baseline HTN was associated with more depressive symptoms approximately 10 years later . HTN was also significantly related to lower well-being scores at follow-up . Number of antihypertensive medications at baseline was not a significant predictor in any longitudinal model . The model fit for the prediction of depressive symptoms increased from a null model consisting only of covariates by ∆adj. R2 = 0.001 .For the multiple linear regression testing longitudinal associations of SBP, HTN, and number of antihypertensive medications with depressive symptoms 28,021 participants could be included in the model, while 29,966 could be included for the multiple linear regression model with well-being as outcome. Longitudinally Fig. , we founN = 25,991 had data available to define hypertension at follow-up). Across all participants, SBP increased from initial assessment to follow-up . People who later developed HTN already had higher SBP levels at initial assessment compared to people who stayed normotensive . However, in the fully adjusted regression model, we observed a main effect of later HTN on baseline mental health , suggesting that when adjusting for SBP levels, people who later developed HTN had lower mood  already at initial assessment compared to people without HTN. The regression model further yielded a significant interaction of SBP at initial assessment and HTN at follow-up with depressive symptoms at initial assessment, showing that the association between SBP and depressive symptoms was moderated by hypertension status at follow-up . Thus, the slope of the relationship between higher SBP and fewer depressive symptoms was steeper in those participants who developed HTN approximately 10 years later. At follow-up, however, HTN status was not a significant moderator for the association of SBP and depressive symptoms . Similarly, a trend of a moderation by HTN status was observed for the association between well-being and SBP at initial assessment, but this effect was not significant . Neither was there a moderation by HTN status for the association between well-being at follow-up and SBP at follow-up .Next, we explored if the relationship between mental health and SBP was moderated by hypertension status at follow-up assessment. First, we excluded participants who were hypertensive at the initial assessment (defined as HTN diagnosis or intake of antihypertensives). This resulted in 315,582 people who could be considered non-hypertensive at initial assessment and who were included in the analysis  and in significant regions resulting from whole-brain analyses  in people with HTN compared to normotensives , suggesting that the negative correlation between SBP at baseline and emotion-related amygdala activity was dampened in participants who developed hypertension. The interaction between baseline SBP and BOLD activity was not significant in the whole-brain analysis .To explore a central nervous representation of emotional reactivity, we assessed how hypertension status relates to emotional processing in the brain using fMRI activity assessed during the Hariri task. BOLD fMRI activity to emotional faces was lower in the amygdala  using the PHQ-9 questionnaire of the 5-year online mental health follow-up as a validated instrument to assess current depressive symptoms, (ii) cross-sectional analyses of mental health outcomes at both follow-up assessments, (iii) association of depressive symptoms within systolic blood pressure categories, (iv) additional relevant covariates, such as socioeconomic status, insomnia, racial/ethnic background, insomnia, etc., (v) using hospital inpatient data for diagnoses of HTN and depression, and (vi) using SBP > 140 mmHg as an additional criterion to define HTN in the moderation analysis. Moreover, sensitivity analyses were performed to test whether the above reported confirmatory results were dependent on (vii) the presence or absence of previous diagnosis of depression or any other severe disease that might affect BP . Similar to the cross-sectional results, higher SBP was related to fewer depressive symptoms at the 6-year-follow-up assessment . Number of antihypertensive medications at baseline was not significantly associated with the PHQ-9 depression score. The results from the PHQ-9 highly resemble the results using the depression score reported in the main manuscript  and negative for well-being  at 10-year follow-up, consistent with the main findings, yet, results were not significant. For the number of antihypertensive medications, we observed significant associations with all mental health outcomes, suggesting that higher hypertension burden, indicated by a higher number of prescribed antihypertensives, negatively relates to mood.We further analysed cross-sectional models at both follow-up time points. Despite smaller sample sizes, resulting in larger 95% confidence intervals, the results yielded robust, significant estimates for SBP in line with our previous analyses . Next, we computed the cross-sectional association between SBP bins and depressive symptoms at baseline while adjusting for the same covariates as in the main manuscript.p = 0.156), which supports our findings that the negative association between SBP and mood might be particularly salient for individuals at risk of high blood pressure.Interestingly, the results indicate fewer depressive symptoms for each unit increment in bins of SBP  as the vast majority of participants self-identified as white. We also included the UK Biobank assessment centre to model that data acquired at the same assessment centre might be correlated. Among these additionally included covariates  and well-being . While all other additionally included covariates also had some effect on mental health, the effects of our main variables of interest  on both mental health outcomes remained virtually unchanged when controlling for all these confounders.Further influencing factors have been previously shown to be important effect modifiers for associations with mental health and/or hypertension, such as insomniaTo complement our results using self-report data with clinical assessments, we repeated the confirmatory analyses using hospital diagnoses for HTN and depression from the HES database. We used the secondary ICD-10 diagnoses codes a participant has had recorded across all their hospital inpatient records , a total of 340,896 individuals had HES data available. HTN was diagnosed in 112,554 (33%) of HES cases and depression in 18,274 (5%) of HES cases, which shows that HES records may underestimate the prevalence of these conditions in the general population41. Agreement between self-reported conditions and HES diagnoses was assessed using Cohen’s kappa. In line with previous research42, we observed moderate agreement for HTN (kappa = 0.583) and fair agreement for depression (kappa = 0.324).Among the baseline sample , whereas HTN was related to more depressive symptoms  and there was a negative relationship between the number of antihypertensive medications taken and depressive symptoms . The results yielded larger effect size estimates  for all these predictors as compared to the analysis with self-reported HTN , yet the standardized beta coefficient was slightly lower than in the analysis using self-reported HTN. HES HTN related to poorer well-being  with a larger standardized beta coefficient than in the analysis using self-reported HTN. Finally, the relation between antihypertensives and well-being was also not significant in the model including HES HTN . Overall, the models including HES HTN explained slightly more variance, as reflected in greater adjusted R2-values compared to the models using self-report HTN .Next, we used HES-diagnosed HTN to repeat our analysis testing the cross-sectional relationship between depressive symptoms/well-being and SBP, HTN and antihypertensive medication. Including HES-diagnosed HTN instead of self-reported HTN replicated our main results , whereas a HTN diagnosis showed a small effect in the opposite direction . There was also a small positive association between the number of antihypertensives taken and the occurrence of depression . The overall model fit was low (adj. R2 = 0.010).Finally, we included an additional analysis testing the relationship of SBP, self-reported HTN and antihypertensive medication with occurrence of HES-diagnosed depression . Among these, those who stayed normotensive until follow-up had a mean SBP of 122 mmHg (SD = 10.0) and those who developed HTN had a mean SBP of 129 mmHg (SD = 7.76). Across all non-hypertensive participants, SBP increased significantly from initial assessment to follow-up . Within this sample, we replicated the results obtained in the larger group: In unadjusted models, there were no significant group differences in mental health at initial assessment between people who developed HTN and those who stayed normotensive . However, in the fully adjusted regression model , we again observed a main effect of later HTN on baseline mental health , suggesting that when adjusting for SBP levels, people who later developed HTN reported more depressive symptoms already at initial assessment compared to people without HTN. We also replicated that the negative association between depressive symptoms and SBP at initial assessment was moderated by HTN at follow-up . The moderation was however not significant for depressive symptoms at follow-up. Neither did we observe any significant moderation effects of developing HTN for well-being at any of the assessments. In sum, these results corroborate our findings that people who developed HTN throughout the course of the study might require higher SBP levels to sustain the same mental health outcomes as normotensives and that the negative relationship between mental health and blood pressure was accentuated in people developing HTN several years before HTN manifested.In the moderation analysis Fig. , we obseWe also tested if any effects of SBP, HTN and antihypertensive intake on current depressive symptoms and well-being depended on the presence or absence of previous diagnosis of depression or any other severe neurological, systemic, or psychiatric diseases that might affect BP . Among the most frequently used medications were pain killers , antihypertensives  and antidepressants . We therefore explored potential effects of these medications on the cross-sectional relationship between blood pressure and mental health at baseline. Again, in separate multiple regression models of groups of participants taking or not taking these medications, we added SBP, HTN and number of antihypertensive medications simultaneously as predictors of depressive symptoms and well-being and corrected the models with the same covariates as described in the confirmatory analyses above.A major characteristic of the UK Biobank sample is the large number of people taking any kind of medication (p < 0.001) and greater well-being .Sub-group analyses of participants taking or not taking antidepressant medication, showed similar associations between SBP, HTN and mental health as analyses on the total sample  and negative associations with unselective reuptake inhibitors . Associations between well-being and antidepressant classes were not significant .With regards to depressive symptoms, we found negative associations with tricyclic antidepressants . Well-being was negatively associated with aldosterone antagonists  and positively with the intake of a combination of beta and alpha1 blockers .We did not observe any significant effects of antihypertensive classes on depressive symptoms . Most missing data occurred in covariates for diagnoses of angina, heart attack and lifetime depression . To impute datasets, we created 20 imputations using multiple imputation by chained equations with the R package MICE (version 3.14.0)44. Linear regression was performed on each imputed dataset and estimates of the results were then averaged across the imputed datasets in accordance with Rubin’s rules45. The results from imputed datasets for the cross-sectional association between mental health and SBP/HTN/number of antihypertensives indicated no sign of bias due to missing data and replicated our results from complete-case analyses . We again observed that SBP was negatively related to depressive symptoms , whereas HTN was related to more depressive symptoms . There was no significant relationship between the number of antihypertensive medications taken and depressive symptoms . Inversely, SBP was positively associated with well-being . The relationship of well-being with HTN  was not significant, while well-being was negatively associated with number of antihypertensives . The results yielded larger effect size estimates  for SBP as compared to the analysis in the surviving sample, which could indicate that the effect of SBP on mental health might be particularly relevant for populations at risk with very high SBP levels. Overall, the models in the non-surviving sample explained slightly more variance, as reflected in greater adjusted R2-values compared to the models in the surviving sample .To assess potential survival bias in our sample, we used UK Biobank’s death records and observed that 20,442 participants died between the two timepoints of our study, i.e., between the baseline visit and the imaging follow-up (~ 10 years later). The non-surviving sample was older, had higher blood pressure and reported more diagnoses than the total sample 46. E-values indicate the minimum strength of association, on the risk ratio scale, that an unmeasured confounder would need to have with both the exposure and outcome to explain away an exposure–outcome association, above and beyond the measured covariates. For continuous exposure variables, such as SBP in our study, the function uses a dichotomisation in the exposure between hypothetical groups of participants per one-unit increase. For the continuous outcome, such as depressive symptoms and well-being in our study, the function uses an effect-size conversion to approximately convert the mean difference between the exposure groups to the odds ratio that would arise from dichotomising the continuous outcome46. As a result, we observed for the association of SBP with depressive symptoms values of E = 1.32 and with well-being of E = 1.30. For the association of HTN with depressive symptoms, we observed E = 1.25 and with well-being E = 1.30. The interpretation of the E-value depends on the context regarding the measured confounders. Given that we have included several plausible confounders in our models, the resulting E-values give further support for the robustness of our results, as an unmeasured confounder would need to be associated with outcome and exposure by a risk ratio of around 1.3-fold each, above and beyond the measured confounders. However, we also note that while E-values have been introduced as robustness analyses for studies aiming to estimate causal effects46, we consider them an additional sensitivity measure for robustness. Potential causal effects should more directly be investigated in future studies with experimental designs or observational designs with dedicated causal identification strategies .To also explore the effect of potential unmeasured confounders on the results, we calculated E-values using the lmer function . Separate models were set up for depressive symptoms and well-being as outcomes, respectively. The full models further included a random intercept per participant, the same covariates of no interest as in the main analyses, fixed effects for SBP, HTN and number of antihypertensive medications, as well as three two-way interactions: SBP*HTN, SBP*time point and HTN*time point. Time point was coded as a dummy variable for “initial assessment” and “imaging follow-up”. Each full model was compared to a null model that was identical but did not include the interactions. The difference between the full and the null model was tested using the anova function and setting the argument test to “chisq” to perform a Chi-squared test. Chi-squared values and p-values for each interaction effect were derived by dropping interactions iteratively (reduced models). Non-significant interactions were dropped from the full model to yield a less complex reduced model. For depressive symptoms, the full-null-model comparison was significant (X2(3) = 10.67, p = 0.014). Iterative model reductions revealed that the interaction of SBP*time point was significant (X2(1) = 10.55, p = 0.001), while HTN*timepoint (X2(1) = 1.78, p = 0.182) and HTN*SBP (X2(1) = 0.11, p = 0.974) were not significant. The significant interaction of SBP and time point indicates that the relationship between SBP and depressive symptoms changes between assessments. Evaluation of the fixed effects revealed that the interaction was driven by a steeper negative slope at baseline than at follow-up. The stronger negative relationship between SBP and depressive symptoms at baseline compared to follow-up supports our observation from multiple linear regression analyses showing that the relationship was stronger for the cross-sectional analysis at baseline than for the longitudinal analysis including follow-up outcomes. As expected, HTN diagnosis showed no significant interaction with time point, but a significant positive main effect (X2(1) = 358.69, p < 0.001) indicating that the effect of HTN diagnosis on depressive symptoms was stable across assessments. No significant difference between individuals with and without HTN was found regarding the relationship between SBP and depressive symptoms across both time points . This observation is in line with the results from the moderation analysis, which showed a moderating effect of impending HTN on the relationship between SBP and depressive symptoms at baseline assessment, but not at follow-up. For well-being, the full-null-model comparison was not significant (X2(3) = 5.39, p = 0.145). While we did not find significant interaction effects on well-being – suggesting that the main effects remained constant over time – the positive effect of SBP and negative effect of HTN on well-being reported in the main manuscript was corroborated by significant main effects of these variables (HTN: X2(1) = 256.54, p < 0.001, SBP: X2(1) = 352.86, p < 0.001). With these additional mixed model analyses, we were able to include all available data including participants with missing data; confirming the findings from multiple linear regression models reported in the main manuscript.To directly model time-varying effects of SBP and HTN in a joint model that accounts for the unbalanced design in the follow-up measures, we explored the longitudinal association with mental health in a Linear Mixed Effects Model framework using R’s later HTN status at 10y-follow-up. Also, (iv) the relationship between blood pressure and mental health – at the initial exam – was moderated by later HTN, such that the negative association between blood pressure and depressive symptoms was stronger in those participants who later developed HTN. Finally, (v) our results from task-based functional brain imaging provide further support for an impact of blood pressure and HTN on central processing of emotions: We demonstrate a negative relationship between SBP – at baseline (~10 years prior to fMRI) and at the time point of imaging – and the BOLD fMRI response to aversive emotional stimuli. This relationship was again moderated by HTN status at follow-up, such that people who developed HTN showed overall lower responses to aversive stimuli and a flattened (negative) relationship between SBP and brain responses. Taken together, our results support the notion that the interrelation between blood pressure and mental health may be involved in the development of high blood pressure with potential implications for developing new preventive and therapeutic approaches for essential hypertension.In this study, we confirmed two seemingly contradictory associations of high blood pressure with mental health: (i) Higher SBP was associated with fewer depressive symptoms and greater well-being at the initial exam as well as at the 5-year mental health online follow-up and the 10-year follow-up including imaging, whereas (ii) the presence of a HTN diagnosis was associated with more depressive symptoms and lower well-being. Given the well-powered cohort of the UK Biobank, we were able to perform sensitivity analyses which confirmed that the observed associations were robust to biases of medications , chronic illness , survival, social factors and unmeasured confounds. Strikingly, we furthermore found that (iii) already at the initial exam, among normotensive individuals, mental health was negatively affected  by the 18, better quality of life18, and reduced self-reported stress15. We extend these findings, which were based on either cross-sectional designs or shorter follow-up periods (1-5 years), by demonstrating that baseline SBP remained a significant predictor of mental health up to 10 years later. The positive effects of high blood pressure on mood might be related to research findings showing that higher blood pressure diminishes emotional experience in experimental manipulations49. It is also well established that elevated blood pressure robustly reduces the perception of physical pain51, but also social pain52. It has therefore been hypothesised that elevated blood pressure relates to a generalised attenuation of emotional valence processing49. Our fMRI findings are consistent with this notion, suggesting an impact of blood pressure on the processing of (negative) emotional faces, even at a follow-up after 10 years. Importantly, while affective attenuation might relate to coping mechanisms to lift mood in stressful situations, it could reinforce staying in potentially harmful circumstances over prolonged periods of time. This may lead to further blood pressure increases and eventually to HTN (see below)29.We preregistered and confirmed a conceptional replication that higher SBP related to better mood ratings: Our findings are consistent with studies reporting positive effects of elevated blood pressure on mental health, including decreased depressive symptoms54 and decreased well-being55. Several potential explanations have been put forward: Biological explanations build on well-known pathophysiological consequences of chronic blood pressure elevations  leading to ischaemic brain damage indicated by white matter lesions, microinfarcts, and cerebral micro-haemorrhages56. White matter lesions, in particular, have been linked to the occurrence of depression with a vascular component58. Systemic mechanisms resulting from unfavourable metabolic alterations, which are common in people with HTN, and an unhealthy lifestyle  have also been linked to depression via metabolic, immuno-inflammatory, and autonomic pathways (reviewed in59). Psychological explanations, on the other hand, emphasise that individuals receiving a diagnosis of HTN are often confronted with a sudden awareness of a chronic illness that requires medical attention and a change of lifestyle. The negative psychological consequences of such a labelling effect could underlie opposing effects of elevated blood pressure and HTN diagnosis on mental health61.Given these consistent findings of a positive association between blood pressure and mood, it seems paradoxical that we found a different pattern for diagnosed HTN; albeit again in line with previous studies in which the presence of vascular risk factors or manifest CVD has been associated with increased depressive symptomsbefore the HTN diagnosis. We found this in two analyses, one in which HTN was defined by previous HTN diagnosis and intake of medication, and one in which SBP > 140 mmHg was also used as criterion. In both analyses — when unadjusted for blood pressure — there were no significant differences in mental health at either visit, while the difference was highly significant when adjusted for blood pressure. Interestingly, we also noted in both analyses that the two groups differed regarding the overall mood-lifting effect of higher blood pressure at the initial visit, such that this effect was more pronounced in the group of those participants who developed HTN later. Thus, it seems that in the HTN-developing group, the relationship between blood pressure and mental health was both shifted in magnitude and had a different slope. This finding cannot be explained by the labelling effect and is also unlikely to be related to vascular damage, such as white matter lesions, as these occur only after long-lasting blood pressure elevations.Based on our data, we cannot exclude contributions of the factors discussed above, however, a major finding of our study , is difficult to reconcile with these explanations: We observed — as expected — that those participants who later developed HTN already had higher blood pressure at the initial visit than those who stayed normotensive. Yet, in the fully adjusted model, i.e., correcting for the baseline differences in blood pressure, the negative impact of (later) HTN on mental health was already significantly present 64. During each heartbeat, baroreceptors are activated during systole and become less active during diastole. They are known to relay phasic and tonic information about blood pressure via the vagal and glossopharyngeal nerves to brain stem nuclei which orchestrate adjustments of blood pressure and heart frequency via the parasympathetic and sympathetic nervous system64. Importantly, in addition to their role in adjusting blood pressure and heart frequency, baroreceptor activation has also been shown to influence emotional and pain processing , thereby mediating behavioural and central effects of blood pressure modulations. Direct evidence comes from animal studies, in which for example, pain-relieving effects of blood pressure elevations were abolished by baroreceptor denervation27 and from studies in humans in whom local baroreceptor stimulation modulated pain perception27. Further evidence has been provided by numerous studies showing different processing of pain, emotion, and sensory stimuli in systole versus diastole65. Importantly, it is also well established that the development of HTN is characterised by a progressive desensitisation of baroreceptors and altered sensory processing66. It, therefore, seems highly plausible that (relatively reduced) baroreceptor signalling might also underlie the observed altered relationship between blood pressure and mental health in hypertensive people. Our results furthermore indicate that the altered relationship between blood pressure and mental health may already be present years before the diagnosis of HTN. In a similar vein, our fMRI findings show an altered relationship between blood pressure and BOLD activation to negative facial expressions in people with HTN, consistent with adjusting central processing of emotions as a response to baroreceptor desensitisation. In sum, there is evidence that baroreceptor signalling can underlie the effect of higher blood pressure on mental health.Obvious candidates for explaining effects of blood pressure on mental health are regulatory circuits linking arterial blood pressure to central processing in the brain. While the causal, and likely multifactorial, pathways between blood pressure and mental health are not fully understood, a shared mechanism between subjective experience, emotional processing and pain involves the regulatory baroreflex system. Baroreceptors, stretch sensitive receptors located in the aortic arch and the carotid artery sinus, are the peripheral sensors of blood pressure29. While psychosocial stress is increasingly accepted as a risk factor for the development of hypertension67, blood pressure adjustments — via baroreceptor signalling — may link stress to a rewarding mechanism decreasing perceived stress. Reinforcement by repeated stress exposure may eventually lead (or contribute) to increases in blood pressure and the development of essential HTN29. Our data further emphasise inter-individual differences: Those individuals who later developed HTN on average showed lower mental health scores when adjusting for SBP. In addition, our moderation analysis yielded that the development of HTN was associated with a stronger negative correlation between mental health and blood pressure at baseline, years before the HTN diagnosis. While the observed inter-individual differences cannot be readily interpreted as indicative of intra-individual mechanisms, it is nevertheless tempting to speculate that people at higher risk of developing HTN require higher blood pressure levels to sustain the same mental health outcomes. These individuals may find themselves on a relatively steeper trajectory towards HTN due to the stronger mood-lifting effect of blood pressure increases. Taken together we propose that (i) feedback loops between blood pressure and rewarding emotional processing during periods of stress may play a role in the pathophysiology of blood pressure increases and HTN and that (ii) alterations of these feedback loops characterised by a shifted blood pressure - mental health relationship may increase HTN risk in affected individuals. Based on our data, we cannot differentiate between potential reasons for the altered blood pressure-mental health relationship in the mostly middle-aged participants, which may include genetics, life-style factors, such as nutrition or the environment, previous exposure to acute and chronic stress, or other factors. Clearly, there is a need for prospective longitudinal studies clarifying this issue.With regard to the development of blood pressure increases over the life course and eventually the pathophysiology of arterial HTN, our findings are consistent with the notion of feedback loops wherein arousing emotional stimuli and stressors elevate blood pressure, which in turn activates baroreceptor pathways that induce analgesia and decrease the perceived affective magnitude of a stressor18 reported lower physical well-being in participants on antihypertensive medication. Boal et al.68 reported differential effects of antihypertensive medication on risk of hospital admissions for mood disorders. Additionally, intake of antidepressant drugs has been previously related to elevated blood pressure16. To account for these potentially confounding factors, we investigated effects of the presence or absence of a lifetime major depression diagnosis, other forms of chronic illness as well as intake of (antihypertensive) medications in sensitivity analyses. Importantly, the findings of our study were robust and consistent: Independent of any potential confounders including medication intake, there was a mood-lifting effect of higher SBP on depressive symptoms and well-being, as well as a negative effect of HTN diagnosis on mood.Beyond effects of blood pressure and diagnosed HTN, other factors such as medication and previous diseases can influence mental health and thus be confounders in our analyses. For example, Hermann-Lingen et al.69. The sample, particularly the neuroimaging sub-sample, displays the healthy volunteer effect, which describes that UK Biobank participants are considered to be more health-conscious, self-reported fewer health conditions and show lower rates of all-cause mortality and total cancer incidence compared to the general population69. Yet, associations between risk factors and disease outcomes in UK Biobank have been reported to be generalisable despite the healthy volunteer effect70.The results reported here are contingent on several limitations. We used UK Biobank data which is not representative of the middle-aged and older UK population71 and may influence subjective health itself61. In addition, participants’ self-reports of prescribed antihypertensive medications might overestimate the actual number of medications taken due to poor adherence72. In addition to self-report measures, we included direct standardised blood pressure recordings, as well as Likert-scale measures of depressive symptoms and well-being, which enabled us to parametrically model these exposures and outcomes in linear regression models. The mental health assessments were, however, not designed for psychiatric diagnostics, which leaves the question open whether the observed effects manifest in the sub-clinical and/or clinical range of psychiatric symptoms.Similar to previous studies, we used self-reports of HTN and antihypertensive medications. Self-reported HTN can underestimate the true underlying prevalence73. While we have not used the blood pressure readings to define HTN in our study, we acknowledge that the procedure of blood pressure readings may have an undetected effect on our results. Yet, our results converge also when using HTN diagnosis from self-reports and hospital records, which strengthens the overall confidence in the robustness of our findings.A recent study also showed that averaging blood pressure values from the first and second reading, as we did here, might underestimate the true prevalence of HTN72.Conceptually, one may question the strict dichotomy between HTN versus no HTN, particularly as blood pressure thresholds for HTN diagnosis have shifted towards lower values in the last decades. However, given the diagnostic criteria for HTN at the time of the study, we assume them to be followed by most physicians in clinical care. Thus, we consider the self-reported HTN status to be a reasonable definition with predictive value for clinical outcomes in an epidemiological study16 showed that non-linear models testing cross-sectional blood pressure-mood associations do not outperform linear models, longitudinal trajectories of both blood pressure, mental health and their interaction over the lifespan are plausible and may reveal diverging patterns. Furthermore, observed effects’ sizes were small and showed point-to-group-level, rather than individual-level patterns. Thus, no direct conclusion can be drawn from our observations relevant for individual patient care. Given the known effects of blood pressure on emotional processing, we hypothesise that —despite the small inter-individual effect sizes in our study — more pronounced intra-individual effects might exist. Our study may motivate future work testing the hypothesis that blood pressure variations and associated mental health need to be taken into account, also in the individual management of people at risk for HTN. Future studies should also address the point of potential practical implications for treating high blood pressure in severe clinical depression. Considering the high prevalence of HTN and its treatment in the general population, as well as rising numbers of sub-clinically elevated blood pressure, small effect sizes may be epidemiologically relevant.Based on our preregistered hypotheses, we only tested linear associations between blood pressure and mental health. While Montano74. While this should be largely accounted for by reporting the BOLD activation contrast between two different types of stimuli , we cannot exclude the remaining impact of impaired neurovascular coupling. Since the Hariri-task was limited to faces with negative emotions, future studies may add information about the impact of blood pressure on the neural processing of positive emotions.Our fMRI findings may be confounded by alterations in neurovascular coupling with HTNImportantly, our results are not ideal to draw firm conclusions about the causality and directionality of the associations between blood pressure, HTN, and mental health, particularly the differentiation between effects of blood pressure per se and HTN remaining complex. Future longitudinal studies should therefore include earlier baseline assessments, repeated and/or continuous blood pressure monitoring over long time periods combined with frequent assessments of mental health and neuroimaging. Finally, randomised controlled trials targeted at assessing the bi-directional relationships of blood pressure and mental health will provide strong designs to elucidate these effects.In summary, in a large British population sample of generally healthy middle-aged and older individuals, we found a relationship of elevated blood pressure with fewer depressive symptoms and greater well-being extending to a follow-up period up to around 10 years. We found the opposite effect for diagnosed HTN – already years before the timepoint of diagnosis. Participants who were normotensive at baseline and later developed HTN showed alterations in the blood pressure-mental health relationship already at baseline. An additional strength of our study lies in the use of fMRI analyses, which suggested an impact of blood pressure levels and HTN development on the neural processing of emotional stimuli. The results were overall robust to bias of medications, chronic illness, survival, social factors, and unmeasured confounds. While the observed effects are small and results from this observational study may not be directly applicable to clinical outcomes, our study adds perspective on how the interrelation of sub-clinical mental health and blood pressure might be involved in blood pressure increases during ageing and development of HTN that could have implications for developing new preventive and therapeutic approaches.http://www.ukbiobank.ac.uk/) to investigate cross-sectional and longitudinal associations between blood pressure, hypertension, and mental health in behaviour and brain. The UK Biobank received ethical approval from the North West Multi-centre Research Ethics Committee  in 2011, with renewed approval every 5 years since. All participants gave written informed consent. This approval means that researchers do not require separate ethical clearance and can operate under the Research Tissue Bank (RTB) approval. We were granted access to UK Biobank’s data resource in May 2018 after an initial application, but embargoed data access until we completed the preregistrations of this and related studies . All analyses and data visualisations were performed with R  and RStudio (version 2022.07.0). To allow for replication studies and reproducibility of our results, the analysis code can be found in the Open Science Framework repository of this study (https://osf.io/v3yxd/).This study was conducted using data from the UK Biobank , the online mental health follow-up at around 5 years from baseline, as well as the follow-up imaging visit  at around 10 years from baseline , and at imaging follow-up which included ongoing brain magnetic resonance imaging (MRI) assessments of 100,000 UK Biobank participants that has started in 201478.Current depressive symptoms: During each assessment centre visit, frequency of current depressive symptoms in the last two weeks  was assessed using a 4-point Likert scale ranging from 0  to 3 (“nearly every day”). The item scores were summarized as mean scores for the purpose of this study. Questions regarding current depressive symptoms were assessed via a touchscreen during baseline and follow-up assessment centre visits79 from the online mental health follow-up assessment which a sub-sample of the whole UK Biobank cohort received40. In the online PHQ-9 questionnaire, the severity of current depressive symptoms in the last two weeks was assessed. Participants indicated presence of recent depressive symptoms on a 4-point Likert scale ranging from 0  to 3 (“nearly every day”). Since UK Biobank applied a different coding scheme, the items were recoded to match the original coding as described above. PHQ-9 symptom scores were summarized as a sum score. The analyses and results of this questionnaire were almost identical to the ones obtained from the main depressive symptoms outcome measure described above.We also preregistered analyses using the Patient Health Questionnaire 9-question version (PHQ-9)Well-being: Seven questions addressing different aspects of participants’ well-being were included at the assessment centre visits. The questions asked how happy/satisfied participants were regarding their happiness, and health, work, family, friendship, and financial situation, respectively. Participants were asked to respond to the questions on a 6-point Likert scale ranging from 1 (“extremely happy”) to 6 (“extremely unhappy”). For the purpose of this study, all item scores were recoded and summarized as mean scores with higher scores representing greater well-being.Systolic blood pressure (SBP): Systolic and diastolic blood pressure readings were taken from all UK Biobank participants. At each assessment centre visit, two readings were recorded with an automated Omron 705 IT electronic blood pressure monitor . The two blood pressure readings were obtained during seated resting periods interleaved with a verbal interview on demographic and health-related data by UK Biobank staff. The procedure was conducted in the following sequence: (1) Interview Part 1 (demographic data), (2) First measurement of blood pressure, (3) Interview Part 2 (diseases and medications), (4) Measurement of Pulse Wave Velocity, (5) Second measurement of blood pressure. A timer ensured the second blood pressure reading could not be taken until at least 1 minute had elapsed. We used the mean of the two readings to derive systolic (SBP) values per participant at baseline and follow-up visit.Hypertension diagnosis (HTN): Complementary to blood pressure readings, we used a categorical measure of HTN diagnosis. Participants indicated on a touchscreen whether a doctor has ever told them that they have had high blood pressure. These self-reports were given at each assessment visit and used in this study as an assessment if a diagnosis of HTN was present (yes/no) at baseline and follow-up.Number of antihypertensive medications: In a nurse interview at each assessment visit, participants reported all medications they were currently taking. A physician from our team (LL) examined these medication lists and identified all antihypertensive drug classes  missing hypertensive cases and (2) confounding influences of antihypertensive intake. Hence, we defined hypertension for this analysis as either having a HTN diagnosis (as described above) or using any antihypertensive medication. For the moderation analysis, this definition was used for exclusion of participants with hypertension at baseline to select a non-hypertensive sample at baseline. At follow-up, this definition was used to define which participants became hypertensive between baseline and follow-up  and who stayed normotensive.76. In brief, the functional MRI task that was implemented in UK Biobank is the Hariri “emotion” task32. Participants were presented with blocks of trials and asked to decide either which of two faces presented on the bottom of the screen match the face at the top of the screen, or which of two shapes presented at the bottom of the screen match the shape at the top of the screen. The faces had either an angry or fearful expression. Trials were presented in blocks of 6 trials of the same condition (faces or shapes), with the stimulus presented for 2000ms and a 1000 ms inter-trial interval. Each block was preceded by a 2000ms task cue (“shape” or “face”), so that each block was 21 seconds including the cue. Each of the two runs included 3 face blocks and 3 shape blocks, with 8 seconds of fixation at the end of each run. IDPs of the Hariri task reflect the strength of response to the stimuli within a given brain region using the blood oxygenation level dependent (BOLD) contrast. BOLD fMRI relies on regional differences in haemoglobin oxygenation  to measure regional brain activity82. Here, we focused on the IDPs of significant clusters in amygdala and whole-brain activation for the faces > shapes contrast (median z-statistics of BOLD activation), which reflects the emotional brain response.Imaging-derived phenotypes (IDPs): For analyses relating to brain function, we utilised the imaging-derived phenotypes (IDPs) available in UK Biobank which have been generated by processing the raw neuroimaging data. Magnetic resonance imaging (MRI) was performed at 3 Tesla and details of the imaging protocols and data processing procedures have been described in detail elsewheregender and not sex, as the UK Biobank defines this variable as a mixture of the sex the NHS had recorded for the participant and self-reported sex, although we acknowledge that this does not capture the full spectrum of gender.To adjust for confounding factors, we included the following variables as covariates in the analyses: age, gender, body mass index (BMI), resting heart rate, diabetes diagnosed by doctor (yes/no), lifetime depression diagnosed by doctor (yes/no), angina diagnosed by doctor (yes/no), myocardial infarction diagnosed by doctor (yes/no). Note that we refer to the variable We performed cross-sectional and longitudinal multiple linear regression models. For cross-sectional comparisons, we used data of the initial assessment visit. Outcomes were current depressive symptoms and well-being, respectively. SBP, HTN and the number of antihypertensives were entered simultaneously as predictors. For longitudinal comparisons, we predicted outcome measures  assessed at the follow-up visit from predictors assessed at the initial assessment visit . The analyses were performed for the total sample, as well as for a subset of participants with HTN diagnosis. All statistical models included the same covariates from initial assessment visit . Missing data were listwise excluded and outcomes, predictors and covariates were z-scored. In all models, we have also assessed any potential influence of multicollinearity by evaluating the Variance Inflation Factor (VIF). The VIFs never exceeded a value of 2, which indicates that multicollinearity is low and inferences from our models are likely not biased due to correlations among the variables included.not hypertensive at baseline, as defined by a HTN diagnosis or intake of antihypertensive medications at this timepoint. We then compared the relationship between SBP and mental health in participants who developed hypertension  until the follow-up assessment, with those who stayed normotensive. The moderation analysis was performed through a multiple linear regression model including depressive symptoms or well-being as outcomes, respectively, and the interaction term of SBP at initial visit and hypertension at follow-up as predictor83. We also included the following covariates: age at initial visit, gender, and BMI at initial visit.Using moderation analysis, we explored whether the relationship between SBP and mental health was dependent on hypertension status at follow-up assessment. For this analysis, we only included participants who were Complementary to self-reports of mental health, we explored the prospective effects of elevated blood pressure on emotion-related brain function as a central nervous outcome measure of emotional reactivity. As described in the introduction, we would expect blood pressure elevations to relate to altered neural processing of affective stimuli due to baroreceptor effects. Measures of brain function included BOLD fMRI activation in significant clusters in the amygdala and whole-brain analyses (see section above).Moderation of the BP-mental health relationship by development of hypertension).We used these measures as outcomes in two-sided t-tests comparing groups of participants with and without HTN, as well as in multiple linear regression models, which included SBP at follow-up , as well as age, gender, and BMI as covariates. In the linear regression models, we further included the interaction of SBP and HTN diagnosis at follow-up as predictor to test if the relationship between blood pressure levels and emotional reactivity differs between individuals who became hypertensive and those who did not (see also section above Further information on research design is available in the Supplementary InformationPeer Review FileReporting Summary