It is well established that decreased kidney function can increase blood pressure (BP), but it is unproven whether moderately elevated BP causes chronic kidney disease (CKD) or glomerular hyperfiltration.2, or urinary albumin:creatinine ratio ≥3 mg/mmol) associated with higher genetically predicted BP using genetic risk scores comprising 219 systolic and 223 diastolic BP loci. Analyses estimating associations with clinical categories of eGFR and urinary albumin:creatinine ratio were also conducted, with an eGFR ≥120 mL (min·1.73m2) considered evidence of glomerular hyperfiltration.311 119 White British UK Biobank participants were included in logistic regression analyses to estimate the odds of CKD  and 19% (1.14–1.25) higher odds of CKD, respectively. Associations were evident for both the reduced eGFR and albuminuria components of the CKD outcome. The odds of hyperfiltration  for each genetically predicted 10 mmHg higher systolic BP. Associations with CKD and hyperfiltration were similar irrespective of preexisting diabetes, vascular disease, or different levels of adiposity.21 623 participants had CKD: 7781 with reduced eGFR and 15 500 with albuminuria. 1828 participants had an eGFR ≥120 mL/min/1.73mIn this general population, genetic epidemiological evidence supports a causal role of life-long differences in BP for decreased kidney function, glomerular hyperfiltration, and albuminuria. Physiological autoregulation may not afford complete renal protection against the moderate BP elevations. Previously genetic studies using UK Biobank data have not identified significant associations between genetically predicted blood pressure and estimated glomerular filtration rate. However, once nonlinear nature of associations is taken into account, life-long moderate differences in genetically predicted systolic blood pressure associate with higher risk of both chronic kidney disease , and also with glomerular hyperfiltration . These associations are similar in size in people with or without diabetes, obesity, or vascular disease.Accelerated-phase hypertension is a recognized cause of chronic kidney disease and acute kidney injury, but renal blood flow autoregulation is considered to protect kidneys from moderate hypertension. The presented findings challenge this notion and strengthen claims for a causal link between life-long moderately elevated blood pressure and risk of developing chronic kidney disease.Renal blood flow autoregulation may not fully protect kidneys from the effects of moderately elevated systolic blood pressure even in apparently healthy adults. Considering early active management of moderate systolic hypertension in all adults could help reduce individuals’ risk of developing chronic kidney disease in later life.1 and risk of developing end-stage kidney disease (known as kidney failure).3 The associations are apparent even among those with only moderate elevations in systolic BP to high-normal levels .3 However, no clear overall benefit on kidney outcomes emerged from meta-analyses of intensive versus standard BP lowering trials which tested an average BP difference of about 7 mmHg (down to on average about 130 mmHg),5 raising doubts about whether moderate elevations in BP (in the absence of accelerated-phase hypertension) are an important cause of CKD.Conventional observational analyses find higher blood pressure (BP) is associated with chronic kidney disease (CKD) progression2682–2684See editorial, pp 7 resulting in spuriously strong BP-CKD observational associations. A second potential explanation is that intensive BP lowering trials may not have been large or long enough to confirm modest benefits of the achieved BP differences on CKD progression risk.8 Thirdly, it has been suggested that moderate elevations of BP may only cause CKD in individuals with certain comorbid diseases. For example, in healthy individuals, physiological autoregulation of renal blood flow at the glomerular afferent arteriole is considered to protect the kidneys from moderate fluctuations in BP by maintaining a steady filtration pressure,10 whereas dysregulated renal blood flow homeostasis which predisposes to the development of glomerular hyperfiltration—has been described in people with preexisting diabetes, vascular disease,11 and obesity.12 Post hoc subgroup analyses of intensive BP lowering trials are consistent with such a concept, having hypothesized that benefits of intensive BP lowering may be evident in people with preexisting proteinuria (a marker of dysregulated glomerular function), but not in those without.13One potential explanation for the apparent discrepancy between findings from conventional cohorts versus randomized trials is reverse causality. Early kidney disease may be undetected and increase BP14 This Mendelian Randomization (MR) approach,16 has been used to show that moderate life-long genetically predicted differences in BP are associated with risk of myocardial infarction and stroke,18 replicating the well-established causal relationships confirmed by randomized trials of antihypertensive drugs.5 MR has a particular advantage in renal epidemiology as it may help to determine whether the relationship between BP and CKD is bidirectional.19 MR evidence supports the existence of causal associations between decreased kidney function and hypertension,7 and conversely, between moderate elevations in BP and risk of albuminuria.20 However, the largest MR studies have found no evidence of association between genetically predicted higher BP and decreased kidney function in adulthood.17Genetic variants are allocated randomly at conception and can be used to proxy an exposure, such as BP, in observational epidemiological analyses, thereby avoiding some of the limitations in conventional observational analyses, such as uncontrolled confounding and reverse causality.21 However, these MR studies did not consider that the shape of any associations may be nonlinear.17 The natural time course of CKD may start with an abnormal increase in kidney function before a subsequent decline in kidney function. Consequently, if genetically predicted BP-eGFR associations are U-shaped , analyses using eGFR as a continuous outcome may miss important associations. We aimed to address this deficiency by performing analyses using outcomes based on a categorical definition of CKD used in previously published MR studies , or urinary albumin:creatinine ratio [uACR] ≥3 mg/mmol),22 and secondarily, using separate clinical categories of eGFR and albuminuria, with an eGFR ≥120 mL (mL/min/1.73m2) considered evidence of glomerular hyperfiltration.Previously published MR experiments using UK Biobank data have not identified significant associations between genetically predicted BP and estimated glomerular filtration rate (eGFR).http://www.ukbiobank.ac.uk) in accordance with their published data access procedures. Summary data from various genetic consortia as referenced are publically available. All other data are within the article and its Supplemental Material.Data supporting this article are available from UK Biobank . The following exclusions were used for all analyses: those who withdrew their data (n=157); those with missing genotype data (n=15 546); those with missing values of BP, age, sex, body mass index (BMI), uACR, or eGFR (n=38 385); non-White British participants (n=71 281) and related individuals (n=65 940).UK Biobank is a large prospective cohort study of 502 650 middle-aged adults aged 40 to 69 years recruited between 2006 and 2010 in 22 assessment centers across the United Kingdom. Data include self-completed touch-screen questionnaires, computer-assisted interviews, physical and functional measurements, biochemical assays, and genome-wide genotyping.18).Measured BP was calculated as the mean of the 2 measurements taken at recruitment. Participants on antihypertensive medications at recruitment had 15 and 10 mmHg added to the measured systolic BP and diastolic BP values, respectively  and a different 223 SNPs (explaining 2.1% of the diastolic BP variance) were selected for respective genetic scores (Tables S1 and S2). Separate genetic risk scores (GRSs) for systolic and diastolic BP were calculated for each participant, based on the weighted sum of the SNP dosages .18For genetic analyses, instruments for systolic and diastolic BP and the associated weights were identified from a published genome-wide association studies which combined data from multiple studies, including UK Biobank.24 calculated from both serum cystatin C and creatinine (eGFRcys-cr) <60 mL (mL/min/1.73m2), or spot uACR ≥3 mg/mmol. Since the composite outcome contains very different clinical outcomes and because the relationship between kidney disease and GFR is nonlinear in the early stages, in secondary analyses, eGFR- and uACR-based outcomes were analyzed separately based on clinical cutoffs.25 For eGFR these were: on long-term kidney replacement therapy or eGFR <45; ≥45,<60; ≥60,<90; ≥90,<120, and ≥120 mL (mL/min/1.73m2), with an eGFR ≥120 mL (mL/min/1.73m2) considered evidence of glomerular hyperfiltration. For uACR, these were: <3; ≥3,<30; and ≥30 mg/mmol. Lastly, analyses on the effect of hospitalization for acute kidney injury (AKI) reported after recruitment were also performed using the International Classification of Diseases, Tenth Revision code N17  from any diagnostic position in linked hospital admission records.The primary outcome (referred to as CKD) was a composite defined as long-term kidney replacement therapy, or the 2009 CKD epidemiology collaboration eGFR2 sex, BMI , top 18 principal components and the array used. For secondary analyses, multinomial logistic regression was used to estimate associations between genetically predicted 10 mmHg higher systolic BP and 5 mmHg higher diastolic BP and odds of each eGFR category versus eGFR ≥60 to <90 mL (mL/min/1.73m2) .Baseline characteristics (including measured BP) by fifths of each BP GRS are presented. The associations between genetically predicted 10 mmHg higher systolic BP and 5 mmHg higher diastolic BP and the primary outcome of CKD (and separately AKI) were estimated using logistic regression with adjustment for age, age,27 and the GIANT (Genetic Investigation of Anthropometric Trait) consortium meta-analysis,28 respectively. For the AKI outcome, analyses additionally adjusted for baseline eGFR and number of hospitalizations were also performed.MR was also performed with further adjustment for the genetic effects of the BP-related SNPs on type 2 diabetes, BMI, and waist-to-hip ratio (WHR), to assess the direct effects of the BP GRSs on kidney outcomes . Weights for these genetic effects were taken from publicly available summary data based on individuals of European ancestry in the DIAGRAM  consortium,12 Stratifying on these characteristics could introduce collider bias if the characteristics are on the causal pathway between the GRS and kidney outcomes. Therefore, sensitivity analyses were conducted stratifying by residual characteristics, defined as the participant’s value of the characteristic minus the genetic contribution to the characteristic from the BP GRS.29Genetic analyses stratified by age, sex, history of diabetes, history of vascular disease, and BMI and WHR (with an interaction term fitted between the BP GRS and the relevant characteristic) explored whether BP associations with CKD, glomerular hyperfiltration, and AKI varied by characteristics which may predispose to dysregulated renal blood flow homeostasis.30 SNPs were excluded if they were in (or close to) genes with differential expression in the kidney  or have been previously linked to the renin-angiotensin system, TGF (transforming growth factor)-beta, and its signaling pathways, or disordered kidney development/ morphology/ physiology.37 SNPs that explained more variation in kidney function than BP when applying Steiger filtering38 were also excluded. See Table S1 for the lists of SNPs excluded in this sensitivity analysis.Analyses excluding SNPs that could potentially have direct effects on the kidney not mediated through BP were also performed.39 MR-Egger provides a robust estimate of the association in the presence of directional pleiotropy (assuming the pleiotropic effects are independent of instrument strength),40 while the weighted median approach gives a robust estimate as long as at least 50% of the weight in the analyses comes from variants with no pleiotropic effects.41 Approaches that remove variants with heterogeneous estimates  were also applied, with outliers identified using a modified Q statistic42 or MR-PRESSO .43The robustness of the MR results to violations of the instrumental variable assumptions, particularly the assumption of no pleiotropic effects, were also explored using standard approaches based on summary data.Conventional cross-sectional observational associations using measured BP were also estimated to compare with the genetic associations. Potential confounders were identified at baseline and based on the assumed pathways between BP and CKD (the primary outcome) and included age; sex; region; education ; Townsend index of social deprivation (fifths); smoking (current smoker versus not); alcohol use ; physical activity ; history of diabetes , and body mass index (BMI [fifths]).44 to account for any measurement error and short-term variability in BP .For the conventional cross-sectional observational analyses, binary and multinomial logistic regression adjusted for the potential confounders listed above were used . These models included a standard adjustment for regression-dilution biasAnalyses were performed in SAS version 9.4  and R v3.6.2.2. 16 282 (5.2%) and 18 168 (5.8%) reported a history of preexisting diabetes or vascular disease, respectively (Table), with 71 784 (23.1%) prescribed antihypertensive medication. Mean (standard deviation) systolic BP was 141.7 (20.6), and diastolic BP was 84.6 (11.2) mmHg.Among the 311 119 participants included in analyses, mean (standard deviation) age was 57 (8) years, 144 667 (46%) were men, and mean (standard deviation) BMI was 27.4 (4.7) kg/mFigure S2).For the systolic BP GRS, the difference in mean systolic and diastolic BP between top and bottom fifths of the GRS were 7.7 and 3.5 mmHg , respectively. For the diastolic BP GRS, the difference in mean systolic and diastolic BP between top and bottom fifth of the GRS was 6.5 and 5.1 mmHg , respectively  for the top fifth of the systolic BP GRS versus 3270 (5.3%) for the bottom fifth: difference 1.2%. There was also a higher prevalence of diabetes among those with higher genetically predicted BP, with a larger association for the systolic BP GRS than the diastolic BP GRS .Table S3). Each genetically predicted 10 mmHg higher systolic BP and 5 mmHg higher diastolic BP was associated with a 37%  higher odds of CKD, respectively .21 623 participants had evidence of CKD at recruitment: 7781 (2.5%) with reduced glomerular filtration and 15 500 (5.0%) with albuminuria .Sensitivity analyses showed that adjustment for the effects of the BP SNPs on type 2 diabetes, BMI, and WHR only modestly attenuated the odds ratio for genetically predicted 10 mmHg higher systolic BP to 1.30 . The odds ratio for genetically predicted 5 mmHg higher diastolic BP was essentially unchanged by such adjustments . Results were also unaffected by removing 19 SNPs associated with diabetes (data not shown). Sensitivity analyses performed using 2-sample summary data approaches were consistent with the MR analyses presented in Figure Figure S6). For systolic BP, the intercept from the MR-Egger analyses suggested the potential presence of some directional pleiotropy  albeit the bias-adjusted effect estimate remained significant, with each genetically predicted 10 mmHg higher systolic BP still associated with 20% higher odds of CKD (1.20 [1.05–1.37]).After excluding 90 SNPs from systolic BP GRS and 67 SNPs from diastolic BP GRS that explain more variation in kidney function than BP, or in genes with differential expression in the kidney, or associated with the renin-angiotensin-aldosterone system or disordered kidney development/morphology/physiology, the association between BP and risk of CKD was, if anything, somewhat stronger (2]) versus normal kidney function and with the odds of having an eGFR ≥90 mL (mL/min/1.73m2) versus normal kidney function ; each 10 mmHg higher systolic BP was associated with a 49% higher odds of hyperfiltration versus normal kidney function  and was at least as large among those without diabetes or without vascular disease . BP-hyperfiltration associations were absent in people with diabetes, but such analyses were based on only 129 participants with hyperfiltration.The positive systolic BP-hyperfiltration association was attenuated but still present after adjustment for the effects of the BP SNPs on type 2 diabetes, BMI, and WHR  with the results in Figure Figure S6).After excluding 90 SNPs from systolic BP GRS and 67 SNPs from diastolic BP GRS that explain more variation in kidney function than BP, or in genes with differential expression in the kidney, or associated with renin-angiotensin-aldosterone system or disordered kidney development/morphology/physiology, the association between systolic BP and hyperfiltration was consistent .For the albuminuria-based outcomes, an exposure-response relationship was apparent with both higher genetically predicted systolic and diastolic BP associated with evidence of increasing odds of higher albuminuria categories Figure . This reFigure S9). Associations were similar irrespective of baseline eGFR category (trend test p =0.14), and the other subgroups . There was no association between genetically predicted diastolic BP and odds of AKI (1.01 [0.94–1.09]).10 122 (3.3%) participants had a record of hospitalization with AKI. Each genetically predicted 10 mmHg higher systolic BP was associated with a 15% (1.15 [1.04–1.28]) increased odds of AKI .Conventional associations between measured BP with risk of CKD were also positive but were found to be somewhat stronger than genetic analyses Figure . ConventWe aimed to assess whether moderate life-long differences in BP are causally related to CKD by harnessing the scale of genetic information within UK Biobank and careful selection of kidney outcomes. We found evidence of a U-shaped association between genetically predicted higher systolic BP and eGFR. This strengthens the hypothesis that life-long higher systolic BP is a causal risk factor for incident CKD , as well as glomerular hyperfiltration (which may be a precursor for kidney function decline). Each 10 mmHg higher genetically predicted systolic BP was associated with higher odds of CKD, and separately hyperfiltration, by about one-third. These associations seemed similar in size in people with or without conditions considered to disrupt renal blood flow autoregulation, including diabetes mellitus, obesity, or vascular disease. These results suggest physiological autoregulation may not afford complete protection against genetically predicted differences in BP.17 The apparently discrepant findings may be due to glomerular hyperfiltration being a precursor to kidney function decline and more advanced stages of CKD, and the consequent nonlinear associations between BP and eGFR (which were not accounted for in previous MR experiments). Our finding of genetically predicted higher systolic BP being associated with glomerular hyperfiltration are consistent with the observed effects of intensive BP lowering in the SPRINT . In the SPRINT population of adults without diabetes, allocation to intensive BP lowering achieved an average systolic BP of 121 mmHg (compared with 136 mmHg in those on standard BP lowering), and an average 3 mL (mL/min/1.73m2) difference in eGFR. The eGFR decline/difference among those allocated intensive BP lowering was associated with reductions in albuminuria and filtered markers of tubular function, and no increase in markers of tubular injury, suggesting hemodynamic changes in the kidney, and perhaps a reversal of single nephron hyperfiltration.46Our results challenge the conclusions from the largest MR studies which reported no evidence of association between genetically predicted higher BP and differences in kidney function.9 The odds of CKD and hyperfiltration with life-long genetically predicted higher systolic BP were at least as large among those without diabetes, without preexisting vascular disease, and among those with ideal levels of adiposity. The lack of a detectable genetic association between diastolic BP and hyperfiltration raises the hypothesis that peak glomerular perfusion pressure rather than mean perfusion pressure may be key to glomerular barotrauma.Our results challenge the notion that renal blood flow autoregulation fully protects against moderate elevations in systolic BP.34 the renin-angiotensin system, or disordered kidney development, morphology, or physiology.18 Findings were unaltered after exclusion of these SNPs from analyses. Second, analyses were based on single measurements of eGFR and albuminuria, meaning BP-CKD associations may be underestimated. Third, although sensitivity analyses stratified by residual characteristics found no clear evidence of such a collider bias, stratification for subgroup analyses could conceivably lead to its introduction and need cautious interpretation. Lastly, the study was restricted to White British adults, meaning results may not be generalizable to other populations.The present study benefits from UK Biobank’s large size and the use of methods that are less susceptible to residual confounding and reverse causality, but some limitations may exist. First, it is possible that some of the BP GRS included SNPs exert a direct effect on the kidney or its vasculature independent of their effect on BP. However, we carefully sought and excluded SNPs that were in, or close to, genes differentially expressed in the kidney, and any SNPs reported as being involved in TGF-beta signaling,In conclusion, the use of nonlinear MR models shows that life-long elevation of BP is a cause of both decreased kidney function which is characteristic of progressive CKD, and glomerular hyperfiltration which may be a precursor for kidney function decline. These results contrast previous findings from MR studies that erroneously assumed linear associations. Higher genetically predicted systolic BP was more strongly related to CKD risk and hyperfiltration than higher diastolic BP, with risks evident in the presence or absence of diabetes, obesity, and vascular disease which predispose to CKD or hyperfiltration. These analyses suggest early active management of moderate systolic hypertension could reduce long-term risk of CKD, even in people without diabetes, obesity, or established cardiovascular disease.The presented analyses from UK Biobank data suggest a causal role for life-long small increases in BP in the development of CKD and glomerular hyperfiltration (a precursor to CKD). Genetically predicted BP associates with CKD outcomes based on decreased kidney function, abnormally increased kidney function, and/or albuminuria. These findings raise a convincing hypothesis that physiological autoregulation may not afford complete renal protection against moderate BP elevations. Consequently, considering early active management of moderate systolic hypertension in all adults—and not just individuals with diabetes, obesity, or other CKD risk factors—may be an important population health strategy. Replicating these findings in other cohorts, including cohorts with a larger number of relevant advanced CKD cases and in non-White populations are important research priorities for renal epidemiology.https://www.ukbiobank.ac.uk/. This article has not been published previously in whole or part.This research has been conducted using the open access UK Biobank Resource (application number 15595), with data available from: N. Staplin, W.G. Herrington, R. Haynes, J.C. Hopewell conceived the study and developed its design; NS performed statistical analyses; F. Murgia and M. Ibrahim performed bioinformatics analyses and functional mapping; N. Staplin and J.C. Hopewell had full access to the data; N. Staplin, W.G. Herrington wrote the first draft of the article; and all authors contributed to data interpretation and revision of the article.Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) has a staff policy of not accepting honoraria or other payments from the pharmaceutical industry, except for the reimbursement of costs to participate in scientific meetings. The Medical Research Council Population Health Research Unit at the University of Oxford, which is part of the CTSU, receives core funding from the United Kingdom Medical Research Council. We also acknowledge support from Health Data Research UK, National Institute for Health and Care Research Oxford Biomedical Research Centre, and British Heart Foundation Centre for Research Excellence, Oxford. W.G. Herrington and K.R. Bull are both supported by Medical Research Council Kidney Research UK Professor David Kerr Clinician Scientist Awards. J.C. Hopewell is supported by a personal fellowship from the British Heart Foundation (FS/14/55/30806).For the purpose of open access, the author(s) has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.


To investigate the characteristics of patients with primary hypertension who had positive responses to the cold pressor test (CPT).This cross-sectional study was conducted between November 2018 to November 2019, and the CPT was performed in patients with primary hypertension in 48 hospitals. The demographic characteristics and complications were collected through a questionnaire and physical examinations. A 12-month follow-up was conducted to identify the occurrence of the following events: a) all-cause mortality; b) myocardial infarction; c) stroke; d) hospitalized for heart failure.2 = 6.756, P = 0.009). After a 12-month follow-up, the incidence of heart failure in the positive CPT group was significantly higher than that in the negative CPT group .The CPT was positive in 30.7% of the patients. Compared with the negative CPT group, the positive CPT group was associated with a lower rate of blood pressure control, and was more likely to have a high salt diet, diabetes, hyperuricemia, left ventricular wall thickening, carotid plaques, coronary heart disease and heart failure. A high-salt diet  was found to be correlated with the positive result of CPT. Among patients in the positive CPT group, those using diuretics had a significantly higher rate of blood pressure control than those not using diuretics (54.6 vs.42.6%, xPatients with positive responses to the CPT had lower rates of BP control and a high risk of heart failure, which may be related to their preference for a high-salt diet. The use of diuretics helps to better control blood pressure in those patients. Hypertension is an important public health challenge worldwide and it contributes to 51% of stroke deaths and 45% of ischemic heart disease death worldwide . StudiesThe cold pressor test (CPT), which was developed by a physician in the division of medicine at the Mayo Clinic Rochester, Edgar A. Hines, Jr. 1906–1978) ( (8), hasThis was an observational, cross-sectional study. Data from the enrolled patients were collected during the first interview and then entered into a database, including their medical and pharmacological histories. The CPT and a physical examination, including measurement of height, weight, and BP were conducted during the first interview.A 12-month follow-up was conducted to identify the occurrence of the following events: a) all-cause mortality; b) myocardial infarction; c) stroke; d) hospitalized for heart failure .Patients were excluded on the basis of the following criteria: primary aldosteronism or other diseases or causes of secondary hypertension; systolic BP (SBP) ≥ 180 mmHg and/or diastolic BP (DBP) ≥ 110 mmHg; severe heart or lung diseases, acute stage stroke (<3 months) or end-tage cancer; inability to undergo the cold pressor test; or pregnancy.The participants were seated, and the blood pressure of the right upper arm was measured three times with a calibrated electronic sphygmomanometer or standard mercury sphygmomanometer after the patients had rested for 20 minutes in a room with appropriate temperature. The average blood pressure of the three measurements was taken as the basic blood pressure. Then, the participants immersed their left hands in ice water at 3–5°C for 1 minute. The blood pressure of the right upper arm was measured 0 min, 1 min, 2 min, and 4 min after removal of the left hand from the ice water. The test was considered positive if the SBP, DBP or mean arterial pressure (MAP) increased ≥ 15 mmHg after cold stimulation. The test was considered negative if the SBP, DBP or mean arterial pressure (MAP) increased <15 mmHg after cold stimulation. MAP = (SBP + 2 × DPB)/3 or MAP = DBP + 1/3 (SBP-DBP).This study was approved by the ethical committee of Chongqing Medical University, and written informed consent was obtained from all patients participating in the study.The standard was based on the Guidelines for the prevention and treatment of hypertension in China (revised in 2018) . The tarp-value < 0.05.All data were input by two independent researchers using EpiData V.3.1 , and the database was established after checking for differences in the two records. SPSS Statistics version 21.0  was used for statistical analysis. Categorical variables were analyzed with χ2 tests. The factors influencing CPT were screened and determined by multivariable binary logistic regression analysis. Statistical significance was defined as a From November 2018 to November 2019, 3132 patients with primary hypertension in 48 hospitals were invited to participate in our study. The CPT was performed in 91.5% of the population (2865 patients); in the rest of the patients, it could not be performed due to cold intolerance (8.5%).A total of 880 patients (30.7%) screened positive with the CPT and were placed in the positive group, and the other 1985 were placed in the negative group.P < 0.05). However, there were no significant differences in the proportion of sex, age, BMI, family history of hypertension, smoking, drinking, hyperlipidemia, or higher values of serum creatinine or proteinuria between the two groups (p > 0.05). A high-salt diet  was found to be correlated with the positive result of CPT . In the positive CPT group, most patients took renin-angiotensin-aldosterone system (RAAS) inhibitors (60.5%) to control blood pressure, followed by calcium channel blockers , diuretics (16%), and beta-blockers (12.5%). The comparison of the blood pressure control rates among four antihypertensive therapies is shown in 2 = 6.756, P = 0.009). However, there was no significant difference in whether CCB, beta-blockers, or RAAS inhibitors were used.Among the 2865 patients included in this study, 2375 patients regularly took antihypertensive drugs, including 766 (87.0%) in the positive CPT group and 1609 (81.1%) in the negative CPT group. Among the patients regularly taking antihypertensive drugs, the blood pressure compliance rate was significantly lower in the positive group than the negative group  and Chongqing Science and Technology Foundation (cstc2017shmsA130086).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.


Decision curve analysis demonstrated that the model was clinically useful. (4) Conclusions: This study presented a reliable nomogram that facilitated individualized preoperative prediction of blood pressure change failure after adrenalectomy in patients with pheochromocytoma, which may help decision-making in perioperative treatment and follow-up strategies.(1) Background: Pheochromocytoma is a common cause of secondary hypertension, which is considered curable; nevertheless, some patients still suffer from hypertension after adrenalectomy. Therefore, we developed and validated a nomogram for predicting blood pressure change failure in patients with pheochromocytoma and concomitant hypertension after adrenalectomy. (2) Methods: The development cohort of this study consisted of 259 patients with pheochromocytoma who underwent adrenalectomy at our center between 1 January 2007 and 31 December 2018. Each patient’s clinicopathologic data were recorded. LASSO (the least absolute shrinkage and selection operator) regression was used to reduce and select the features of the data. Furthermore, we used multivariate logistic regression analysis to develop the prediction model. An independent cohort of 110 consecutive patients from 1 January 2019 to 31 December 2021 was used for validation. The performance of this nomogram was assessed with regard to discrimination, calibration, and clinical usefulness. (3) Results: 40.9% and 46.4% of patients experienced blood pressure change failure in the development and validation cohorts of this study, respectively. We found that older patients with a longer duration of hypertension and concomitant cardiovascular events were more likely to suffer from blood pressure change failure. In the validation cohort, the model manifested great discrimination with an AUROC (area under the receiver operating characteristic) of 0.996 ( Pheochromocytoma is a rare tumor that grows from chromaffin cells in the adrenal medulla. The incidence of pheochromocytoma is 0.6 cases per 100,000 person-years in the general population, and the prevalence is 0.1–0.6% in patients with hypertension ,3,4. It Adrenalectomy after preoperative medical preparation with α-blockade is the cornerstone of treatment, which has been shown to normalize blood pressure ,10. HoweA nomogram derived from a predictive model is accepted as a reliable tool for predicting risk by incorporating and illustrating important predictors of significant clinical outcomes . To the The development cohort of this study consisted of 259 patients who underwent pheochromocytoma adrenalectomy at our center between 1 January 2007 and 31 December 2018, while the validation cohort consisted of 110 consecutive patients from 1 January 2019 to 31 December 2021, who met the same inclusion and exclusion criteria. A flow chart illustrating the patient selection process is detailed in Ethical approval  was offered by the Ethics Committee of Shengjing Hospital Affiliated to China Medical University in Shenyang, China. All the informed consent of these patients in this study has been obtained. Inclusion criteria: Those patients with persistent hypertension before surgery who underwent laparoscopic or open unilateral adrenalectomy , and whose pathologic results showed pheochromocytoma were finally included in this research. The clinical stage was localized (no adjacent organ invasion or metastasis). Exclusion criteria: Those with pheochromocytoma familial history, or malignancy were excluded from this study. The preoperative diagnoses were based on laboratory tests and diagnostic imaging. For patients who present typical biochemical manifestations of pheochromocytoma, α adrenoreceptor antagonists  were conventionally used at least two weeks before the operation. Intravenous crystalloid or colloid fluid were admitted for volume expansion about three days before the operation. The criteria for preoperative medical preparation success included a blood pressure < 130/80 mmHg, a heart rate < 90/min, and a hematocrit < 0.45.Patient’s demographic characteristics , comorbidities , disease characteristics  difference [between plain phase and arterial phase], types of α adrenoreceptor antagonists use [prazosin vs. others], use of crystalloid and colloid infusion, and 24-h urine vanillylmandelic acid/upper limits of normal value), intraoperative data , and postoperative data  were recorded.For each participant, preoperative blood pressure was measured three times at 2-min intervals after at least 5 min of rest in a seated position using a standardized automatic electronic sphygmomanometer  before α-blockade treatment. Those with known hypertension and treated with anti-hypertension drugs were also recorded as having hypertension. Blood pressure was ascertained by self-report through telephone interview at three months postoperatively. The definition of hypertension was based on the 2003 World Health Organization International Society. Blood pressure change failure was defined as patients with a sustained BP of 140/90 mm Hg or more and those who still need to take antihypertensive drugs at three months postoperatively. Diabetes Mellitus was defined as a fasting blood glucose level greater than seven mmol/L or a non-fasting blood glucose level greater than 11 mmol/L. Cardiovascular events (CVE) were defined as proven myocardial infarction, angina pectoris, cerebral vascular accidents, and transient ischemic attacks [http://www.Rproject.org (accessed on 1 January 2022)) were used to analyze the data. In this investigation, the R packages “rms” and “glmnet” were utilized. The statistical significance levels presented were all two-sided, with statistical significance defined as a probability (p) value of less than 0.05. The median (interquartile range) is used to represent continuous variables. The independent samples Student’s t-test was used to compare the means of two continuous normally distributed variables. To compare two continuous non-normally distributed variables, the Mann–Whitney U-test was utilized. The number of categorical variables is provided (percentage). To compare categorical variables, the chi-squared and Fisher’s exact tests were used. IBM SPSS Statistics for Windows, version 22.0 , STATA 15.0 , and R software  method was utilized to choose the most valuable predictive features from the primary data set in this study, which is suitable for decreasing high-dimensional data. Using the LASSO binary logistic regression model, all clinicopathologic variables were reduced to a small number of possible predictors based on 259 patients in the development cohort. There is no influence on the predicted regression parameters if the penalization coefficient lambda (λ) is big, but as it goes smaller, some coefficients may be decreased to near zero. We then used 10-fold cross-validation using minimum criteria and one standard error of the minimum criteria to find the best in the LASSO model (the 1-SE criterion). Finally, the model was re-fit using all of the non-zero coefficients selected by the Lasso method. p > 0.05 indicates good calibration). Perfect calibration was indicated by a slope on the 45-degree line. By measuring the net benefits at different threshold probabilities in the validation cohort, decision curve analysis was used to determine the model’s clinical usefulness.The model’s performance was evaluated in an independent validation cohort. The validation cohort was given the logistic regression formula established in the development cohort, which was used to compute the likelihood for each patient. To quantify the model’s discrimination performance, the area under the receiver operating characteristic (AUROC) curve was measured. A 0.5 AUROC indicated no discrimination, whereas a 1.0 AUROC indicated perfect discrimination. The model’s calibration was evaluated using calibration plots, as well as the unreliability test and the Hosmer–Lemeshow (H-L) chi-square statistic  of patients in the development cohort, while 46.4% (51/110) of patients in the validation cohort suffered from blood pressure change failure after successful surgery. , 40 months of hypertension (57 points), and no concomitant cardiovascular events (0 points). The total points were 73, and the predicted probability of blood pressure change failure was approximately 70% . This cap-value was 0.359, Emax was 0.331, and Eavg was 0.028, indicating that the model was well-calibrated. This curve suggests that it would be more beneficial to use this nomogram to predict blood pressure change failure in patients after adrenalectomy. The net benefits are comparable across all ranges . The unreliability test statistic of calibration in this validation cohort was 0.015, the l ranges .Although pheochromocytoma has been considered a curable cause of secondary hypertension, half of the patients still suffer from continuous hypertension after successful adrenalectomy. Therefore, we developed and validated a nomogram for predicting the probability of blood pressure change failure in patients after adrenalectomy. In this study, 40.9% and 46.4% of patients experienced blood pressure change failure in the development and validation cohorts, respectively. Based on the results of LASSO regression, older patients with a longer duration of hypertension and concomitant cardiovascular events were more likely to suffer from blood pressure change failure. In previous studies, the prevalence of blood pressure change failure ranged from 30–70% after successful adrenalectomy ,15,16. IThis study revealed that older age at presentation was a significant predictor of blood pressure change failure in patients after adrenalectomy. In line with this, Paolo et al., in a retrospective study on 48 patients with benign adrenal tumors, found that 29% of patients still suffered from persistent hypertension that required antihypertensive drugs, and 25% of patients required less intensive hypertensive treatment than before adrenalectomy after 77 months of follow-up, and showed that aging was the only significant factor predictive of persistent hypertension . In addiCardiovascular events are a common consequence of long-standing hypertension due to its role in the progression of arteriosclerosis ,20. In tp = 0.04) [In this study, diabetes mellitus was not a predictor of blood pressure change failure in patients after pheochromocytoma surgery. However, Pradeep et al. found that a high ratio of patients concomitant with diabetes mellitus was observed in the blood change failure group ( = 0.04) . This diPheochromocytoma is generally considered to be a curable cause of hypertension. However, in this study, blood pressure change failure was presented in nearly half of the patients with pheochromocytoma after successful adrenalectomy; thus, it should not be unreservedly considered as a surgically remediable cause of hypertension. The plausible explanation may be that patients are also likely to have non-catecholamine-induced hypertension, which may be essential or perhaps due to another underlying secondary cause. In addition, individuals with long-term hypertension lose the ability, with increasing age, to reverse the structural vascular changes associated with secondary hypertension . TherefoThis study has certain limitations. First, our study followed a retrospective design from a single center. Second, due to the long recruitment time, perioperative preparation strategies were diverse and non-standard, which might have influenced the outcome. Third, several potential factors were not included, such as genetic mutation data. Fourth, some factors related to blood pressure change after surgery were not considered, such as a family history of hypertension, which suggests the presence of a predisposition to essential hypertension . Fifth, Blood pressure change failure is presented in less than half of patients with pheochromocytoma after successful adrenalectomy; we identified three independent risk factors: older age with a longer duration of hypertension and concomitant cardiovascular events. This is a reliable nomogram that can facilitate the individualized preoperative prediction of blood pressure change failure after successful adrenalectomy in patients with pheochromocytoma, which may help in perioperative management and follow-up strategies. This section is not mandatory but may be added if there are patents resulting from the work reported in this manuscript.


Chronic kidney disease (CKD) is a complex condition with a prevalence of 10–15% worldwide. An inverse-graded relationship exists between cardiovascular events and mortality with kidney function which is independent of age, sex, and other risk factors. The proportion of deaths due to heart failure and sudden cardiac death increase with progression of chronic kidney disease with relatively fewer deaths from atheromatous, vasculo-occlusive processes. This phenomenon can largely be explained by the increased prevalence of CKD-associated cardiomyopathy with worsening kidney function. The key features of CKD-associated cardiomyopathy are increased left ventricular mass and left ventricular hypertrophy, diastolic and systolic left ventricular dysfunction, and profound cardiac fibrosis on histology. While these features have predominantly been described in patients with advanced kidney disease on dialysis treatment, patients with only mild to moderate renal impairment already exhibit structural and functional changes consistent with CKD-associated cardiomyopathy. In this review we discuss the key drivers of CKD-associated cardiomyopathy and the key role of hypertension in its pathogenesis. We also evaluate existing, as well as developing therapies in the treatment of CKD-associated cardiomyopathy. Chronic kidney disease (CKD) and kidney failure with replacement therapy (KFRT) are complex chronic conditions with a combined prevalence of 10–15% worldwide , 7, withAn inverse graded relationship exists between cardiovascular events and mortality with estimated glomerular filtration rate (eGFR), which is independent of age, sex, and other risk factors –18. The In this state-of-the-art review, we will discuss some of the key drivers of CKD-associated cardiomyopathy and the key role of hypertension in its pathogenesis, and evaluate existing, as well as developing therapies in the treatment of CKD-associated cardiomyopathy.Increased left ventricular (LV) mass and left ventricular hypertrophy (LVH),Diastolic and systolic LV dysfunction,Profound myocardial fibrosis on histology , 31–44.The concept of CKD-associated cardiomyopathy Fig.  first ap2 compared to those with eGFR greater than 60 ml/min/1.73 m2 [Whilst these features have been predominantly identified in patients with KFRT, who are undoubtedly uraemic, those with mild to moderately reduced eGFR already exhibit structural and functional changes consistent with CKD-associated cardiomyopathy . This is/1.73 m2 .The LV is a main target for end-organ damage in hypertension, resulting from a combination of cardiomyocyte hypertrophy and expansion of the extracellular space caused by interstitial myocardial fibrosis from activated fibroblasts  depicted with meticulous detail first observations of LVH present on autopsies of patients with albuminuria [The connection between CKD, hypertension and LVH was first described by several 19uminuria . Years luminuria . Furtheruminuria , 63.Recent imaging studies confirm that increased LV mass and LVH are common manifestations of CKD-associated cardiomyopathy Fig. . LVH is LVH is associated with an increased risk of arrhythmia, which may explain, in part, the increased incidence of cardiovascular death in CKD . A meta-Diastolic dysfunction is highly prevalent in patients with CKD  with stuThe presence of LVH has also been associated with the risk of development of systolic dysfunction in hypertensive subjects –92. The It has been suggested that myocardial fibrosis may be the unifying pathophysiological process underlying CKD-associated cardiomyopathy . In the A post-mortem study of LV tissue from patients with KFRT found reduced capillary density, increased cardiomyocyte cross-sectional area and expansion of interstitial matrix. The apparent myocyte-capillary mismatch brought about by the reduction in capillary supply within a hypertrophied myocardium increases the oxygen diffusion distance, thereby exposing the heart to the risk of ischaemic injury and subsequent cardiac dysfunction . Recent Studying myocardial fibrosis in CKD/KFRT has been challenging given that myocardial biopsies are ethically difficult to justify , 105. CoIncreased afterload ,Increased preload ,Intrinsic factors not directly to afterload or preload .The pathogenesis of CKD-associated cardiomyopathy is likely to be multifactorial but can broadly be divided into three categories:Although these categories are considered separately, it is important to note that there is considerable overlap between them , 115. FaRaised intra-arterial pressure induces cardiac hypertrophy through chronic haemodynamic stress on the myocardium. In vitro experimental models of cardiomyocyte and non-myocyte stretch resulted in cell hypertrophy and hyperplasia, induction of protein synthesis and increased expression of prohypertrophic proto-oncogenes such as fos, jun, myc, Ha-ras, and genes encoding atrial natriuretic factor and β-myosin heavy chain –118. ThiArterial stiffening occurs from the early stages of CKD and increases with the progression to KFRT –126. TheArterial stiffness is both a cause and result of systolic hypertension, although extricating the bidirectional relationship can be challenging , 130. StIn addition to elevated blood pressure, there are several other postulated pathophysiological drivers of increased arterial stiffness in CKD such as activation of the renin-angiotensin-aldosterone system (RAAS), build-up of uraemic toxins, disordered bone and mineral metabolism (CKD-MBD), accumulation of advanced glycation end-products, chronic inflammation and oxidative stress which adversely affect endothelial function and calcific remodelling of the vessel wall , 129. ThIntravascular volume expansion/hypervolaemia, secondary to salt and water loading, is a frequent occurrence in CKD/KRFT and a determinant of LV mass and mortality , 142. InAs haemoglobin concentrations fall, complex haemodynamic compensatory mechanisms are activated to increase cardiac output and blood flow to compensate for tissue hypoxia . These iThe use of arteriovenous fistulas for haemodialysis is preferrable to vascular catheters due to improved dialysis quality and reduced infection rates –159. HowIn addition to the haemodynamic factors already discussed, several other factors that become dysregulated in patients with CKD are involved in the pathogenesis of CKD-associated cardiomyopathy. These include activation of RAAS, sympathetic nervous system overactivity, increased transforming growth factor-beta (TGFß) signalling, insulin resistance, uraemic toxins , increase in cardiotonic steroids, oxidative stress and factors associated with CKD-MBD namely hyperparathyroidism, vitamin D deficiency, increased circulating fibroblast growth factor-23 (FGF-23), decreased Klotho expression and hyperphosphataemia , 164–166Given that CKD-associated cardiomyopathy, and its individual components, are powerful predictors of cardiovascular mortality in patients with CKD and KFRT, targeting the mechanisms involved seems a practical approach to improve outcomes. However, a meta-analysis assessing the validity of LV mass reduction as a surrogate marker of all-cause and cardiovascular-mortality in patients with CKD and KFRT concluded there was no clear association between intervention-induced change in LV mass and mortality . It shouStudies have shown that longer, frequent ‘intensive’ dialysis regimens Fig.  are assoThe previously discussed effects of intensive dialysis on reduction of hypertension and improvement in LV mass are encouraging, however it is still unclear as to whether this leads to better patient survival. A recent meta-analysis encompassing 70,506 patients found that intensive dialysis was associated with reduced mortality when compared to conventional dialysis, but the overall quality of the evidence was low . Whilst The gold-standard for the treatment of KFRT is kidney transplantation . The assA recent systematic review and meta-analysis has indeed confirmed that many echocardiographic studies reported significant reductions in LV mass after kidney transplantation . HoweverIntriguingly, a small study in 44 kidney transplant recipients found a significant reduction in native T1 time at 6 months after transplantation with no reduction in LV mass  A smallePrior to publication of the SPRINT trial results , most soThese data have resulted in lowering of both American and European blood pressure targets in their respective 2017  and 2018In the general population, regression of LVH is associated with a significant improvement in cardiovascular events . SeveralFactors associated with persistent LVH and lack of regression of LVH with antihypertensive treatment include older age, higher body mass index, sub-optimal blood pressure control, duration of hypertension and crucially, the presence of CKD , 220. ThThe confounding effect of blood pressure reduction on changes in LV mass are highlighted by a study examining the cardiovascular effects of spironolactone compared with placebo in early-stage CKD . In 112 Sacubitril/valsartan are the first in this new class of angiotensin receptor neprilysin inhibitors (ARNI), approved for the treatment of heart failure with reduced ejection fraction (HFrEF) in conjunction with other standard therapies . The nepIt is well-established that aldosterone promotes cardiovascular damage and high concentrations are associated with LVH , 245 andWhether the lowering of LV mass in CKD patients is dependent on the blood pressure lowering effect of MRAs is unclear , 234. ReSodium-glucose co-transporter-2 (SGLT2) inhibitors are a recent class of oral antidiabetic agents , 261. ThA recent meta-analysis of large RCTs clearly demonstrated a 23% reduction in CV morbidity and mortality, especially heart failure hospitalisations in patients with diabetes mellitus . SimilarSeveral mechanisms have been proposed for the reduction in LV mass and improved diastolic dysfunction observed with SGLT2-inhibitors  Fig. 9)9). TheirHypertension can be challenging to control in CKD, with the prevalence of apparent resistant hypertension reported to be as high as 40% . Whilst The presence of anaemia is associated with the development of LVHH and heart failure in patients with CKD , 283, KFCKD-MBD encompasses the progressive deterioration in the homoeostasis of calcium, phosphate due to disruption in circulating hormones FGF23 and its co-receptor Klotho, PTH and vitamin D Fig. . Higher 3/calcitriol) deficiency because of a lack of its precursor, 25-hydroxyvitamin D3 and impaired activity of the kidney enzyme 1α-hydroxylase [Low levels of vitamin D have been associated with higher blood pressure , a higheroxylase . Observaroxylase –305 withroxylase , 306–309roxylase , 311.The phosphaturic hormone FGF23 is markedly increased in patients with CKD, and dialysis , 312–314The FGF23 co-receptor αKlotho is a protein severely downregulated in CKD  due to v2, is a strong predictor of metabolic syndrome and plays a critical role in the development of cardiovascular and kidney disease [Obesity, defined as a body mass index of ≥30 kg/m disease –353. In  disease . Whilst  disease . A rando disease . This is disease –359. How disease  and 20 [ disease  years of disease –364. HowThe pathophysiology of CKD-associated cardiomyopathy is extremely complex and involves multiple inter-related mechanisms. Increasing evidence linking individual factors to its aetiology may well lead to novel treatments in the future. However, the current evidence continues to suggest that the diagnosis, characterisation, and optimisation of treatment of hypertension is the cornerstone of treatment for now. To date, specific, blood pressure independent, beneficial treatment effects on either LV mass or hard clinical end points have not been convincingly demonstrated. While further research into potential treatments targeting molecular aetiological pathways needs to continue, research into the optimal blood pressure targets, monitoring strategies and antihypertensive regimens, for individuals at different stages of CKD and with KFRT needs to progress in parallel.


Patients with masked hypertension (MH) and masked uncontrolled hypertension (MUCH) are easily overlooked, and both cause target organ damage. We propose a prediction model for MH and MUCH patients based on clinical features at a single outpatient visit. Data collection was planned before the index test and reference standard were after. Thus, we retrospectively collect analyzed 804 subjects who underwent ambulatory blood pressure monitoring (ABPM) at Renmin Hospital of Wuhan University. These patients were divided into normotension/controlled hypertension group (n = 121), MH/MUCH (n = 347), and sustained hypertension (SH)/sustained uncontrolled hypertension group (SUCH) (n = 302) for baseline characteristic analysis. Models were constructed by logistic regression, a nomogram was visualized, and internal validation by bootstrapping. All groups were performed according to the definition proposed by the Chinese Hypertension Association. Compared with normotension/controlled hypertension, patients with MH/MUCH had higher office blood pressure (BP) and were more likely to have poor liver and kidney function, metabolic disorder and myocardial damage. By analysis, [office systolic blood pressure (OSBP)] (P = .004) and [office diastolic blood pressure (ODBP)] (P = .007) were independent predictors of MH and MUCH. By logistic regression backward stepping method, office BP, body mass index (BMI), total cholesterol (Tch), high-density lipoprotein cholesterol (HDL-C), and left ventricular mass index are contained in this model [area under curve (AUC) = 0.755] and its mean absolute error is 0.015. Therefore, the prediction model established by the clinical characteristics or relevant data obtained from a single outpatient clinic can accurately predict MH and MUCH. Hypertension is an overarching risk factor for cardiovascular morbidity and mortality, and it is the most critical contributor to the burden of disease and the leading cause of mortality worldwide.,3 Studies have shown that hypertension is responsible for almost 13% of all deaths.,4,5 Based on the current international guidelines, ambulatory blood pressure monitoring (ABPM) is widely accepted as the gold standard for the diagnosis of hypertension.–8Cardiovascular diseases are the leading cause of death and account for an estimated 30% of deaths worldwide. MH refers to patients in the untreated or initial stage of treatment, and masked uncontrolled hypertension (MUCH) refers to patients with prior hypertension treatments.,11 A large number of studies have shown that the risk of target organ damage and cardiovascular and cerebrovascular disease in patients with MH and MUCH is similar to that in patients with sustained hypertension (SH) or sustained uncontrolled hypertension (SUCH), and is significantly higher than that in patients with normotension (NH) and CH.–15Masked hypertension (MH) and masked uncontrolled hypertension are used to define people with normal office blood pressure (BP) but hypertension out-of-office, which ABPM determines. Then, MH and MUCH patients are always ignored because of normal office BP. In conclusion, the above reasons often limit the popularity of ABPM.However, when performing ABPM, the number of measurements is higher, and the measurements are also taken during sleep, so it can produce discomfort and affect the patient’s sleep, acceptance, and compliance. Moreover, few primary care providers screen for MH, and little is known about primary care providers’ awareness, knowledge, and attitudes toward MH.The purpose of this study is to identify MH/MUCH patients through the prediction model established by the clinical characteristics of a single outpatient and the data of examination results.,17,18 The exclusion criteria include secondary hypertension, life expectancy less than or equal to 12 months, serious diseases , mental diseases, inability to cooperate with ABPM, and other diseases leading to inaccurate BP measurement.,19,20Ethics Committee of Renmin Hospital of Wuhan University approved the study, and the study involves patient consent. Data collection was planned before the index test and reference standard were after. The patients who underwent ABPM in our hospital from September 1st, 2020 to December 31st, 2020 were selected retrospectively. The inclusion criteria included age over 18 years’ old and complete and accurate ambulatory BP data .–22 The diagnostic criteria of hypertension proposed in this study are implemented according to the diagnostic criteria of Europe and China, that is, the diagnostic threshold of hypertension is 140/90 mm Hg.,19,23The clinical BP was recorded by trained nursing staff in 3 separate visits on 1 day. During each measurement, use the verified upper arm electronic sphygmomanometer with a standard cuff to read the sitting BP twice, with an interval of 2 min. Rest quietly for 5 min before measurement, and record the average value of the two BP readings as the measured value of this BP. The mean value of three BP measurements was taken as the study’s consulting room BP value.,24Participants completed 24-h ABPM using an ABPM instrument with an appropriately sized cuff in the arm where their BP measurements were high. Ambulatory BP monitors were read at least once per hour and at least 27 times throughout the day (at least 20 times during the day and 7 times during the night). ABPM was uniformly divided into a whole day, daytime (8:00‐22:00), and night periods (22:00‐8:00).All tests were obtained as fasting in the early morning before the patient underwent ABPM. The collected parameters included the following: liver function , aspartate aminotransferase (AST)), lipid profiles , triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small dense low-density lipoprotein cholesterol (sdLDL-C), arteriosclerosis index ), renal function (uric acid (UA), urea, creatinine (Cr), estimated glomerular filtration rate (eGFR)), fasting plasma glucose (Glu), electrocardiographic indicators ), Echocardiographic parameters (diameter of ascending aorta (AAOD), left atrial diameter (LAD), left ventricular end diastolic diameter (LVDD), right atrial diameter (RAD), right ventricular end diastolic diameter (RVDD), end diastolic interventricular septal thickness (IVSD), left ventricular posterior wall thickness at end diastole (LVPWD), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI)). Statistical analysis was performed by R 4.1.3 and SPSS 27.0 in this study. Quantitative variables are expressed as mean ± SD (x ± s), and categorical variables are expressed as percentages (%). Continuous parametric data were compared using an unpaired Student t test. Non-parametric data were compared using the Mann–Whitney U test. Categorical variables were analyzed using the Chi-square test or Fisher exact test. Spearman rank correlation coefficients were calculated between candidate variables. Statistical significance was inferred at a two-sided P value < .05.Because this study had partially missing data, imputation of missing values took the method of multiple imputations five times, and the numerical value of these imputations was taken as the final data of the study while missing categorical variables took the method of deletion and were excluded from this study.Univariate logistic regression analysis was used to find out the clinical characteristics and relevant data that have a potential relationship with MH. The clinical features strongly correlated with MH were found by multivariate logistic regression analysis. The model is simplified and the error caused by the overfitting of the model is prevented by the backward step method of logistic regression.The risk prediction model is visualized by transforming the regression coefficient into the Nomo coefficient. According to the degree of influence of each variable on the model, the corresponding score is given, and the score of each patient is calculated after adding all the scores, to determine the probability of disease of the patient.Area under curve (AUC) value, sensitivity, specificity, and a cutoff value of the model were calculated by receiver operating characteristic (ROC) analysis. A new sample is established by repeated return sampling, and the model is tested with the new sample.Of all 804 patients, 121 were NH and CH, 343 were MH and MUCH, and 302 were SH and SUCH. No adverse events occurred when index tests or reference standards were performed. Among these 804 patients were 458 (57%) males with an age interval distribution of 61 ± 0.5. In the subsequent subgroup analysis, we found that in terms of baseline characteristics, compared with patients with NH and CH, MH and MUCH patients were younger, had higher office BP, and presented with poorer metabolic profiles, including higher body mass index (BMI) and serum TG levels. Meanwhile, MH showed that the structure of the left ventricle was more abnormal. And the difference between MH/MUCH and SH/SUCH is the same as the difference between NH/CH and MH/MUCH. However, SH/SUCH patients presented with medication nonadherence, and more of them did not take any antihypertensive drugs . Through the above principles and steps, we developed two scoring systems to predict MH and MUCH ), set the maximum score of the maximum factor of the coefficient as 10 points, and reduce the other factors in equal proportions , and the sensitivity and specificity were within the acceptable range. Through ROC analysis, the cutoff value of our model is 0.787, and the score corresponding to the modified value on the nomogram is about 24 . Therefore, it is unrealistic to conduct an ABPM examination for all populations. It is important to identify those at high risk of MH through the clinical characteristics related to a single outpatient visit.,29Our study found that high office BP was highly correlated with MH and was an independent risk factor for MH. The results of the Spanish ambulatory BP registry and two other cohorts are also consistent with our findings.–32 This is also consistent with our findings. In addition, relevant studies have also confirmed that obesity or high BMI is highly correlated with MH and MUCH.,34Our results also found that patients with MH and much showed worse metabolic status. These patients often have higher BMI, lower HDL-C, and higher serum Tch. Some previous studies have found MH to be more likely to be present in hyperlipidemia.,36 This is consistent with our findings. However, we evaluated the prevalence of left ventricular hypertrophy (LVH) among each group according to the LVH standard , but we found no significant statistical difference. This may be related to the selection of the population, the size of the sample, and the length of the course of hypertension.In addition, our study also found that higher LVMI was associated with MH as well as much. Related studies on target organ damage of MH and MUCH found that MH and MUCH patients had higher LVMI. In echocardiography, we found that the AAOD of MH/ MUCH patients was larger. Wang et al used a machine learning approach to perform automatic aorta measurement in thoracic CT images at nine key positions of 801 patients to predict MH. Better results were also finally obtained (AUC = 0.78). Therefore, this indicator may also be potentially related to MH and MUCH.In addition to the above indicators included in the model, our research results are worth discussing. Our study found no significant difference in the use of antihypertensive drugs between MH/ much patients and NH/ CH patients. This also indicates that much is not related to drug noncompliance. Relevant studies have also confirmed our view.,40 CKD and hypertension share similar risk factors and mutually contribute to each other. Still, our study did not find an association due to insufficient sample size and different study populations in our analysis. Our study only found that Cr was associated with MH and MUCH, and Cr in our study population was within the normal range. Furthermore, there is no relevant study evidence for a causal link between a history of chronic kidney disease (CKD) and MH.Whereas, in theory, a considerable proportion of studies found a strong association between CKD and MH.In conclusion, our study provides a good evaluation model for predicting patients with hypertension outside the office. As far as we know, this is the first risk prediction model established by the relevant data obtained from a single outpatient service in China. By changing the scoring model, we can be sure to determine the patients who really should undergo ABPM. This can increase the patient’s medical experience and save medical costs.Compared with NH/CH, patients with MH/MUCH had higher office BP and were more likely to have poor liver and kidney function, metabolic disorder and myocardial damage. The proposed model accurately predicts MH and MUCH based on the clinical features.This study is a retrospective study, and there will inevitably be a lack of relevant data. Although various statistical methods process these missing values, it is still difficult to avoid the relevant errors. Secondly, because the concept of occult hypertension is not popularized in China, most patients with normal BP in the clinic do not carry out ABPM in time, leading to a certain selection bias in the study. And this study only included the patient data for 4 months. Although the total sample number is more than 800, the sample number of this study is still small for the high prevalence of hypertension, which may also lead to some “no significant difference” results in this study. Therefore, future research in this area may include a larger sample size.Conceptualization: Bin Kong.Data curation: Hong Meng.Formal analysis: Liang Guo.Methodology: Bin Kong.Project administration: He Huang.Supervision: He Huang.Software: Liang Guo.Writing – original draft: Hong Meng.Writing – review & editing: He Huang, Wei Shuai.


This study aims to examine the interactions between brain glycolytic metabolism and hemodynamic parameters in different age groups.Brain Methods: A total of 72 patients  without any cerebral diseases but with available cardiac, arterial peripheral, and central blood pressure measurements as well as arterial stiffness parameters obtained from brachial pressure and applanation tonometry and a brain 18F-FDG PET scan were prospectively included into this study. Quantitative voxel-to-voxel analyses were carried out to test for negative associations between brain glycolytic metabolism and individual hemodynamic parameters (p-voxel of <0.001 for the whole population and <0.005 for age groups).Results: The heart rate parameter of the whole population showed the most extensive associations with brain metabolism , predominantly affecting the frontal and temporal regions (69% of the volume). Heart rate for the younger age group, systolic and pulse pressure for the 41–60-year-old group, and diastolic pressure for the older group were most extensively associated with brain metabolism and mainly involved the fronto-temporal lobes  which are also the regions implicated in accelerated brain aging.Conclusion: This cross-sectional prospective study identified extensive associations between cerebral metabolism and hemodynamic parameters, indicating common aging mechanisms. Heart rate throughout adult life, systolic and pulse pressure parameters around middle age, and diastolic pressure parameters in older patients, suggest the existence of potentially therapeutic targets to prevent accelerated brain aging. Associations between hemodynamic parameters and accelerated cerebral aging are now widely established, in particular chronic high blood pressure, which is the most important risk factor for cognitive decline in older adults , which allows to investigate brain glycolytic metabolism  study . Participants were age-stratified, at their time of inclusion into the study, and consisted of a 25% distribution of 18- to 40-year-old participants, 25% of 41- to 60-year-old participants, and 50% over 60-year-old participants. Pregnant women, minors, persons under judicial protection, participants with a history of psychiatric or neurological cerebral pathologies, or patients taking psychotropic drug treatments, participants who received chemotherapy or encephalic radiotherapy, and participants with atrial fibrillation or severe carotid stenosis were not included. Main indications for the 18F-FDG PET were: (1) an initial assessment or follow-up of inflammatory diseases (44%) such as granulomatosis (18%), vasculitis (8%), and others , with all these PET indications retained as covariates in our voxel-to-voxel quantitative analyses; (2) an etiological assessment of hyperthermia, decline in general condition (17%); (3) an initial assessment of cancer or suspected cancer, before any treatment ; (4) an assessment of adenopathy or investigation of a hematological syndrome prior to any treatment (11%); and (5) an initial assessment or follow-up of an infectious pathology (8%), mainly alveolar echinococcosis.One hundred participants referred to the University Hospital of Nancy (France) for an 18F-FDG PET scan patients, included in the study, initially performed a battery of neuropsychological tests: Mini-Mental State Examination . All participants signed an informed consent form before enrollment. This research complied with the principles of the Declaration of Helsinki. This clinical trial was reported in the Clinical Trials database (NCT03345290).18F-FDG PET scan and after resting 15 min in the supine position, participants were set up in a quiet room and three peripheral arterial pressure measurements were taken with an automated monitor  and averaged to improve representativity . Peripheral pulse pressure (pPP) was obtained by subtracting pDBP from pSBP.Before their ®, San Donato Milanese, Italy; Salvi et al., Central pulse parameters were measured by two experienced physicians  using applanation tonometry (Pulsepen DiaTecne®), after a neurosensory rest of 45 min following the intravenous injection of 3.5 MBq of 18F-FDG. All participants had fasted at least 6 h prior to receiving the injection and had blood glucose levels < 10 mmol/L. Acquisitions were recorded over a 15 min single bed position and all brain PET scans were reconstructed with the OSEM iterative reconstruction algorithm, as used in clinical practice, and corrected for PSF (Point Spread Function), attenuation, random coincidences, and scatter. Reconstruction parameters were based on two iterations of 10 subsets, displayed in a 256 × 256 matrix with 1 × 1 × 1 mm3 . An initial spatial normalization step was carried out with the low-dose scanner which is required for attenuation correction using the adaptive template registered to the Montreal National Institute (MNI) space. Transformations applied to the CT images of each patient were then applied to the co-registered PET images. The size of the scan voxels was set to 1 × 1 × 1 mm3. Intensity was normalized to the pons, a reference region with a glycolytic metabolism that is only weakly influenced by age  were considered as significant. Images were visually inspected at different stages of the pre-processing procedure to ensure the quality and convergence of the different methods applied (MD).Statistical analyses were performed at group-level and voxel-to-voxel using linear regression models of previously detailed hemodynamic parameters with an exclusive white matter mask. Covariates evaluated included age, considered as a continuous variable as well as sex, education level, the presence/absence of anti-hypertensive therapy, and the presence/absence of an inflammatory disease that may affect brain metabolism . The statistical analysis for SPM is detailed in the previous section.−2)  abnormal neuropsychiatric tests (four participants with an MMSE < 27 and/or MINI < 15 and/or major depressive syndrome), (ii) the identification of unsuspected brain lesions , (iii) technical difficulties relating to applanation tonometry (eight participants), especially in patients with high body mass index . There were no significant differences between the three age groups in terms of the sex distribution and the presence/absence of an inflammatory disease. As expected, there were significant differences in blood pressure  and arterial stiffness (cf-PWV) between the younger and older patients. Clinical and hemodynamic characteristics of the whole population and of the three age groups are given in Patients ranged from 23 to 88 years of age (mean age = 55.4 years ± 17.1) and were stratified into three age groups  specifically with the frontal (35.8% of cumulative volume) and temporal lobe (33.2% of cumulative volume) regions. The T-maps projected onto two-dimensional slices of axial T1-weighted MRIs are given in We then evaluated the relative associations of each hemodynamic parameter with cerebral metabolism within each of the three age groups.3, T-score peak: 10.5) with fronto-temporal predominant localizations (52.8% of the cumulative volume of the clusters).In the youngest age group, HR showed the most extensive associations with cerebral metabolism  and cSBP , and to a lesser extent for the peripheral parameters: pPP  and pSBP . Spatial localization analyses showed diffuse metabolic abnormalities related to these parameters, with fronto-temporal predominance in particular for cPP and for cSBP .In the 41- to 60-year-old patient group, systolic and pulse pressure parameters exhibited the most extensive associations with cerebral metabolism . This effect was particularly prominent for the central hemodynamic parameters: cPP . As depicted in In addition to associations between cerebral metabolism and HR in the oldest age group, cerebral metabolism showed the most extensive associations with the cDBP parameter . Several studies have shown significant associations between high pDBP values and cognitive decline in a middle-aged population  and all hypertensive participants were receiving anti-hypertensive treatments, but this is quite representative of the proportion of hypertensive patients in France, based on the latest available epidemiological data SPF, .To conclude, we report extensive associations between hemodynamic parameters, specifically HR, and cerebral metabolism throughout adult life. This suggests that brain metabolism and heart function may share common pre-symptomatic aging mechanisms. While systolic and pulse pressure parameters were more prominently involved around middle age, the number of interactions with diastolic pressure parameters were more extensive in older patients. These data suggest the presence of potentially useful therapeutic targets which may be exploited, during specific periods of life, to prevent accelerated brain aging.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the ethics committee of CHRU of Nancy (CPP accreditation N°2018/26). The patients/participants provided their written informed consent to participate in this study.AV, LJ, and VR: conceptualization. PSc, GZ, and RG: collection of clinical data. PSc, LJ, and PSa: measurements/analysis of haemodynamic parameters. RG: data curation. GZ, AV, and MD: SPM analysis. GZ, AV, LJ, AB, P-YM, and PSa: redaction—review and editing. 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.


Anxiety and depression have deleterious effects on health. Numerous studies have demonstrated the negative impact of emotions such as stress and anxiety on heart rate (HR), blood pressure (BP), and heart disease. These mood states have been linked to stroke, heart failure, diabetes, heart disease, respiratory problems, and drug abuse. Negative emotions can affect the HR and BP through the link between the nervous system and the cardiovascular system. Our study demonstrates the positive effect of classical music on HR, BP parameters, and mood states. Anxiety and depression have deleterious effects on health. Several studies have demonstrated the negative impact of emotions such as stress and anxiety on heart rate (HR), blood pressure (BP), and heart disease . These mIncreasing evidence has linked the beneficial effect of music and managing anxiety and depression. Cherry concluded that the psychological effects of music can be powerful and wide-ranging including improving cognitive performance, reducing stress, improving athletic performance, and enhancing sleep . Gold etEven though there is evidence to support the positive effect of music on HR, BP, and mood there are many inconsistencies in prior studies driven by heterogeneity and small sample sizes. Additional limitations include a lack of a broad range of ages and not including a mood survey.We aimed to expand on prior studies looking at the effect of music on HR, BP, and mood states utilizing two classical pieces, “Symphony of Fate” by Beethoven and “Moonlight Sonata” by Beethoven.MaterialsFor the study, we utilized wireless headphones, Kardia electrocardiography system, autonomic blood pressure cuff, fast song: Beethoven’s Symphony of Fate, slow song: Beethoven’s Moonlight Sonata, mood survey, and tablet.A five-questionnaire mood survey was designed by the study authors specifically for this study.ProcedureAfter participants were briefed about the study and consent was obtained, subjects sat for one minute and then asked for his/her age, gender, if he/she enjoys classical music, takes any medications, and is a musician. Then the resting heart rate and blood pressure of the subject were taken using an EKG system and a blood pressure monitor. The subject then listened to a fast classical piece (first movement of Symphony of Fate). The heart rate was recorded on the EKG system 40 seconds into the song. The blood pressure of the same subject was recorded after the performance. The study subject then completed a mood survey followed by a minute break to allow the heart rate and blood pressure to normalize.Next, the subject listened to a slow classical piece (Moonlight Sonata 1). The heart rate was checked on the EKG system 90 seconds into the song. The blood pressure of the same subject was recorded after the performance. The study subject then completed a mood survey.Data analysisThe mean heart rate, systolic blood pressure, and diastolic blood pressure were calculated using a two-tailed t-test. Statistical significance was defined by a p-value <0.05. Excel  and SPSS 28.0 software  were utilized for statistical analysis.Subgroup analysisSubgroup analysis was performed by age stratification , gender, and if a participant is a musician. All data was stored confidentially. Patient names were de-identified and listed as numerical values.The study was approved by The Avery Coonley School institutional ethics committee, Downers Grove, Illinois.A total of 100 participants were enrolled in the study. There were 53 males and 47 females. The mean age for participants was 39.8 years old +/- 17.8. Forty percent of the participants were musicians. Thirty-five percent of the subjects were on medications. Sixty-two percent of participants enjoyed classical music.Subjects had a mean resting HR of 75.7 +/- 17.8 beats per minute, mean resting systolic blood pressure of 116.0 +/- 10.9 millimeters of mercury, mean resting diastolic blood pressure of 73.15 +/- 10.0 millimeters of mercury, and a mean arterial pressure of 87.5 +/- 9.4 millimeters of mercury. With fast music, the mean heart rate was 83.0 +/- 11.9 beats per minute, mean systolic blood pressure of 122.1 +/- 13.9 millimeters of mercury, and a mean diastolic blood pressure of 79.7 +/- 11.2 millimeters of mercury. For slow music, the mean systolic blood pressure was 110.5 +/- 9.7 millimeters of mercury, and a mean diastolic blood pressure of 70.7 +/- 9.8 millimeters of mercury. The mean difference in resting, fast music, and slow music heart rate, systolic blood pressure, and diastolic blood pressure was statistically significant . The mean score for mood survey Q1 “how uplifting the song was” was 4.2 +/- 1.0 for fast music and 2.9 +/- 1.0 for slow music .The resting systolic blood pressure for <25, 25 to 55, and >55 years old was 107.0 +/- 10.7 millimeters of mercury, 117.8 +/- 10.5 millimeters of mercury, and 117.7 +/- 13.2 millimeters of mercury. After listening to fast music, the systolic blood pressure for <25, 25 to 55, and >55 years old increased to 106.6 +/- 12 millimeters of mercury, 125.6 +/- 11.7 millimeters of mercury, and 124.3 +/- 10.8 millimeters of mercury, respectively. After listening to slow music, the systolic blood pressure for <25, 25 to 55, and >55 years old decreased to 106.2 +/- 8.7 millimeters of mercury, 111.6 +/- 9.5 millimeters of mercury, and 110.4 +/- 10.8 millimeters of mercury. With regards to systolic blood pressure, those subjects <25 years old had a statistically lower systolic blood pressure as compared to the other two groups .The major findings of this study include: one, listening to fast music increased heart rate, systolic, and diastolic blood pressure; two, listening to slow music decreased heart rate, systolic, and diastolic blood pressure; three, mood survey scores were favorable for both fast and slow music. Fast music was viewed as uplifting with a mean score of 4.2 +/- 1.0 (out of 5). Listening to slow music was viewed as calming with a mean score of 4.5 +/- 0.8 (out of 5). For fast and slow songs, 98% and 99% of subjects reported that the music could help manage stress respectively. The mean difference in resting, slow, and fast heart rate, systolic blood pressure, and diastolic blood pressure were all statistically significant.To further analyze the study data, the following subgroup analysis was completed: age stratification , gender differences, and whether subjects were musicians. Subjects <25 years old had a statistically lower resting systolic blood pressure as compared to the other two groups (p = .001). Listening to slow music reduced all systolic blood pressures highlighting the calming effect of slow music and the therapeutic potential for slow, classical music.The study did not identify gender differences in resting heart rate, systolic, and diastolic blood pressure, emphasizing the uniform benefit of music in both males and females. Musicians did have a statistically significantly lower systolic blood pressure after listening to music (p = .001) possibly related to pleasant memories from prior musical experiences.The physiologic changes in heart rate and blood pressure while listening to fast and slow music are complex. Music affects the cardiovascular system through multiple potential mechanisms. One pathway includes brain signals responding to music rhythms through signal activations to organs of the body, including the heart, which then respond to the tempo of the song -- i.e., when the tempo is fast, the heart rate and blood pressure speed up, and when the tempo is slow the heart rate and blood pressure slow down . SimilarAnother pathway explaining the effect of music on the cardiovascular system is the role of the autonomic system. Ellis and Thayer described how heart rate is under the control of the parasympathetic nervous system through the vagus nerve , 9. The Music also affects other parts of the brain, which in turn affects the mood through the release of neurotransmitters such as dopamine. Ellis and Thayer described the release of dopamine from the nucleus accumbens after listening to pleasurable, classical music . SalimpoFinally, nearly all subjects in the study found that music can help manage stress. This has been previously reported. Agrawal et al. demonstrated that people use music as a tool to improve their emotions or their athletic performance . AdditioThe study has several important limitations. First, there were fluctuations in the testing environment and in the subjects’ baseline stress levels. For example, some subjects were not comfortable being tested inside due to the COVID-19 pandemic which resulted in varying conditions that could potentially affect outcomes. Also, subjects who entered the study with higher levels of stress may have experienced a higher heart rate and blood pressure than those who were more relaxed. Second, while the study enrolled 100 subjects, the standard deviations of approximately +/- 10 in each cohort can be improved by a larger sample size. Additionally, only 16% of subjects were under the age of 25 years old and 18% >55 years old. There were no significant outliers in the study.In conclusion, our study suggests classical music has a positive impact on the cardiovascular system and potential emotional benefits. Music affects the cardiovascular system through multiple potential mechanisms including the autonomic nervous system and the vagus nerve which responds to musical vibrations by triggering the body to relax. Music also affects other parts of the brain, which in turn affects the mood through the release of neurotransmitters such as dopamine. Dopamine release may contribute to the study findings which found that 83% of subjects found fast music uplifting. Finally, nearly all subjects believe music can help manage stress. Listening to music may be a potential therapeutic method for reducing anxiety and depression. Given the large sample size, the study adds greatly to the current literature by validating the results of other smaller studies.