Female patients suffer from the risk of upper limb lymphedema after breast cancer removal surgery. At present, the detection and the adjuvant treatment of this disease are not convenient enough, leading to delay of the disease and increase in the burden of patients. This paper presents a portable monitoring and treatment device for upper extremity lymphedema, enabling patients to monitor the symptoms of upper limb lymphedema and auxiliary rehabilitation. This design utilizes the arm circumference measurement and contrast method to realize symptom monitoring. The device realizes auxiliary rehabilitation using the regional pressure method to imitate traditional manual lymphatic drainage technology. According to the MRI images of volunteers’ upper limbs, the upper arm and forearm’s finite element models are reconstructed in ANSYS. The static simulation experiment is completed. The working mode and parameter design of each rehabilitation module of the device are obtained. The experimental results show that the integrated design principle of monitoring and treatment proposed in this paper has good feasibility, has auxiliary rehabilitation effect, and meets the principle of human comfort. The device can help patients find lymphedema in time and implement auxiliary treatment, which can effectively avoid the further deterioration of lymphedema. Breast cancer is the leading cancer disease in women. After breast cancer surgery, 15–30% of patients  in rehabAt present, there is no effective monitoring method for early occult lymphedema. For clinical dominant lymphedema, the following technical methods are generally used for evaluation and measurement: (1) direct measurement of limb circumference or volume, including limb circumference measurement, water substitution method, higher-precision professional equipment Perometer , etc., , and (3)For patients with upper extremity lymphedema, this study can shorten the detection time and increase the convenience of rehabilitation treatment. Compared with the existing clinical diagnosis and rehabilitation treatment technology, this study provides a new and innovative convenient monitoring integrated method and can be used with the existing clinical technology, which will greatly increase the recovery rate of upper limb lymphedema and reduce the delay of rehabilitation treatment due to time. At present, this research belongs to the forefront in China, which will greatly enrich the research field of lymphedema. The device will reduce the pain of patients with lymphedema, achieve the purpose of early detection and treatment, and effectively control the patient’s condition. According to the needs of patients with upper limb lymphedema, this paper designs a portable monitoring and treatment integrated device for upper limb lymphedema and carries out static finite element simulation of human upper limb through ANSYS software, which further optimizes the design of the device, improves the rehabilitation treatment effect of the device, and effectively avoids the further deterioration of patients with lymphedema. Further improvement and application of the device will further improve the living conditions of patients with upper extremity lymphedema and further improve the development of human health.In this study, female patients with grade 0 lymphedema after breast cancer surgery (patients with mild or who might have tissue damage) were selected as design users. It can be found that the users lack a device for basic monitoring and auxiliary treatment at home. According to the needs of users, a portable monitoring and auxiliary treatment device for upper limb lymphedema is proposed, which belongs to wearable medical equipment.For the portable lymphedema monitoring method, the arm circumference measurement comparison method  is more For portable lymphedema rehabilitation methods, the mainstream method is pressure-assisted therapy . BecauseAs shown in The detailed structure of each module is as follows: (1) positioning glove, (2) forearm low-ductility massage belt C, (3) forearm low-ductility massage belt B, (4) forearm low-ductility massage belt A, (5) forearm rehabilitation module, (6) elastic fabric, (7) upper arm rehabilitation module, (8) forearm monitoring module, (9) forearm signal processing module, (10) upper arm monitoring module, (11) upper arm signal processing module, (12) upper arm low-ductility massage belt C, (13) upper arm low-ductility massage belt B, and (14) upper arm low-ductility massage belt A.The principle of the scheme can solve the problem of inconvenient wearing by one user, monitoring the lymphedema function of the user’s upper limbs, and auxiliary treatment of lymphedema of the upper limbs. Patients can use this device according to their needs after breast cancer surgery.The principle of the monitoring method is the arm circumference measurement comparison method in portable monitoring and auxiliary treatment device for upper extremity lymphedema. The principle of the device is that the arm circumference measurement module is set in different parts of the upper limb. The user measures the circumference of the same part of his arm every time and compares it with previous data to determine whether the arm circumference changes so as to judge whether the upper limb has lymphedema. Positioning gloves can be used to help in device wear positioning. The principle of rehabilitation is to simulate manual lymphatic drainage treatment and pressure-assisted treatment by mechanical massage. There are two rehabilitation modules in the device that are wrapped in the forearm and the upper arm of the upper limb, which are, respectively, the forearm rehabilitation module and the upper arm rehabilitation module. Each rehabilitation module is provided with three low-ductility massage belts with a width of 50 mm. In the upper arm from top to bottom are the upper arm low-ductility massage belt A, the upper arm low-ductility massage belt B, and the upper arm low-ductility massage belt C. In the forearm from top to bottom are the forearm low-ductility massage belt A, the forearm low-ductility massage belt B, and the forearm low-ductility massage belt C. Each massage belt can apply a fixed output pressure load to each part of upper limb through motor driving or air compression to simulate manual lymphatic drainage.The subjects of this paper were women aged 20–30 years old with healthy upper limb. The inclusion criteria were breast cancer patients who might have slight upper limb lymphedema after partial mastectomy. The exclusion criteria were other physical defects of the upper limb, such as abnormal growth of lymphatic vessels, partial resection of the upper limb, etc. The middle part of the upper arm and the middle part of the forearm are taken as the rehabilitation reference parts. The simulation of the upper arm low-ductility massage belt B and the forearm low-ductility massage belt B is carried out to improve the parameter design and optimization of the total rehabilitation module of the device. As an excellent finite element analysis software, ANSYS has been more and more used in biological simulation experiments . AccordiThere are many ways to build the finite element model of biology. Some researchers  use an MBiologically, the cross-sectional structure of the human upper limb is composed of skin, subcutaneous fat, muscle, inner fat, blood, lymph, tissue fluid, and bone. As shown in The human upper arm model was constructed based on the upper limb data of female patients with grade 0 lymphedema (patients with mild or who might have tissue damage). In order to build the finite element model, it is necessary to reasonably stratify the tissues and simplify them according to their similarities and differences, as shown in In this paper, the structure of the human upper limb is simplified into five parts, which are as follows: bone layer, inner soft tissue layer, lymph and blood layer, outer soft tissue layer, and skin layer. The images of the bone layer were layered obviously and were constructed according to MRI scanned images. Lymph and blood are distributed in the soft tissue layer. Muscle, inner fat, and subcutaneous fat are regarded as soft tissue layer, and they are divided into inner soft tissue layer and outer soft tissue layer by dividing the lymphatic and blood layer. Because the biological structures of lymph and blood are similar due to their physical characteristics, in order to simplify the model, the lymph and blood vessels were divided into a layer with an average width of 4 mm, distributed between the inner and outer soft tissue layers. According to previous research results , the widIn this paper, static structural module of ANSYS Workbench 19.0 is used for static simulation, and the 3D model built by SOLIDWORKS.2016 in the previous step is imported, as shown in In order to get an accurate simulation effect, it is necessary to mesh each layer structure and refine the important parts. The skin layer, as the unimportant part, is set as 5 mm, the outer soft tissue layer, lymph and blood layer, and inner soft tissue layer as important parts had a node size of 1 mm, and the bone layer is 2 mm. The mesh generation of the 3D reconstruction model is shown in According to the node size divided, the number of elements and nodes of different structural layers in the upper arm model are obtained, as shown in The simulation experiment should be similar to the actual massage effect of the device. The boundary conditions are defined as follows: The internal load pressure is applied to the outer surface of the skin layer, and the bone layer is set as fixed. Different pressure was applied to the surface of the skin layer, and the pressure direction was around the skin layer and pointed to the center.In order to promote the reflux of intralymphatic fluid, the pressure in lymphatic vessels should be increased appropriately. The lymphatic research of Olscewski’s team  showed tIn the upper arm model experiment, after the continuous test of ANSYS simulation experiment, as shown in -shaped” line mark is used for point selection and positioning, as shown in -shaped” line. Eight rays from the origin intersect with the midline of the lymph and the blood layers, respectively, and eight intersections are obtained. The eight points were marked clockwise as points D1, D2, D3, D4, D5, D6, D7, and D8. Each point can be selected to obtain the pressure load at this point. In the pressure load diagram of each fixed point, when the values of four random points among the eight points are greater than 0.03 MPa, these indicate that the load of the lymph and the blood layer is too large, indicating that the external load force exerted by the skin layer is too large.In order to locate the accurate range of external load pressure, the “As shown in The data obtained by ANSYS software are sorted out and analyzed. In the upper arm model and the forearm model, when the external load pressure of the skin layer is 0.002–0.006 MPa, the pressure range of the internal lymphatic and blood layer is within 0.03 MPa. The experimental results are refined again, and the parameters are optimized according to the design principle of the device.In order to verify that the eight punctuation points measured in each picture have a reference value, the 10 groups of data obtained are sorted and analyzed. Shown in formula (1) is the variance formula that was used:Shown in formula (2) is the standard deviation calculation formula:The average pressure load and error range of each group of data were analyzed.F = P ⋅S, there is greater force on the upper arm. According to the variance and standard deviation data in As shown in Through the ANSYS simulation experiment, in the rehabilitation module of the portable upper limb lymphedema monitoring and auxiliary treatment integrated device, aiming at female patients with grade 0 lymphedema (patients with mild or who might have tissue damage), the optimization design scheme of the device rehabilitation module parameters is obtained.The working mode of the upper arm low-ductility massage belt B in the upper arm rehabilitation module will be set to three pressure ranges: weak grade, 0.003 MPa; medium grade, 0.004 MPa; and strong grade, 0.005 MPa. In order to form a pressure gradient, the pressure at the distal end of the upper limb should be greater than that at the proximal end. The working mode of the forearm low-ductility massage belt B in the forearm rehabilitation module will also be set to the pressure range of the three gears: weak grade, 0.0035 MPa; medium grade, 0.0045 MPa; and strong grade, 0.0055 MPa. The application range of the low-ductility massage belt of the rehabilitation module is 260 mm in length and 50 mm in width. The range of applied force can be obtained.According to these data, the device parameters in each rehabilitation module are set in detail. In order to achieve the recovery effect of pressure reflux of lymph, it is necessary to adjust the pressure intensity to form a pressure gradient. The working mode values of each low-ductility massage belt of the upper arm rehabilitation module and the forearm rehabilitation module in Compared with this device, the traditional detection methods, such as measuring with a tape measure, need the help of others every time and cannot guarantee an accurate measurement of the same marked point of the upper limb; measuring with a measuring cylinder with water displacement method, the measurement error of the patient’s upper limb is great, and the front and rear measurement is cumbersome and inaccurate than using professional equipment, such as Perometer, isotope lymphography, near-infrared fluorescence imaging, etc., Every time the cost is more; each test costs 1,000–3,000 yuan, which ordinary patients cannot afford. For the function of adjuvant therapy, many treatment equipment are time-consuming and expensive; non-surgical treatment methods need long-term and timely treatment, such as strength training, skin care, lymphatic massage, etc., which cost 300–1,000 yuan each time; surgical treatment costs 20,000–50,000 yuan each time, which is particularly expensive, and the patients feel uncomfortable. This device uses arm circumference measurement method, the test results are more accurate and cheap, and the cost of the device is controlled within 2,000 yuan. The auxiliary treatment module can also simulate manual lymphatic drainage, which can replace the traditional rehabilitation treatment method and be used directly at home.There are some limitations in this paper. We only take the middle part of the upper arm and the middle part of the forearm as the research model, and other parts of the experiment are regarded under the same experimental conditions, but there are still some errors. This device is still in the early stage of development, and there is no good rehabilitation verification effect for different disease stages of upper limb lymphedema. In the future, it will further refine the construction of upper limb finite element model and simulation experiment, further improve the accuracy of experimental data, and provide a more significant auxiliary treatment device for patients with upper limb lymphedema. In this paper, only one female volunteer was scanned, and data were collected. In future research, the database of the upper limb will be enriched and data will be collected and analyzed.In this paper, the demand status of female patients with lymphedema of the upper limb after breast cancer surgery was analyzed. Combined with wearable design and detection and rehabilitation of lymphedema, a portable monitoring and auxiliary treatment device for upper limb lymphedema was designed. In order to optimize the parameters of the rehabilitation module of the device, ANSYS software was used for static finite element simulation. By simplifying the biological model of the upper arm and the biological model of the forearm, a 3D reconstruction of the model, reasonable layering and simulation experiments are carried out. After a detailed analysis of the simulation results, the specific parameters of the refining device are obtained according to the simulation results. At the same time, setting the pressure range and working time of the device can further improve its rehabilitation effect. The design of this scheme can solve the problem such that patients with upper extremity lymphedema can complete the process of edema monitoring and adjuvant treatment at home, achieving the purpose of early detection and early treatment and effectively controlling the patient’s condition. This paper makes up for the research content of female patients with upper limb lymphedema after breast cancer surgery and provides a design scheme and optimization method for other researchers.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.XY contributed to the methodology and project administration of the study. ZX wrote the original draft of the manuscript and contributed to the product conceptualization and formal analysis. YW contributed to the software and review of the study. YS provided supervision and resources of the study. LS provided experimental equipment and organized the data curation. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


After adjustment for various well-known cofounders, multivariate Cox analysis showed that the association between increased circulating ox-LDL levels and the composite kidney endpoint remained significant . Regarding the secondary outcome of eGFR decline, the assessment of areas under the curves (AUC) showed that ox-LDL outperformed several cofounding factors  and had better accuracy to predict deterioration of eGFR over time than baseline proteinuria . Increased ox-LDL might be associated with disease progression in proteinuric DKD.Diabetic kidney disease (DKD) is a highly heterogenous disease, including the proteinuric and the nonproteinuric pattern. Oxidized low-density lipoprotein (ox-LDL) is progressively increased in DKD and causes direct damage to kidney tubular epithelial cells through a mechanism similar to that underlying the deleterious effect of lipid peroxides in the vascular endothelium. We aimed to examine the association between plasma ox-LDL cholesterol and clinical endpoints in DKD patients. Ninety-one patients with established proteinuric DKD and diabetic retinopathy were enrolled and prospectively followed for 10 years or the occurrence of death, or at least 30% decline in eGFR, or progression to end-stage kidney disease (ESKD) requiring renal replacement therapy (primary outcome). At the end of the study, both eGFR and proteinuria were reassessed. Secondary outcomes of the study were the percentage change in eGFR and proteinuria over time for each patient. At baseline, patients were divided into 2 groups according to the median ox-LDL value . Both Kaplan-Meier curves ( Diabetic kidney disease (DKD) presents in approximately 40% of type 2 diabetes mellitus (T2DM) subjects over lifetime and remains the leading cause of end-stage kidney disease (ESKD) worldwide . Since DDue to the imbalance between pro and antioxidants in favor of the former, oxidative stress (OS) is present even at early stages of DKD and progresses along with disease deterioration to ESKD , 5. OS pAim of this study was to examine the association between plasma ox-LDL cholesterol and mortality, deterioration of kidney function, and proteinuria increase in a cohort of patients with established proteinuric DKD.A total of 91 patients with established DKD were enrolled from the Diabetic Chronic Kidney Disease Department's outpatient clinic of the General University of Alexandroupolis in Greece. Participants provided their written, informed consent at recruitment. The study protocol was approved by the PhD Scientific Committee (1046/01 November 2007) and further approved by the Ethics Committee of the Scientific Council of the University General Hospital of Alexandroupolis (1130/25 November 2011) and was in accordance with the Helsinki Declaration of Human Rights. Eligible patients for enrolment were those who had a history of T2DM of at least 7 years, presence of diabetic retinopathy, and CKD, defined by persistent proteinuria and/or eGFR below 90 ml/min. The exclusion criteria included acute illness, chronic inflammatory disease, urinary tract disease, laboratory or clinical evidence of nondiabetic CKD, and documented transitory of permanent eGFR decline > 30% during the last 6 months before recruitment. At baseline, we documented somatometric, biochemical and clinical data and history of smoking habit, T2DM duration, and previous CV disease. Definition and classification of DKD stages were done according to the clinical practice guidelines  establisΔeGFR/baseline eGFR and ΔUPCR/baseline UPCR, respectively) divided by the follow-up time) for each patient. Follow-up data were collected from regular follow-up visits, death certificates, and via integrated telephone interviews.After enrolment, all participants were prospectively followed for a period of 10 years (from 20 November 2008 to 21 November 2018), or the occurrence of death, or at least 30% decline in eGFR, or progression to ESKD requiring renal replacement therapy (primary outcome). At the end of the study, both eGFR and UPCR were reassessed. Secondary outcomes of the study were the percentage change in eGFR and UPCR over time . Data were tested for normality with the Kolmogorov–Smirnov test, and normally distributed continuous variables were expressed as the mean (standard deviation), whereas nonnormally continuous variables were expressed as (range) and binary variables as percent frequency. Differences of variables among groups were explored using the chi-square test for frequencies (dichotomized variables) and the Mann–Whitney test for continuous variables. We used the Kaplan–Meier actuarial method and the log-rank test to compare survival curves to estimate the primary outcome  for the median plasma ox-LDL level. Univariate and multivariate Cox proportional hazard analysis (forward stepwise regression) was performed to evaluate adjusted hazard ratios (HRs) and 95% confidence intervals (Cis) for the associations between groups of ox-LDL and the primary, composite outcome. Multivariate models were adjusted for all variables that were associated with the primary outcome in univariate models . The multivariate Cox proportional hazard analysis for the primary, composite outcome was also performed in 500 bootstrap samples.ΔeGFR/baseline eGFR and Δproteinuria/baseline proteinuria, respectively, and divided by the follow-up time for each patient), after the end of the follow-up period, we categorized our cohort to slow and fast decliners. Mann–Whitney U test and chi-square test were used to identify differences of all the variables assessed at baseline  of 140/80 mm Hg and median glycated hemoglobin (HbA1c) of 7.2%, whereas the majority of patients (70.3%) had history of CV disease. The median value of ox-LDL was 66.22 (22.9-123.4 U/L) at baseline. The baseline demographic, somatometric, and clinical characteristics of the study cohort according to median plasma ox-LDL levels are shown in The study population included 91 DKD subjects , with T2DM for a median time of 13 years and median eGFR 59.6 ml/min and UPCR 0.15 g/g at baseline, at different stages of CKD: 19 at CKD stage 1, 26 at CKD stage 2, 23 at CKD stage 3, and 12 at CKD stage 4. At baseline, 41/91 patients had normal to mildly increased albuminuria (A1 stage), 33 moderately increased (A2 stage), and 17 severely increased albuminuria (A3 stage). Among CKD stages, A1 was more prevalent at CKD stage 1 (89.5%) and A3 at CKD stage 4 (75%). Participants were mainly overweight and obese, with a mean body mass index (BMI) of 31.4 ± 5.4 kg/mp = 0.001, log-rank test, p = 0.17). We performed Kaplan-Meier analysis again and found that patients with high ox-LDL levels (3rd group) had significantly increased risk for the primary outcome , p < 0.001), baseline UPCR , triglycerides , and serum albumin  were the only factors associated with the study outcome, whereas the association with duration of T2DM was marginally nonsignificant (p = 0.057). After adjustment for these well-known cofounders, multivariate Cox analysis showed that the association between increased circulating ox-LDL levels and the study endpoint remained significant , whereas the only other factor associated with the study outcome was baseline eGFR , p = 0.046, Supplementary Table During the follow-up period , 30/91 patients presented the composite endpoint , 10 in the low, and 20 in the high ox-LDL group. The prevalence of our primary outcome increased progressively among CKD stages . Fast eGFR decliners were the 21% of patients with CKD stage 1 and 36.4%, 65.5%, and 100% of patients with stages 2, 3, and 4, respectively. Kaplan-Meier curves showed that patients with circulating Ox-LDL cholesterol above the median (>66.22 U/L) had a significantly higher risk for the composite outcome , increased duration of T2DM, higher triglycerides and ox-LDL levels, and higher baseline UPCR values . After testing the predictive performance of all these factors associated with fast eGFR decline in p = 0.001, p = 0.014, After the follow-up period of 10 years, 22 patients had stable or increased kidney function, whereas 56 experienced reduction of eGFR. Patients were divided in two groups according to the calculated eGFR decrease over the time period: fast decliners (those who had above the median eGFR change over time) and slow decliners. In this study, we aimed to assess whether ox-LDL, a biomarker of OS and ED, is associated with progression of DKD, in a cohort of 91 patients with established proteinuric DKD. Our outcomes of interest  have been widely used as validated endpoints in several prospective studies before –14. The Ιt is hypothesized that the main pathogenetic mechanism driving progression of nonproteinuric DKD is macroangiopathy, whereas microangiopathy is responsible for progression of proteinuric DKD. We found that proteinuria was associated with the primary composite outcome of mortality, at least 30% reduction in eGFR or EKSD in univariate analysis, but this association was lost in multivariate analysis. Moreover, proteinuria predicted eGFR decline. Our findings are in line with data from large epidemiological studies showing that eGFR and proteinuria are independent predictors of kidney outcomes in T2DM patients [In our study, after a 10-year follow-up, 22 patients had stable kidney function, whereas 56 experienced reduction of eGFR, similarly to previous reports , 15. Ιt patients , 16. Furpatients .The main finding of our study was that among patients with established proteinuric DKD and presence of retinopathy, circulating ox-LDL was associated with the composite renal outcome of all-cause mortality, at least 30% reduction of eGFR and/or progression to ESKD. Moreover, ox-LDL predicted eGFR decline over the follow-up period of 10 years with better accuracy than proteinuria. There is a growing body of evidence suggesting that hyperglycemia and uremia independently trigger accumulation of reactive oxygen species (ROS) and depletion of antioxidant defense mechanisms , 5, 18. Several clinical studies are aimed at assessing the possible association between ox-LDL and DKD; however, the majority of these studies had cross-sectional design and focused only on proteinuria. In a cohort of 70 T2DM patients, Ujihara et al. showed that compared to those with normo and microalbuminuria, patients with macroalbuminuria exhibited significantly higher plasma ox-LDL levels, regardless of glycemic control . The autIn two cross-sectional studies, circulating ox-LDL was not significantly increased in ESRD patients  compared to predialysis CKD , 40. HowThe majority of the forementioned studies are either experimental or cross-sectional and therefore are limited by design to assess the predictive value of ox-LDL on clinical hard endpoints. The accumulated data suggesting a pivotal role of OS on development of DKD encouraged research on the possible renoprotective effect of antilipidemic and antioxidant supplementation. Although antioxidant treatment in experimental studies generated favorable results , clinicaTo our knowledge, this is the first study showing that circulating ox-LDL might be a predictor of DKD progression in patients with proteinuric DKD. However, our study has certain limitations. The observational design cannot establish any causality, and we did not measure any other markers of lipid peroxidation status and circulating antioxidants. Moreover, the relatively small sample size is also recognized as limitation; although, several studies with similar design and population have used similar sample sizes. The evaluation of ox-LDL as a potential biomarker for the development of DKD still remains for research.In conclusion, our study demonstrated that ox-LDL, a marker of OS and ED, might be associated with mortality and deterioration of the kidney function in a cohort of proteinuric DKD patients with diabetic retinopathy. No association was found between ox-LDL and proteinuria increase in these patients. Future, larger randomized controlled studies targeting the ox-LDL suppression are needed in order to draw definite conclusions regarding the possible association between ox-LDL and deterioration of DKD.


The efficacy of renal denervation has been controversial, but the procedure has now undergone several placebo-controlled trials. New placebo-controlled trial data has recently emerged, with longer follow-up of one trial and the full report of another trial . We therefore sought to evaluate the effect of renal denervation on ambulatory and office blood pressures in patients with hypertension.We systematically identified all blinded placebo-controlled randomized trials of catheter-based renal denervation for hypertension. The primary efficacy outcome was ambulatory systolic blood pressure change relative to placebo. A random-effects meta-analysis was performed.p < 0.0001), ambulatory diastolic blood pressure , office systolic blood pressure size  and office diastolic pressure . Adverse events were rare and not more common with denervation.6 studies randomizing 1232 patients were eligible. 713 patients were randomized to renal denervation and 519 to placebo. Renal denervation significantly reduced ambulatory systolic blood pressure (−3.52 mmHg; 95% CI −4.94 to −2.09; The totality of blinded, randomized placebo-controlled data shows that renal denervation is safe and provides genuine reduction in blood pressure for at least 6 months post-procedure. If this effect continues in the long term, renal denervation might provide a life-long 10% relative risk reduction in major adverse cardiac events and 7.5% relative risk reduction in all-cause mortality. •In this updated meta-analysis of 6 trials and 1232 patients, renal denervation reduced ambulatory systolic, ambulatory diastolic, office systolic, and office diastolic blood pressure.•The totality of blinded, randomized placebo-controlled data shows that renal denervation is safe and provides genuine reduction in blood pressure for at least 6 months post-procedure.•If this effect continues in the long term, renal denervation might provide a life-long 10% relative risk reduction in major adverse cardiac events and 7.5% relative risk reduction in all-cause mortality. Early trials of RDN were unblinded and showed reductions in office blood pressure (OBP) of ~30 mmHg . HoweverRDN has now undergoing several placebo-controlled trials, and meta-analysis of these trials has shown significantly reduced ambulatory and office systolic BP compared with placebo . HoweverWe therefore conducted an updated meta-analysis of RDN for hypertension, including the totality of randomized placebo-controlled trial data now available.2We carried out a prospectively registered (PROSPERO ID 190939) meta-analysis of randomized placebo-controlled trials of RDN for hypertension in accordance with published guidance .2.1We performed a systematic search of MEDLINE and EMBASE databases and the Cochrane Central Register of Controlled trials from 2000 to November 2020 using the search strategy outlined in the Supplementary Appendix. Two independent reviewers performed the search and literature screening (YA and JPH), with disputes resolved by consensus. There were no language restrictions. We also hand-searched the bibliographies of relevant selected studies, reviews and other meta-analyses to identify any further studies. Recent conference abstracts were also searched to identify newly published studies. Abstracts were reviewed for suitability and full-text articles retrieved appropriately.We included all randomized placebo-controlled studies of RDN for hypertension if they reported either office or 24-hour ambulatory BP changes from baseline. Unblinded studies were not considered as several previous meta-analyses have shown these provide inaccurate estimations of effect size .2.2The primary efficacy endpoint was change in 24-hour ambulatory systolic blood pressure (ASBP). Secondary efficacy endpoints were change in 24-hour ambulatory diastolic blood pressure (ADBP), change in office systolic blood pressure (OSBP), change in office diastolic blood pressure (ODBP), change in day-time ambulatory systolic blood pressure (DSBP), change in day-time ambulatory diastolic blood pressure (DDBP), change in night-time ambulatory systolic blood pressure (NSBP), change in night-time ambulatory diastolic blood pressure (NDBP).For all blood pressure endpoints, where trials quoted a baseline-adjusted estimate for the effect size using analysis of covariance, this was used. Otherwise, the difference in change in blood pressure from baseline to final value between arms was used.We extracted the BP endpoint effect sizes from the analysis of covariance, where possible, along with its 95% confidence interval (CI). In trials where analysis of covariance was not available, we extracted the change in BP from baseline to final in both the RDN and control arms, along with their 95% CIs. The longer-term follow-up of RADIANCE adjusted for baseline BP and also medications at 6 months; for the primary analysis, this measure was used, and a sensitivity analysis would be conducted using 2-month data performed off medication. All endpoints were assessed on an intention-to-treat basis.Three authors independently extracted data from included trials, with discrepancies resolved by consensus.2.32 statistic [We performed a random-effects meta-analysis using the mean difference in effect sizes and their associated standard errors using the restricted maximum likelihood (REML) estimator. Standard errors for the trials were calculated by dividing the difference between the upper and lower 95% CIs by 2× the appropriate normal score (1.96). Interactions between important characteristics that varied across trials were assessed by performing a mixed-effects meta-analysis with the characteristic as a moderator. A meta-analysis was also performed to ascertain any difference between office and ambulatory blood pressure outcomes in trials which reported both, by calculating the mean and its associated standard error for the difference between the two outcomes. The statistical programming language R  with thetatistic .Sensitivity analyses were performed using a fixed effect analysis, as well as a Jackknife sensitivity analysis excluding each trial in turn. We pre-specified first- and second-generation RDN trials as subgroup analyses, with tests for interaction for the primary outcome.Included studies were assessed for bias using the Cochrane Risk of Bias tool by two authors independently, with disagreements resolved by consensus. Tests for publication bias would not be performed unless the number of studies analyzed exceeded 10 .36 trials , randomiRisk of bias assessment is shown in 3.1There was no significant heterogeneity in outcome measures unless stated.p < 0.0001; p = 0.0006; RDN resulted in a significant reduction in ASBP .RDN resulted in a significant reduction in DSBP .RDN also resulted in a significant reduction in DDBP .RDN resulted in a significant reduction in NSBP . There was significant heterogeneity (I2 = 74.9%).RDN did not result in a significant reduction in nighttime diastolic blood pressure . There were 4 strokes in the denervation arm and 5 in the control arm. There was one embolism and one vascular complication in the denervation arm (again both in Symplicity HTN 3), as well as 1 case of new renal artery stenosis. 1 patient in the denervation arm required renal artery stenting .3.5p = 0.514).There was no significant effect of first versus second generation trials on either ASBP (p for interaction = 0.199) or OSBP (p for interaction = 0.1713). Meta-regression using mixed effects models were used to investigate any significant interaction between trial characteristics and ambulatory systolic blood pressure effect size. There was no significant interaction between the presence of background antihypertensive medications and effect size . A sensitivity analysis using the initial 2-month off-medication results from RADIANCE was consistent with the primary analysis (see Supplementary Appendix). A full jackknife sensitivity analysis was performed by excluding each individual trial and repeating the meta-analysis for all endpoints. All results were consistent with the primary analyses (see Supplementary Appendix).4RDN successfully lowers BP when measured under blinded placebo-controlled conditions, whether BP is documented in the office or by ambulatory recording. Both SBP and DBP are significantly reduced by RDN. The effect size is completely different in magnitude to that reported in unblinded trials .Our analysis includes the longer-term follow-up of RADIANCE, as well as the full results from SPYRAL HTN OFF MED; the latter trial represents 27% of the total placebo-controlled trial data. Prior meta-analytic work has claimed that second generation catheters are effective in reducing BP, whereas first generation devices are not . Our anaEarly research in the field, reporting large office blood pressure reductions (~30 mmHg) and much smaller ambulatory blood pressure reductions ~10 mmHg), was interpreted as genuine  and evid0 mmHg, wBased on trial data of antihypertensive drugs, an effect size of 5 mmHg on OSBP persisting in the long term should confer 10% reduction in major adverse cardiac events and 7.5% reduction in all-cause mortality . It is nThis meta-analysis also indicates that the effect size of renal denervation is consistent regardless of whether it is used in patients who have not yet started medications or in patients who are already established on medications but have inadequate control. This suggests it could be used at several points within the overall strategy of hypertension management.Renal denervation seems to have a reasonable safety profile. Major adverse events were rare, and were no more common than following a placebo procedure.4.1All trials in this analysis report results between 2 and 6 months from RDN, so there is currently no bias-resistant evidence of what happens to the effect size after this. Safety events are relatively rare after RDN and therefore this analysis cannot exclude a low rate of excess events with RDN over placebo.5The totality of blinded, randomized placebo-controlled data shows RDN is safe and provides genuine reduction in BP for at least 6 months post-procedure. If this effect continues long term, RDN might provide a life-long 10% relative risk reduction in major adverse cardiac events and 7.5% relative risk reduction in all-cause mortality.Yousif Ahmad: Conceptualization, Methodology, Software, Formal analysis, Data Curation, Writing - Original Draft, Writing - Review & Editing, Visualization, Supervision.Christopher Kane: Data Curation, Investigation, Writing – Review & Editing.Ahran D Arnold: Data Curation, Investigation, Writing – Review & Editing.Christopher M Cook: Data Curation, Investigation, Writing – Review & Editing.Daniel Keene: Data Curation, Investigation, Writing – Review & Editing.Matthew Shun-Shin: Data Curation, Investigation, Writing – Review & Editing.Graham Cole: Data Curation, Investigation, Writing – Review & Editing.Rasha Al-Lamee: Data Curation, Investigation, Writing – Review & Editing.Darrel P Francis: Writing – Original Draft, Writing – Review & Editing, Supervision.James P. Howard: Conceptualization, Methodology, Software, Formal analysis, Data Curation, Writing - Original Draft, Writing - Review & Editing, Visualization, Supervision.All authors have nothing to declare.


If non-alcoholic fatty liver disease (NAFLD) frequency is very high in stroke patients, NAFLD may be a risk factor for stroke and identifying factors of NAFLD presence may lead to stroke prevention. This retrospective study aimed to investigate whether NAFLD frequency was very high and identify factors associated with NAFLD presence at acute stroke admission.We included stroke patients aged 40 − 79 years who (1) were admitted from 2016 to 2019, within 24 h of onset; (2) underwent abdominal ultrasonography; and (3) underwent blood examination of biomarkers. We evaluated the frequency and significant factors of NAFLD presence.Among 1672 stroke patients, 676 patients met our inclusion criteria, and 267 patients (39.5%) had NAFLD. Compared to patients without NAFLD, patients with NAFLD were young; had high anthropometric values; high blood pressure; low aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT) ratio; high levels of liver enzymes, serum albumin, HbA1c, and serum lipids; low-density lipoprotein; high serum level of some fatty acids; and high fatty acid% of palmitic acid (PA) and dihomo-gamma-linolenic acid (DGLA). After excluding variables with multicollinearity, independent NAFLD-presence factors were high body mass index (BMI), low AST/ALT ratio, high serum albumin level, high PA%, and high DGLA level.The frequency of NAFLD was high in our patient group. Significant NAFLD-presence factors were high BMI, low AST/ALT ratio, high serum albumin level, high PA%, and high DGLA level. A further study is warranted to determine the effects of the NAFLD-presence factors on stroke onset or prevention.The online version contains supplementary material available at 10.1007/s12072-021-10253-z. Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases. Metabolic syndrome is a strong predictor of NAFLD that frequently occurs with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension , 2. HighNAFLD may predispose one to ischemic and hemorrhagic stroke , 9. A crWe included patients with stroke who were admitted to our institution from May 2016 to July 2019. We excluded patients who (1) were younger than 40 years or older than 79 years; (2) had an onset-to-door time of > 24 h; (3) did not undergo body weight measurement; (4) did not undergo abdominal ultrasonography within 5 days of onset of symptom; (5) did not undergo blood examination for serum fatty acids at admission; or (6) had alcoholic fatty liver disease.n-9 monounsaturated fatty acids such as oleic acid; n-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid (LiA), DGLA, and arachidonic acid (AA); n-3 PUFAs such as alpha-linolenic acid (AlA), eicosapentaenoic acid, and docosahexaenoic acid; and FA%. LDL concentration was calculated using the Friedewald formula: LDL = total cholesterol − HDL – triglycerides/5. Mean blood pressure was calculated with the following formula: mean blood pressure = (SBP − DBP)/3 + DBP.We evaluated age; sex; ischemic or hemorrhagic stroke; anthropometric variables, such as body weight, body height, and BMI; variables of blood pressure such as systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure; biomarkers, such as serum glucose, HbA1c, total cholesterol, low-density lipoprotein (LDL), HDL, triglycerides, AST, ALT, AST/ALT ratio, and GGT; serum concentration of FAs such as saturated fatty acids, lauric acid, myristic acid, PA, and stearic acid; The levels of FAs in 1 mL of serum were measured at BML, Inc. . FAs were extracted using tricosanoic acid  as an internal standard. Lipid extracts were hydrolyzed, extracted with chloroform, and dried under nitrogen gas. After 30% potassium methoxide methanol solution  was added to the residual sample, it was incubated at 100 °C for 5 min, then cooled. Samples were extracted with hexane and analyzed on a GC-2010 Plus Capillary Gas Chromatograph  equipped with a flame ionization detector and a BPX70 column . Component identification was performed by comparing retention times with those of the respective standards . The serum concentrations of the FAs were determined using internal standard ratios.Fatty liver was diagnosed according to the findings of abdominal conventional B-mode ultrasonography performed by trained technicians. Of four known criteria , hepatorenal echo contrast and liver brightness were used to diagnose fatty liver , 20. In rs) was calculated to measure the strength of the relationships. We defined 0 ≤|rs|< 0.1 as no correlation, 0.1 ≤|rs|< 0.5 as weak correlation, and 0.5 ≤|rs| as strong correlation. Variable candidates for multiple logistic regression analyses were those with significant differences in the Wilcoxon rank-sum test between the two groups. We adopted the variable candidate with a smaller or the smallest probability (p) value or a larger or the largest absolute value of the Wilcoxon rank-sum test statistic (|z|) between or among variable candidates with mutually strong correlations. Multicollinearity was defined as variance inflation factor (VIF) ≥ 3. Using variables without multicollinearity, we conducted multiple logistic regression analyses to identify independent variables that distinguish NAFLD presence from NAFLD absence. We estimated the threshold values of independent variables for NAFLD presence using the area under the curve values derived from receiver operating characteristic curves of the logistic regression model. A p value < 0.05 was considered statistically significant. We used the JMP software  for all statistical analyses. One author (TM) had full access to all the data in the study and took responsibility for its integrity and the data analysis.The chi-square test was used to compare the categorical variables. We expressed non-normally distributed continuous variables as medians and interquartile ranges. The Wilcoxon rank-sum test was used to compare continuous variables in unpaired groups by normal approximation. We compared all possible pairs of variables with significant differences between patients with NAFLD (NAFLD presence group) and patients without NAFLD (NAFLD absence group). A dummy variable was used to represent categorical data, such as data on sex, and Spearman’s rank correlation coefficient , and the factors associated with NAFLD presence were high BMI, low AST/ALT ratio, high albumin level, high PA%, and high DGLA level. The NAFLD frequency was 88% in acute stroke patients with the five risk factors.In the present study, the NAFLD frequency was very high in the middle-aged and older acute stroke patients compared to the NAFLD prevalence of 26.4% in the general Japanese population . Blood pn-6 PUFA% [n-6 PUFA family. The Japanese diet successfully decreased BW, BMI, and systolic and diastolic blood pressure [In Japan, the National Health and Nutrition Survey reported that mean BMI slightly increased in men and women from 1995 to 2016 and the total energy intake and energy intake from proteins decreased, whereas energy intake from fats increased from 1995 to 2016 . Obesity-6 PUFA% . Serum Dpressure . If seruOur study had several limitations. First, a small number of patients were included, and the study was based on a retrospective cross-sectional design without control. We compared acute stroke patients with NAFLD to those without NAFLD but did not compare them with a control population. Furthermore, a cross-sectional study cannot exclude reverse causality. Second, although ultrasonography has a sensitivity of 100% in detecting > 33% of fat, ultrasonography does not always find ≤ 33% fat and cannot distinguish steatohepatitis from simple steatosis , 20, 31.In acute stroke patients aged 40 − 79 years, the NAFLD frequency of 39.5% at acute stroke admission was very high. The factors associated with NAFLD-presence were high BMI, low AST/ALT ratio, high albumin level, high PA% level, and high DGLA level. A further study is warranted to determine the effects of the NAFLD-presence factors on stroke onset or prevention.Supplementary file1 (PDF 180 KB)Below is the link to the electronic supplementary material.


Catheter ablation is an established therapy for atrial fibrillation but is limited by recurrence; efforts have been made to identify biomarkers that predict recurrence. We investigated the effect of baseline NT-proBNP on AF recurrence following catheter ablation in patients randomized to aggressive (< 120/80 mmHg) or standard blood pressure management (< 140/90 mmHg) in the Substrate Modification with Aggressive Blood Pressure Control trial (SMAC-AF).The SMAC-AF study included 173 patients resistant or intolerant to at least one class I or III antiarrhythmic drug. We studied the effect of baseline NT-proBNP on the primary outcome of AF recurrence > 3 months post-ablation.p = 0.04, adjusted HR 1.43, p = 0.03), while in the standard cohort, it did not . NT-proBNP ≥ 280 pg/mL also predicted occurrence in the aggressive  but not the standard cohort .Of the 173 patients, 88 were randomized to the aggressive cohort, and 85 into the standard group. The primary outcome occurred in 61.4% of those in the aggressive arm, versus 61.2% in the standard arm. In the aggressive group, logNT-proBNP predicted recurrence (HR 1.28, We conclude that pre-ablation NT-proBNP may be useful in predicting recurrence in hypertensive patients and identifying patients who benefit from aggressive blood control and upstream therapies.Trial registration: NCT00438113, registered February 21, 2007. Radiofrequency catheter ablation has been established as a valuable therapeutic option for atrial fibrillation (AF), although high rates of recurrence after ablation are a limitation. Factors predicting recurrence include type of AF , ejection fraction, structural heart disease and hypertension , 2. The The purpose of this study was to explore whether NT-proBNP is useful as a marker of recurrence post-ablation in hypertensive patients. NT-proBNP has not been shown to be elevated in those with hypertension without cardiac dysfunction . Furtherp ≥ 130/80 mmHg), resistant or intolerant to at least one class I or III antiarrhythmic drug, and scheduled to undergo catheter ablation, were randomized to undergo aggressive blood pressure management (target of 120/80 mmHg) or standard management (target of 140/90 mmHg), in the time leading up to ablation (0–6 months), and throughout study follow-up. The primary outcome was time to symptomatic AF, atrial tachycardia, or atrial flutter lasting more than 30 s, 3 months after ablation. The study took place from July 2011 to October 2015; the median follow-up was 14.0 months. The protocol of the original study was approved by the local ethics review board at all participating institutions  All methods were carried out in accordance with relevant guidelines and regulations.This is a secondary analysis of the SMAC-AF study, the details of which have been published previously NCT00438113). [8113. [3]All patients underwent pulmonary vein isolation with either cryoballoon therapy or radiofrequency ablation. All ablations were performed within 0–3 months of randomization. Antiarrhythmic medications were discontinued 5 half-lives prior to the ablation with the exception of amiodarone, which was discontinued for four weeks prior to ablation. Peri-procedural anticoagulation was instituted in all patients for one month prior to the procedure, and for three months post procedure. Long-term anticoagulation was left to the discretion of the investigator. Three-dimensional maps of the left atrium were constructed with the use of a nonfluoroscopic navigation system . Continuous wide-area circumferential lesions were created encircling right and left pulmonary venous ostia guided by electroanatomic mapping with an irrigated, cooled-tip radiofrequency ablation catheter with pulmonary vein isolation being the endpoint. A maximum temperature of 40 °C with maximum power of 40 W was to be delivered, except for the posterior wall, where the power was not to exceed 25 W. Lesions were complete when electrogram amplitude was reduced by ≥ 80% of baseline. Additional non-pulmonary vein ablation was left to the discretion of the operator, including complex fractional atrial electrogram ablation and additional linear ablation.NT-proBNP and C-reactive protein (CRP) levels were pre-specified in the trial protocol as a secondary outcome. The biomarker levels were measured at time of randomization, as well as 12 months after randomization, using a standard CRP and NT-proBNP assay . These assays reliably measure NT-proBNP concentrations from 0.6–4130 g/mL, and CRP concentrations between 0.3 and 350 mg/L.Baseline clinical characteristics were measured at time of randomization. Patients were seen in clinic with a 12-lead electrocardiogram at 3 months, 6 months and every 6 months thereafter for a maximum of 24 months. Recurrence of AF was documented using transtelephonic monitoring, performed routinely twice weekly for 2 weeks, then every 3 months for the duration of the study until a primary outcome was reached. The primary outcome was atrial fibrillation, atrial tachycardia or atrial flutter  lasting longer than 30 s and was adjudicated by a blinded committee.Baseline characteristics are described as mean (standard deviation) or median  for continuous variables, and count (percent) for categorical variables, where appropriate. Comparisons between groups were made using t-tests for continuous variables, and chi-square tests for categorical variables. We examined for correlation between baseline logNT-proBNP and baseline characteristics, using Pearson coefficient method for continuous variables, and chi-square for categorical variables.To investigate the effect of baseline NT-proBNP on the primary outcome, a Cox proportional hazard model was used.. A receiver operator curve was used to determine a stratification level for NT-proBNP; a cutoff of 280 pg/mL was found to have maximum area-under-curve. Kaplan–Meier product-limit estimates were used to compare those with elevated NT-proBNP (≥ 280 pg/mL) and without (< 280 pg/mL); hazard ratios were calculated using a Cox proportional model. This was repeated for those in the aggressive and standard pressure control cohorts. Adjusted analysis was performed, using baseline characteristics that were clinically relevant, including sex and age, as well as those characteristics that differed between the two groups determined by p-value of < 0.10 in univariable testing, in a multivariable Cox proportional hazard model. Change in NT-proBNP from baseline to 12 months was also tested using Cox proportional hazards modeling on the primary outcome.There were 173 patients included for analysis, 88 of whom were randomized to the aggressive cohort, and 85 to the standard group. The baseline characteristics for these patients is shown in Table p = 0.76). NT-proBNP data was available for 153 patients (88.4%). There was no difference in baseline NT-proBNP (p = 0.73), LVEF (p = 0.72), age (p = 0.70), sex (p = 0.51), AF duration (p = 0.14) or baseline systolic blood pressure (p = 0.67) between aggressive and standard groups. AF type, mean blood pressure and number of antihypertensives agents were similar at baseline. Patients in the aggressive blood pressure arm were treated for a median of 3.5 months  before ablation; the standard blood pressure arm received usual care for a similar duration . At time of ablation, patients in the aggressive arm were on more antihypertensives . At 6 months, compared to the standard cohort, the aggressive cohort had lower blood pressure .The primary outcome occurred in 61.4% of those in the aggressive arm, versus 61.2% in the standard arm (p < 0.0001), LVEF . LogNT-proBNP was higher in those with persistent AF (p = 0.0018). There was no relationship found between logNT-proBNP and pre-randomization AF duration (p = 0.43), LA size (p = 0.54), systolic blood pressure (SBP) (p = 0.17). Women had higher NT-proBNP levels: 38.8% of those with NT-proBNP ≥ 280 pg/mL were female, compared with 20.2% of those with NT-proBNP < 280 pg/mL (p = 0.01).There was a correlation between logNT-proBNP and age , while in the standard cohort, it did not . After controlling for age, sex, LVEF, baseline SBP, and AF type, logNT-proBNP was still a predictor in the aggressive group , but not in the standard group  (Table p = 0.74). The test for interaction between treatment arm and baseline logNT-proBNP on the primary outcome demonstrated a trend to statistical significance (p = 0.07).The correlation between baseline logNT-proBNP and outcomes is shown in Table p = 0.11) ; in the standard group, there was no difference   but not in the standard group .Stratifying by baseline NT-proBNP using a cutoff of 280 pg/mL, there was no difference in AF recurrence in the entire cohort , but not in the aggressive group .Decrease in logNT-proBNP at 12 months compared to baseline was associated with decreased AF recurrence in the standard group .Patients with baseline NT-proBNP ≥ 280 pg/mL had more additional (non-pulmonary vein) ablation , but not age . In the standard group, age (HR 1.03 p = 0.04) predicted outcome, but not SBP .Univariable predictors of recurrence in each group are shown in Table p = 0.77), age , LVEF , AF type , sex  and baseline systolic pressure  were not predictors. Table ,p = 0.0498) in the aggressive group, but not the standard group .In the whole study cohort, in multivariable analysis, logNT-proBNP  but not in the standard group  suggests that aggressive blood pressure control may be more beneficial in reducing AF recurrence in those with milder forms of hypertension.A “J-curve” phenomenon has been described with BP lowering, where targeting levels too low results in harm , 24. Forsk of AF . Thus, t. Another example is a recently identified measure of collagen type I cross-linking and deposition that can reflect excessive atrial myocardial interstitial fibrosis [The extent to which structural remodeling in AF is related to inflammation has been of significant interest. Elevation of CRP, interleukin-6 (IL-6), atrial and brain natriuretic peptide (ANP/NT-proBNP), and apelin in patients with AF suggests the presence of systemic inflammation in these patients; whether this is due to structural remodeling or not is unclear , 26–30. fibrosis . Alteredfibrosis . HoweverThere are some limitations to our observations. The outcome of NT-proBNP was a prespecified secondary outcome; however, since this was a secondary analysis, and we did not correct for multiple testing, the usual limitations of a secondary analysis apply. The results should be considered hypothesis-generating, however raises the issue of whether or not patients with AF and hypertension have early or subclinical heart failure, and if this contributes to their symptoms and clinical outcomes; this will require further study. Not all patients (11.6%) in the cohort had a baseline NT-proBNP checked. The relatively few number of patients who had a low NT-proBNP level prior to ablation prevented us from investigating if the randomized intervention of aggressive blood control decreased recurrence in this population.In a hypertensive population undergoing AF ablation, baseline NT-proBNP levels predict recurrence in patients receiving aggressive blood pressure control, an association not seen in those receiving standard blood pressure control. This suggests that NT-proBNP levels may be useful as a biomarker to help select a subset of hypertensive patients who would benefit from aggressive blood pressure management, or other upstream therapies to target atrial substrate, to reduce AF recurrence post-ablation.


Background: Acute kidney injury is an adverse event that carries significant morbidity among patients with acute decompensated heart failure (ADHF). We planned to develop a parsimonious model that is simple enough to use in clinical practice to predict the risk of acute kidney injury (AKI) occurrence.Methods: Six hundred and fifty patients with ADHF were enrolled in this study. Data for each patient were collected from medical records. We took three different approaches of variable selection to derive four multivariable logistic regression model. We selected six candidate predictors that led to a relatively stable outcome in different models to derive the final prediction model. The prediction model was verified through the use of the C-Statistics and calibration curve.Results: Acute kidney injury occurred in 42.8% of the patients. Advanced age, diabetes, previous renal dysfunction, high baseline creatinine, high B-type natriuretic peptide, and hypoalbuminemia were the strongest predictors for AKI. The prediction model showed moderate discrimination C-Statistics: 0.766  and good identical calibration.Conclusion: In this study, we developed a prediction model and nomogram to estimate the risk of AKI among patients with ADHF. It may help clinical physicians detect AKI and manage it promptly. Acute kidney injury is a complex systemic syndrome associated with high morbidity and mortality. In patients with acute decompensated heart failure (ADHF), the incidence and impact of acute kidney injury (AKI) have been reported mainly in subjects hospitalized with acute HF (AHF), in which the prevalence of AKI is about 20% . In patiEarly detection of patients at higher risk for AKI occurrence would help physicians to plan and initiate appropriate managements to improve the renal safety of therapies, augment surveillance of cardiac and renal dysfunction, and develop renal-preserving treatments. A substantial proportion of cases of AKI are thought to be preventable with early treatment , 5.Many studies have revealed the mechanism of AKI in patients with heart failure through common hemodynamic, neurohormonal, and immunological and biochemical feedback pathways –8. An evThe methods described in this article are in accordance with the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) statement .This study was approved by the ethics committee of the Aerospace Center Hospital, Beijing, China; written informed consent was waived owing to the use of anonymous retrospective data. Data for each patient were collected from the medical records. A team of experienced cardiology clinicians reviewed and cross-checked the data. Each record was checked independently by two clinicians.A total of 1,081 patients diagnosed with ADHF who were admitted to Aerospace Center Hospital  from January 2017 to December 2019 were retrospectively recruited. ADHF was diagnosed based on the European Society of Cardiology guidelines .We excluded patients who met the following exclusion criteria: chronic kidney disease requiring regular dialysis, <18 years old, pregnant women, dementia, psychosis, length of stay <2 days, underwent surgery, and injection contrast agent in hospital. When there were two or more admissions for the same patient, only the most recent was considered. Electronic medical records were then screened, and patients were excluded if critical data for the diagnosis of AKI (such as serum creatinine levels and urine output) were missing .Consistent data for each patient were collected from the medical records. All candidate predictors were selected based on detailed literature reviews and clinical evidence within the confines of data availability .Potential predictive variables included the following patient characteristics at hospital admission: clinical signs and symptoms, imaging results, laboratory findings, demographic variables, medical history, and treatment. Demographic variables collected for the study included sex, age, height, and weight. Medical history included diabetes, hypertension, coronary artery disease, previous heart failure, atrial fibrillation, previous renal dysfunction, cerebral infarction, cancer, and cirrhosis. Clinical signs and symptoms included categorical and continuous variables: New York Heart Association (NYHA) functional class, heart rate, systolic blood pressure, diastolic blood pressure, rales (>1/2 lung fields), jugular venous distension, and peripheral edema. Imaging results included left ventricular ejection fraction (LVEF) by two-dimensional transthoracic echocardiography. Laboratory findings included B-type natriuretic peptide, hemoglobin, hematocrit, C-reactive protein, alanine aminotransferase, total bilirubin, blood urea nitrogen, creatinine, albumin, serum sodium, serum potassium, uric acid, and glucose. We recorded the baselines of these tests with the first value being within 2 days of onset admission. Treatment included aldosterone antagonists, loop diuretic, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-Is/ARBs), beta-blockers, anticoagulants, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), vasopressor use, intra-aortic balloon pump (IABP), and mechanical ventilator. These detailed and specific definitions are listed in The outcome was the occurrence of AKI during the hospital stay of the patients, according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines . Any patWe originally considered events per variables (EPV) ratio between 5 and 10 acceptable, with EPV of 10 as the optimal number to minimize overfitting of the regression model. According to this rule, we needed 60 ADHF inpatient AKI occurrence to evaluate six candidate predictors. Assuming that the prevalence of acute kidney injury was 20% among patients with ADHF , a totalBefore data analysis, predictor variables were inspected for missing values. Among the predictors, the proportion of missing data was 0.3–6 %. To include these data from the analyses, we imputed missing data by multiple imputations by chained equations, using the mice package for R, in which predictive mean matching is embedded with the cases (k) = 5 default. Baseline clinical characteristics before and after imputation are listed in t-tests when the data were normally distributed; otherwise, the Mann–Whitney U test was performed. Proportions for categorical variables were compared by the χ2 test, although the Fisher exact probability test was performed when the data were limited. The significance level of the above statistical analyses was set as α = 0.05, and P < 0.05 (two-tailed) was considered statistically significant.Data are presented as frequencies (percentages) for categorical variables and mean (standard deviation) or medians (interquartile ranges [IQRs]) for continuous variables. Means for continuous variables were compared by Different models will be constructed based on different variables. Some variables, which may be closely related to the true world, will lead to a relatively stable outcome even in different models , 27. To If the relationship between the variable and the outcome is not linear, the variable can be transformed with the MFP model . LASSO rThe analysis results and clinical reasons, sample size, and statistical power should be considered at the same time. We evaluated the C-Statistics and calibration curve of each model, evaluated the variables of the four models, and selected six most stable predictors based on their clinical significance .Finally, we selected six candidate predictors to derive the prediction model, and built a nomogram based on the results of a logistic regression model. If the relationship between the variable and the outcome is not linear, the variable can be transformed by the MFP model. We evaluated the C-Statistics of the two models.We carried out internal validation of the model development process using a bootstrap resampling process (500 bootstrap samples per model) to provide an unbiased estimate of model performance . Then, tP value of < 0.05 to be statistically significant. If there is an interaction between sex or age and creatinine, we divided the cohort into two subgroups based on sex and age (threshold of 65 years) to investigate whether the prediction model performed equally well.Given the heterogeneity of sex and age, to investigate whether the predictive strength of nomogram would change by sex or age, we investigated the interaction between creatinine and sex or age with the Wald test. We considered a two-sided http://www.r-project.org; version 3.4.3) and Empower (R) .Data were analyzed with the use of the statistical packages R . In total, 650 patients with ADHF were enrolled in this study, and 278 had AKI, meaning that the incidence of AKI was 42.8%. With the mean age of 74.8 years, 298 (45.8%) of the patients were male. Compared with non-AKI patients, patients with AKI were significantly older .Based on LASSO analysis , we idenWe evaluated the C-Statistics  and a caWe selected the six most stable candidate predictors to derive the prediction model, and built a nomogram based on the results of a logistic regression model .A risk score was calculated for each patient using a formula derived from the expression levels of the six variables weighted by their regression coefficients: Risk score = −3.02492 + 0.04100 × age (years) + 0.48031 × (diabetes = 1) + 0.69499 ×  + 0.00851 × creatinine (μmol/L) + 0.00026 × B-type natriuretic peptide (pg/ml) −0.056 × albumin (g/L).As the relationship between four variable and the outcome is not linear, the variable was transformed by the MFP . We found that two models had similar prediction performance in terms of C-Statistics , so we finally selected the prediction model for validation, taking into consideration the clinical significance, in which there is no need for variable divided by 100 or 1,000.The bootstrap method showed a moderate discriminative ability of prediction model . We found the interaction between age (threshold of 65 years) and creatinine . Given the heterogeneity of age, we divided the cohort into two subgroups (122 younger and 528 older patients) based on the age threshold of 65 years to investigate whether the prediction model performed equally well in the older and younger patients. The discrimination of the prediction model was consistent for the younger subgroup  and the older subgroup . The calibration curve indicated that the prediction model was similar calibrated in subgroups (We did not find the interaction between sex and creatinine (ubgroups .The point in Heart and kidney interactions are complex and a subject of immense clinical and scientific interest and debate. The coexistence of acute cardiac and renal dysfunction, termed as acute cardiorenal syndrome, has been shown to correlate with increased mortality and all manners of adverse outcomes . CurrentBased on different regressions, we found six most stable risk factors of AKI occurrence in this retrospective study, namely, advanced age, diabetes, previous renal dysfunction, high baseline creatinine, high B-type natriuretic peptide, and hypoalbuminemia. Some established risk factors are advanced age, chronic heart disease, and previous renal dysfunction . AdvanceThe discussion on variable screening has been going on for a long time. We found out the most stable factor for the outcome from results based on C-Statistics and plotted the calibration curve of four models by three different approaches. The analysis results and clinical reasons, sample size, and statistical power were considered at the same time. A prediction model is constructed with traditional clinical features and laboratory test results. The predictive variables in the nomogram model are convenient for clinical acquisition, and the construction of these models is feasible. These parsimonious models will be sufficiently stable for application . SometimIn addition to these findings, some limitations to our study should be addressed. First, this is an observational study that cannot directly draw causal conclusions. Second, this study excluded patients of injection contrast agent and surgery, so this population could not be extrapolated. Third, some pieces of information, such as a history of myocardial infarction and etiology of heart failure, were not inputted into the analysis, and this may need to be investigated in future research. Finally, as this study was based on a single center in China, it will inevitably have sample selection bias. We lack external validation of the study. As such, prospective validation to examine model stability, reproducibility, and external validity in independent samples is needed.Acute kidney injury is an adverse event that carries significant morbidity among patients with ADHF. Currently, there is no effective practical tool for estimating the likelihood of AKI occurrence after ADHF. In this study, we developed a risk score and nomogram to estimate the risk of AKI among patients with ADHF. It may help clinical physicians detect AKI and manage it promptly.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by 航天中心医院医学伦理委员会. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Y-TZ and LW made contributions to data collection, drafted the manuscript, and analysis and interpretation of the data. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Supplemental Digital Content is available in the text. Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% , with similar estimates obtained for coronary artery disease  and stroke . Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD. For the patients with elevated cardiovascular risk recruited to the SPRINT , SBP lowering to <120 mm Hg as compared with 140 mm Hg resulted in fewer major cardiovascular events.11 However, no high-quality clinical trials have investigated the effect of blood pressure lowering below this level. Excessive blood pressure reduction in patients with atherosclerotic disease can reduce organ perfusion and increase CVD risk.12 Insight into the shape of the relationship between blood pressure and CVD risk is, therefore, critical for informing optimal prevention strategies.Large observational studies have previously explored the relationship between blood pressure and cardiovascular risk, potentially identifying linear associations in individuals free of CVD at baseline13 In the same way as treatment allocation in a randomized controlled trial setting, random allocation of genetic variants means that they are unlikely to be affected by confounding from environmental factors.14 Recent methodological developments have allowed for MR investigation into the shape of the relationship between risk factors and outcomes.17 In this study, we use MR to investigate the shape of the relationship between genetically proxied blood pressure and incident CVD in a general population without a history of CVD or antihypertensive medication use. Our analyses aim to provide novel insight that can be used to inform public health strategies toward the primary prevention of CVD.In the Mendelian randomization (MR) paradigm, genetic variants can be used as proxies for studying the effect of varying blood pressure.Data Supplement. All results from the analyses performed in this work are presented in the main article or its Data Supplement. This article has been reported based on recommendations by the STROBE-MR Guidelines (Checklist in the Data Supplement).18 The study protocol and details were not preregistered.All data supporting the findings of this study are available from the corresponding author upon reasonable request. The UK Biobank study was approved by the North West Multicentre Research Ethics Committee, and all participants provided informed consent. All variants used as instruments in this study and their genetic association estimates are provided in the 19The UK Biobank cohort is comprised of ≈500 000 people (94% of self-reported European ancestry) aged 40 to 69 years at baseline and recruited between 2006 and 2010 at 22 assessment centers throughout the United Kingdom. Participants were followed up until January 1, 2018, or their date of death. Along with genotyping, the resource has information on clinical measurements, assays of biological samples, and self-reported health behavior. Moreover, it is supplemented by linkage with electronic health records including hospital inpatient data, mortality data, and cancer registries.For the exposures of interest, SBP and diastolic blood pressure (DBP), data were collected using an automated reading when participants attended the assessment center for baseline measurements (UK Biobank fields 4080 for SBP and 4079 for DBP). When multiple baseline measurements were available, the mean of the measured values was used.InternationalClassification of Diseases, Tenth Revision, and Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures (fourth revision) codes to identify events (Table S1 in the Data Supplement). For individuals with multiple incident events , the first event recorded was used. Related individuals  and those with prevalent CVD  were excluded from the analyses. Individuals taking antihypertensive medications at baseline (UK Biobank field 20003) were also excluded from the analyses because their observed blood pressure is not reflective of their genetically predicted blood pressure, thus introducing bias into the nonlinear MR estimates.17As our primary outcomes, we selected a combined incident cardiovascular end point of CAD and stroke (referred to hereafter as CVD), incident CAD, and incident stroke. We used hospitalization-based 2<0.1) single-nucleotide polymorphisms as candidate instrumental variables for SBP and DBP based on their previously published associations with blood pressure traits.20 Their associations with SBP and DBP were estimated in a genome-wide association study of 299 024 European ancestry individuals performed by the International Consortium of Blood Pressure study, which did not include UK Biobank participants.20 Using the coefficients for association with SBP and DBP (Table S2), a weighted allele score for each participant was created by multiplying the blood pressure–increasing allele dosage with the variant’s association with SBP or DBP, respectively, and summing across the 253 variants. The above genetic association estimates were taken from a study that adjusted for body mass index. As this could theoretically bias the analyses,21 we further performed a sensitivity analysis that selected variants from a genome-wide association study meta-analysis of 2 non-UK Biobank cohorts that did not adjust for body mass index . Fixed-effects meta-analysis was performed using METAL,22 and variants reaching genome-wide significance (P<5×10−8) were clumped to correlation r2<0.01 using PLINK.23 We extracted 22 uncorrelated variants as instrumental variables for SBP and 27 uncorrelated variants as instrumental variables for DBP in this sensitivity analysis (Tables S3 and S4).For our primary analysis, we selected 253 uncorrelated  and incident CVD, CAD, and stroke risk. Analyses were performed by modeling a linear relationship between genetically proxied blood pressure and the outcomes (linear MR)24 and also using the fractional polynomial method to test for a nonlinear relationship between genetically proxied blood pressure and the outcomes (nonlinear MR).17All statistical analyses were performed using R (version 3.6.2). Differences in characteristics between UK Biobank population subgroups were assessed using a Student 25 This represents the association of the allele score with the cardiovascular outcome  divided by the association of the allele score with the blood pressure trait (either SBP or DBP).26 Linear regression was used to estimate the association of the allele score with blood pressure, incorporating age, sex, principal components 1 to 10 of genetic ancestry, genotyping chip, and assessment center as covariates. The proportion of blood pressure variance explained by the allele score and its F statistic were calculated to estimate instrument strength.27 Cox proportional hazard regression was used to estimate the association of the allele score with the outcomes, incorporating age, sex, principal components 1 to 10 of genetic ancestry, genotyping chip, and assessment center as covariates. As sensitivity analyses, we considered each variant in the allele score separately and performed MR methods that differ in their requisite assumptions regarding the inclusion of pleiotropic variants: random-effects inverse-variance weighted MR, MR-Egger, weighted median MR, and MR-PRESSO.28 An intercept term in MR-Egger differing from zero can be used to evidence the presence of directional pleiotropy,29 and MR-PRESSO is able to identify variants with outlying estimates that may in turn be excluded from analyses.30We used the ratio of coefficients method to perform MR analyses that assumed a linear association of genetically proxied blood pressure with the risk of incident CVD, CAD, and stroke.17 and is outlined in Methods in the Data Supplement. Briefly, we stratified the population into centiles based on residual blood pressure, defined as a participant’s blood pressure minus the genetic contribution to blood pressure from the allele score. By doing this, we aimed to compare individuals in the population who would have similar blood pressure values  if they had the same genetic predisposition. Stratifying on blood pressure directly would introduce collider bias to distort estimates, as blood pressure is on the causal pathway from the genetic variants to CVD.31 For each centile, we calculated a linear MR estimate for the association of genetically proxied blood pressure with the outcome using the ratio of coefficients method, as described above.26 Using a flexible semiparametric framework, we then performed a meta-regression of the linear MR estimates obtained for each centile against the mean blood pressure in that centile.17 A fractional polynomial test was used to investigate whether a nonlinear model fit this meta-regression better than a linear model (further detailed in Methods in the Data Supplement). A Bonferroni correction was applied to account for multiple testing of the 2 blood pressure traits and 3 outcomes, with P<8×10−3 representing statistical significance. We further conducted a priori–specified subgroup analyses considering men and women separately to investigate potential sex-specific effects.We applied the fractional polynomial method to investigate for evidence of a nonlinear relationship between genetically proxied blood pressure and risk of incident CVD, CAD, and stroke. This approach has been described previously in detailData Supplement.Individuals with elevated blood pressure are more likely to be prescribed antihypertensive medications, and, therefore, exclusion of these individuals from the main analysis could potentially distort MR estimates due to selection effects and introduction of collider bias. Inverse probability weighting was, therefore, performed in a sensitivity analysis to investigate this, as described in Methods in the International Classification of Diseases, Tenth Revision, based) and 2176 incident stroke events. The allele score explained 4.8% and 4.5% of the variance for SBP and DBP, respectively, corresponding to F statistics of 58.6 and 54.1 and low risk of substantial weak instrument bias. The distribution of CVD risk factors for individuals in the analyzed population that had a weighted allele score for SBP and DBP above and below the population median in the main and sensitivity analyses is provided in Table A total of 255 714 participants were included in analyses, after excluding 66 011 individuals with a history of antihypertensive medication use and 6506 individuals with a history of CVD (but not on antihypertensive medications). There were 10 606 incident CVD events, including 8430 incident CAD events (68.1% P=7×10−25), incident CAD was 1.50 , and incident stroke was 1.44 . For a 5-mm Hg increase in genetically proxied DBP, the HR of incident CVD was 1.35 , incident CAD was 1.36 , and incident stroke was 1.39 . The MR-Egger test did not detect significant directional pleiotropy (Table S6), and MR-PRESSO only identified 16 single-nucleotide polymorphisms as outliers in the analysis of genetically proxied SBP and CAD (Table S2). Similar MR estimates were obtained in sensitivity analyses .Linear MR analyses identified a strong association of both genetically proxied SBP and DBP with the cardiovascular outcomes. For a 10-mm Hg increase in genetically proxied SBP, the hazard ratio (HR) of incident CVD was 1.49  pathways—an assumption that cannot be tested and if violated could introduce bias to the obtained estimates. Our used MR method also explores the effects of lifelong changes in blood pressure, and its estimates should, therefore, not be extrapolated to quantify the effect of blood pressure modification in adult life, such as through use of antihypertensive medications. Finally, there were differences in the distribution of risk factors between individuals in the highest and lowest deciles of residual blood pressure (Table S5), suggesting that this MR analysis may still be vulnerable to environmental confounding.Our study also has limitations. This work only considered participants without a history of CVD or antihypertensive medication use, and its findings should not be extrapolated to populations with established CVD.For a population without a history of CVD or antihypertensive medication use, genetically proxied blood pressure reduction was associated with lower CVD risk at all levels of blood pressure. These findings provide evidence to support that public health interventions achieving persistent, population-wide blood pressure reduction will be of considerable benefit in the primary prevention of CVD.https://www.ukbiobank.ac.uk/register-apply. The Trøndelag Health Study is a collaboration between the HUNT Research Centre , Nord-Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotype quality control and imputation in HUNT has been conducted by the K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology. D. Gill, R. Malik, M. Vujkovic, S. Burgess, and M.K. Georgakis designed the study. R. Malik, M. Vujkovic, J.N. Hellwege, M.M. Shuey, T.L. Edwards, B.M. Brumpton, T. Rogne, C. Fava, and A. Giontella analyzed the data. R. Malik, D. Gill, J.N. Hellwege, B.M. Brumpton, and M.K. Georgakis drafted the manuscript. All authors interpreted the results and critically revised the manuscript for intellectual content.This research has been conducted using the UK Biobank Resource (UK Biobank application No. 2532). The UK Biobank data are available on application at https://victr.vumc.org/biovu-funding/. The genotyping in HUNT was financed by the NIH, University of Michigan, the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway, and the Joint Research Committee between St. Olav’s Hospital and the Faculty of Medicine and Health Sciences, NTNU.This work was supported by the UK National Institute for Health Research Cambridge Biomedical Research Centre. M.K. Georgakis is funded by a scholarship from the Onassis Foundation. S.M. Damrauer was supported by the Department of Veterans Affairs Office of Research and Development (IK2-CX001780). P. Elliott acknowledges support from the British Heart Foundation (RE/18/4/34215), the Medical Research Council (MR/S019669/1), the National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London (RDF03), the UK Dementia Research Institute (DRI) at Imperial College London funded by UK DRI, Ltd , and Health Data Research (HDR) UK London funded by HDR UK, Ltd . J.N. Hellwege is supported by K12 HD04348. M.M. Shuey is funded by the National Institutes of Health (DK108444). S. Burgess is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). M. Dichgans acknowledges funding from the European Union Horizon 2020 research and innovation programme (666881), SVDs@target (667375), CoSTREAM, SyNergy , the CRC 1123 (B3 and project DI 722/13-1), the Corona Foundation, the LMUexcellent Fond, the e:Med program (e:AtheroSysMed), and the FP7/2007-2103 European Union project CVgenes@target . D. Gill is supported by the Wellcome Trust 4i Programme (203928/Z/16/Z) and British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London, and a National Institute for Health Research Clinical Lectureship at St. George’s, University of London (CL-2020-16-001). The BioVU dataset used for the analyses described was obtained from the Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the National Institutes of Health (NIH)–funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711 and additional funding sources listed at D. Gill is employed part-time by Novo Nordisk and has received consultancy fees from Abbott Laboratories. S.M. Damrauer has received grants from the US Department of Veterans Affairs, Calico Labs, and Renalytix AI plc outside the submitted work. The other authors report no conflicts.