Background:Cystatin C (CysC), a low-molecular-weight protein, is widely used as a biomarker of renal function. The relationship between CysC and cognitive impairment remains controversial. This study aimed to investigate the association between CysC and cognitive impairment in the Hanzhong Adolescent Hypertension Study. Methods:A total of 2,347 participants completed the Mini-Mental State Examination (MMSE) in 2023, after excluding the participants missing data, 1929 participants were included. Multivariable logistic regression was used to assess the cross-sectional association between serum CysC levels and cognitive impairment. Subgroup and interaction analyses were performed to examine effect modification by albuminuria status. The nonlinear relationship was explored using restricted cubic splines (RCS). Results:Cognitive impairment was identified in 149 participants (7.72%). Each 1-SD increase in CysC levels was significantly associated with 49% higher odds of cognitive impairment after full adjustment [odds ratio (OR) = 1.49, 95% confidence interval (CI): 1.24-1.79, p < 0.001]. Compared with participants in the lowest CysC quartile, those in the highest quartile had significantly higher odds of cognitive impairment (OR = 1.79, 95% CI = 1.09-2.98, p = 0.022). The association was stronger in participants without albuminuria (OR per SD = 1.48, 95% CI: 1.22-1.80, p < 0.001) but absent in those with albuminuria (OR per SD = 1.00, 95% CI: 0.73-1.25, p = 0.981), with a significant interaction when CysC was modeled continuously (p for interaction = 0.028). A linear and positive association was observed between cystatin C levels and the prevalence of cognitive impairment (p for linearity < 0.001). This association remained significant in the non-albuminuria subgroup. Conclusion:Elevated CysC is associated with cognitive impairment assessed by MMSE in this midlife natural population cohort. This association is stronger in participants without albuminuria.

Aims: This study aims to characterize the heterogeneity of the cardiovascular-kidney-liver-metabolic (CKLM) spectrum and to assess the independent, synergistic, and competitive effects of liver fibrosis risk (FIB-4 index) and cardiovascular-kidney-metabolic (CKM) risk on mortality. Methods: This study included 28,056 U.S. adults from the NHANES (2005-2016) with a median follow-up of 9.08 years. Using Cox proportional hazards regression, restricted cubic splines, and sensitivity analyses, the primary analysis evaluated the associations of composite heterogeneous phenotypes—defined by CKM stage (low-risk: 0-2; high-risk: 3-4) and FIB-4 index (low, intermediate, high)—with all-cause and cardiovascular mortality. Results: In the community-based population, detectable liver disease risk often precedes CKM risk and affects a broader population. Among the five high-risk heterogeneous phenotypes (collectively 31.2%), the "CKM-low/FIB-4-intermediate" phenotype was the most prevalent (16.2%), carried a significant mortality risk, and increased over the study period. The "CKM-low/FIB-4-high" phenotype (1.4%) represents a cardiometabolically healthy but high-mortality-risk phenotype. Compared to the dual-low-risk phenotype (68.8%), the dual-high-risk phenotype (1.3%) was associated with a 621% (HR=7.21) and a 1307% (HR=14.07) increase in all-cause and cardiovascular mortality risk, respectively. Individually, elevated FIB-4 conferred similar magnitudes of increased risk for all-cause and cardiovascular mortality, whereas elevated CKM conferred a cardiovascular mortality risk increase approximately twice that of all-cause mortality. A competitive risk interaction was observed: the hazard ratio (HR) for all-cause mortality associated with an increase in FIB-4 from low to high was 5.29 in the CKM-low group, compared to 2.98 in the CKM-high group. Among individuals with high FIB-4 risk, further progression from low to high CKM risk did not contribute additional mortality risk. Conclusions: Liver fibrosis risk (FIB-4 index) and CKM stage independently, synergistically, and competitively increase mortality risk. Their combined stratification identified six heterogeneous CKLM phenotypes, increasing the proportion of the population identified as high-risk from 13.6% (using CKM alone) to 31.2%, thereby achieving more precise risk stratification.KeywordsCKM syndrome​, FIB-4 index​, Liver fibrosis​, All-cause mortality​, Cardiovascular mortality​, Risk stratification

BackgroundEvidence is limited on the prospective prognostic value of longitudinal blood pressure (BP) and resting heart rate (RHR) dynamics after percutaneous coronary intervention (PCI).AimThis study aimed to identify joint BP-RHR trajectories and evaluate their impact on net adverse clinical events (NACE).MethodsIn a prospective post-PCI cohort, latent class trajectory modeling identified 6-month patterns of systolic BP, diastolic BP, and RHR, classifying patients into four joint trajectories. Inverse probability of treatment weighting (IPTW) was employed to rigorously balance baseline confounders. The primary endpoint was NACE. The incremental predictive value of the joint trajectories was assessed using the C-index, continuous net reclassification improvement (cNRI), and integrated discrimination improvement (IDI).ResultsAmong 736 patients (71 NACE events during follow-up), four distinct joint trajectory groups were identified: Double Stable (n = 329), BP-Fluctuating (n = 215), RHR-Fluctuating (n = 108), and Double Fluctuating (n = 84). After IPTW adjustment, compared with the Double Stable group, the risk of NACE was significantly elevated in the BP-Fluctuating group (HR: 2.21, 95% CI: 1.23–3.97), the RHR-Fluctuating group (HR: 1.85, 95% CI: 1.09–3.13), and peaked in the Double Fluctuating group (HR: 2.69, 95% CI: 1.18–6.14). Furthermore, incorporating the joint trajectory groups into a baseline clinical risk model significantly improved prognostic discrimination and reclassification, with significant increases in the C-index (p < 0.001), IDI improvement (p = 0.033), and continuous net reclassification improvement.ConclusionJoint BP and RHR trajectories effectively stratify post-PCI NACE risk. Patients with combined fluctuations face the highest risk, highlighting the need for dynamic hemodynamic monitoring over static single-point assessments.

OBJECTIVE:To investigate how integrated patterns of time use behaviors (sleep, work, and physical activity) within a fixed limited time frame associate with health outcomes related to cardiovascular disease (CVD) and depression, as well as their potential mediating role in the relationship between depression and CVD. PARTICIPANTS AND METHODS:Using the National Health and Nutrition Examination Survey (NHANES 2005-2018), we analyzed cross-sectional (n≈37,939 to 42,395) and prospective cohort (n≈23,625 to 29,698) data. Outcomes included all-cause/cardiovascular mortality, major adverse cardiovascular events, CVD risk factors, and depression. A novel time use optimization algorithm defined 27 distinct behavioral patterns (classified as favorable, moderate, or unfavorable) based on joint sleep-work-activity ranges. Associations were assessed via Cox regression and generalized linear models; mediation analysis quantified behavioral contributions to depression-CVD comorbidity. RESULTS:Among 23,625 participants, 6 favorable patterns (eg, stable work with protected sleep/activity) were associated with half the risk of all-cause mortality (hazard ratio, 0.52; 95% CI, 0.40 to 0.67) and depression (odds ratio, 0.50; 95% CI, 0.39 to 0.64) vs moderate patterns, alongside reduced cardiovascular risks. Three unfavorable patterns (eg, unemployment with sleep dysregulation) doubled mortality (hazard ratio, 2.06; 95% CI, 1.83 to 2.31) and depression risk (odds ratio, 2.47; 95% CI, 2.11 to 2.89). Crucially, these patterns mediated 44.4% (0.0023 of 0.0052) of the depression-major adverse cardiovascular events association and 44.6% (0.5521 of 1.2383) of the reverse association. CONCLUSION:Within the 24-hour time constraint, integrated sleep-work-activity patterns are strongly associated with cardiometabolic/mental health and mediate nearly half of depression-CVD comorbidity. This finding supports a paradigm shift toward personalized time use recommendations for joint disease prevention.

OBJECTIVE:We investigated the associations between BMI transitions from childhood to adulthood and cardiovascular-kidney-metabolic (CKM) syndrome and its components in midlife. RESEARCH DESIGN AND METHODS:Using data from the Hanzhong Adolescent Hypertension Study, 1,997 participants aged 6-18 years were followed for 36 years into midlife (mean age 48.12 years). Participants were categorized into four groups based on BMI transitions from childhood to midlife: control, incident, persistent, and resolution. CKM stages ranged from early (stages 0-1), to intermediate (stage 2), to advanced (stages 3-4), defined by cardiovascular disease, chronic kidney disease, and metabolic disorders. Multivariable regression models were used to assess associations between BMI transitions and CKM outcomes. RESULTS:Individuals transitioning from normal childhood BMI to overweight in adulthood had higher risks of intermediate (odds ratio [OR] 5.19 [95% CI 3.15-8.53]) and advanced CKM stages (OR 6.70 [95% CI 3.96-11.33]) compared with those with persistently normal BMI. These risks were attenuated if elevated childhood BMI resolved by adulthood. For specific CKM components, individuals with normal childhood BMI but overweight in adulthood showed higher risks of left ventricular diastolic dysfunction, subclinical kidney damage, albuminuria, and metabolic abnormalities compared with those with persistently normal BMI. These risks were reduced if high childhood BMI normalized by adulthood. CONCLUSIONS:Transitioning from normal childhood BMI to overweight in adulthood is associated with increased risks of higher CKM stages in midlife. However, individuals whose high childhood BMI resolved by adulthood exhibit similar risk to those with persistently normal BMI.

MicroRNAs (miRNAs) are small endogenous RNA molecules that play an essential role in various disease processes including elevated blood pressure (BP). Although the effects of dietary salt and potassium intake on BP regulation have been established, their co-interaction with miRNAs are still unclear. The purpose of the current study was to explore the connection between miRNA gene polymorphisms and BP response to salt and potassium intake, and the relationship between miRNA gene polymorphisms and long-term BP changes and hypertension development. A total of 333 participants underwent a chronic sodium-potassium dietary intervention trial, which included a 3-day normal diet, followed by a 7-day low-salt diet, then a 7-day high-salt diet, and finally a 7-day high-salt with potassium-supplemented diet. This cohort was subsequently followed for up to 14 years. Single-nucleotide polymorphisms (SNPs) rs115254818 in miR-26b-3p, rs11191676 and rs2292807 in miR-1307-5p, and rs4143957 in miR-382-5p were significantly correlated with systolic BP (SBP) and mean arterial pressure (MAP) responses to high-salt intake, whereas rs11191676 and rs2292807 in miR-1307-5p exhibited significant associations with SBP response to potassium-supplemented diet. Furthermore, SNPs rs2070960 in miR-3620-5p and rs12364149 in miR-210-3p demonstrated significant correlations with diastolic BP and MAP alterations at 14 years of follow-up. Generalized linear mixed model analysis revealed a significant association between rs2070960 in miR-3620-5p and hypertension development over a 14-year period. Our study indicates that miRNA gene polymorphisms are pivotal in the salt and potassium sensitivity of BP, as well as in the longitudinal BP progression and hypertension incidence. Trial Registration: ClinicalTrials.gov identifier: NCT02734472.

Background Elevated blood pressure (BP) in childhood is associated with adult hypertension and arterial stiffness. However, the effect of long-term time in target range (TTR) for BP since childhood on the risk of arterial stiffness in midlife remains unclear. Objectives The purpose of this study was to determine the independent association of TTR for systolic blood pressure (SBP) from childhood to midlife with arterial stiffness in adulthood. Methods This study used data from the ongoing cohort of the Hanzhong Adolescent Hypertension Study. SBP-TTR was assessed over 36 years, with the target ranges of SBP defined as the 90th to 95th percentile of SBP for age, sex, and height in childhood, and 110 to 130 mm Hg in adulthood. Arterial stiffness was defined as brachial-ankle pulse wave velocity >1,400 cm/s. Results Of the total 1,959 participants, 55.5% (1,088 of 1,959) were men, and the mean age was 49 years. The risk of arterial stiffness exhibited a gradual decrease with increasing SBP-TTR over the 36-year follow-up. Compared with the participants in the lowest quartile of SBP-TTR from childhood to midlife, those in the highest quartile showed significantly reduced arterial stiffness risk in midlife. This association persisted even after adjusting for mean SBP and SBP variability. Furthermore, men in the highest quartile of SBP-TTR demonstrated a markedly lower arterial stiffness risk than those in the lowest quartile, whereas this effect was not observed in women. Conclusions Higher long-term SBP-TTR from childhood to midlife is associated with a reduced risk of arterial stiffness in midlife, regardless of the mean SBP or SBP variability.

Salt-sensitive hypertension (SSH) is a major risk factor for cardiovascular disease, but its metabolic mechanisms remain unclear. This study investigates the plasma metabolic profile of SSH patients to identify potential therapeutic targets. Additionally, SSH patients were identified through an oral salt-loading test. Plasma metabolomics was performed by utilizing GC-MS and LC-MS, followed by network correlation analysis, pathway enrichment, receiver operating characteristic analysis, and linear regression analysis. The findings were validated in Dahl salt-sensitive (SS) rats, with glycine supplementation evaluated as a potential therapeutic intervention. Firstly, plasma metabolomics illustrated distinct metabolic alterations in SSH patients, with substantially increased levels of fumaric acid, pyruvat,e and lactic acid, as well as significantly decreased levels of glycine, leucine and β-alanine (p < 0.05). Additionally, Glycine and β-alanine levels decreased by 61% and 68% compared to the control group. Secondly, pathway enrichment analysis identified disruptions in amino acid metabolism, particularly Arginine biosynthesis pathway, TCA pathway, glycine, serine, and threonine metabolism pathways were significantly enriched (p < 0.05). Correlation network analysis identified fumarate as a hub metabolite in the pathophysiology of SSH. Glycine showed the highest predictive value for SSH (AUC = 94.6181%) and was negatively correlated with blood pressure. Finally, glycine supplementation in SS rats substantially reduced salt-induced hypertension (p < 0.001) by improving renal amino acid metabolism and enhancing nitric oxide production. This study identifies glycine as a crucial metabolic target for SSH intervention. Glycine supplementation effectively alleviates SSH in animal models, indicating its potential for clinical applications. Future research should focus on exploring glycine-based therapies in clinical trials. Intervention targets and validation of salt-sensitive hypertension.

On the basis of the contribution of the gut microbiota to hypertension development, a novel strategy involving fecal microbiota transplantation (FMT) has been proposed to treat hypertension, but its efficacy has not been investigated in the clinic. In a randomized, blinded, placebo-controlled clinical trial (2021/03–2021/12, ClinicalTrials.gov, NCT04406129), hypertensive patients were recruited from seven centers in China, and received FMT or placebo capsules orally at three visits. The patients were randomized at a 1:1 ratio in blocks of four and stratified by center by an independent statistician. The intention-to-treat principle was implemented, as all randomized participants who received at least one intervention were included. The primary outcome was the decrease in office systolic blood pressure (SBP) from baseline to the day 30 visit. Adverse events (AEs) were recorded through the 3-month follow-up to assess safety measures. Alterations in BP, the fecal microbiome, and the plasma metabolome were assessed via exploratory analyses. This study included 124 patients (mean age 43 years, 73.4

Objective: Elevated blood pressure (BP) in childhood is associated with adult hypertension and arterial stiffness. We aimed to determine the independent association of time in target range (TTR) for systolic blood pressure (SBP) from childhood to midlife with arterial stiffness in midlife. Design and method: Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, 1959 children and adolescents aged 6 to 18 years were enrolled at baseline. We assessed SBP-TTR from childhood to adulthood for 36 years, with the target range of SBP defined as 90th – 95th percentile for age, sex, and height in childhood, and 110 to 130 mmHg in adulthood. Results: During the 36 years of follow-up, the risk of arterial stiffness gradually decreased with increasing TTR for SBP. After fully adjustment for traditional cardiovascular risk factors, comparing the highest vs. lowest quartiles of TTR for SBP, the odds ratios (ORs) [95% confidence intervals (CIs)] were 0.642 (0.452-0.911) for the risk of arterial stiffness in adulthood. TTR remained significantly associated with arterial stiffness despite adjustment for mean SBP or SBP variability. In addition, males with highest quartile of SBP-TTR was significantly associated with a decreased risk of arterial stiffness [OR 95% CI, 0.432 (0.262-0.710)], while no significant difference was found in females compared with the lowest TTR group. Conclusions: Higher long-term TTR for SBP from childhood to adulthood was associated with a decreased risk of arterial stiffness in adulthood independent of mean BP or BP variability. Therefore, SBP-TTR from an early age might serve as a modifiable risk factor for future cardiovascular diseases in later life.

BACKGROUND:The association between the serum uric acid-to-high-density lipoprotein cholesterol ratio (UHR) and cardiovascular disease (CVD) risk in Asian populations with metabolic dysfunction-associated steatotic liver disease (MASLD) remains insufficiently elucidated. AIM:To investigate the relevance and dose-responsive relationship between UHR and 10-year CVD risk among Asian MASLD patients. METHODS:In this retrospective analysis, 3901 MASLD patients were enrolled based on established screening criteria. As measured by the Framingham risk score, participants were stratified according to their 10-year CVD risk. The association between UHR and CVD risk was evaluated using binary logistic regression, while dose-response patterns were explored through restricted cubic spline (RCS) modeling. The discriminatory capability of UHR, in comparison with conventional biomarkers, was further examined by receiver operating characteristic curve analysis. RESULTS:Multivariable-adjusted analyses revealed that elevated UHR levels were significantly associated with an increased likelihood of intermediate-to-high CVD risk. RCS modeling demonstrated a linear dose-response relationship between UHR and the Framingham risk score (P for nonlinearity = 0.114). Sex-stratified RCS analyses further indicated that this linear association persisted among males (P for nonlinearity = 0.167) but was not statistically significant in females (P for nonlinearity = 0.476). Further stratified analyses revealed that the association was particularly pronounced among younger individuals (< 50 years), males, and those with central obesity, whereas it was attenuated in older adults (≥ 50 years) and females. Receiver operating characteristic analysis demonstrated that UHR outperformed individual biomarkers in predicting 10-year CVD risk, showing an area under the curve of 0.655 (95% confidence interval: 0.635-0.674). CONCLUSION:UHR functioned as an independent predictor of 10-year CVD risk in Asian patients with MASLD, demonstrating a linear dose-response association and superior discriminative performance relative to conventional biomarkers, especially among younger individuals, males, and those with central obesity.

Aim: Despite the well-documented pathogenic role of insulin resistance (IR) and hypertension in nephropathy progression, the prognostic value of the estimated glucose disposal rate (eGDR) for incident renal dysfunction remains unclear. This population-based longitudinal analysis specifically examined the eGDR-renal dysfunction relationship in middle-aged and elderly populations, with a particular focus on the potential mediating role of systolic blood pressure (SBP) based on a nationwide longitudinal study. Methods: Utilizing data from 8,136 participants in the China Health and Retirement Longitudinal Study (CHARLS, 2011- 2015), we conducted multivariable-adjusted logistic regression analyses combined with a restricted cubic spline model to assess the association between eGDR and incident renal dysfunction. Mediation analysis was employed to assess the proportion of the association mediated by SBP in this relationship. Results: Over a median follow-up period of 4 years, 2,223 participants developed renal dysfunction. Both eGDR and SBP were significantly and independently associated with incident renal dysfunction. The odds ratio (OR) for eGDR was 0.73 (95%CI: 0.58- 0.92), while the OR for SBP was 1.20 (95%CI: 1.05- 1.38). Restricted cubic spline analysis identified critical thresholds, with eGDR levels below 11.6 mg/kg/min and SBP levels above 125 mmHg being associated with a higher risk of renal dysfunction. Mediation analysis further demonstrated that SBP acted as a significant mediator in the relationship between eGDR and renal dysfunction, accounting for 42.6% of the total effect (95%CI: 19.9%- 86.7%). Conclusion: This prospective cohort study identifies eGDR as an independent predictor of renal dysfunction, with nearly half of its effect mediated by SBP. These findings highlight the potential benefit of integrated management strategies targeting both insulin sensitivity and blood pressure control to reduce the risk of renal dysfunction in aging populations.

Aim: The post-COVID-19 pandemic era has witnessed changes in psychological states and lifestyles. This study aims to explore the associations between depression, obesity, and hypertension, and further assess the mediating effects of lifestyle factors such as sleep duration, working hours, and physical activity on these disease relationships. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2023, we calculated long-term trends in depression, sleep duration, working hours, metabolic equivalent of exercise, obesity, and blood pressure. Data from 42,395 (sleep duration), 23,101 (working hours), and 20,435 participants (physical activity) were used to evaluate the relationships between lifestyle factors, depression, obesity, and blood pressure. Results: Between 2021 and 2023, the average depression score in the U.S. increased to 4.13 (4.74), with prevalence rising to 13.2%. Over the past 18 years, national body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and sleep duration increased (P < 0.001), while working hours decreased (P < 0.001) and physical activity declined post-pandemic (P < 0.001). Depression was positively correlated with BMI, WC, WHtR, and diastolic blood pressure (DBP) (P < 0.0001), and negatively correlated with systolic blood pressure, sleep duration, and physical activity (P < 0.0001). Sleep duration and physical activity mediated 1.72%- 4.52% and 9.28%-14.79%, respectively, of the positive correlation between depression and obesity. Physical activity mediated 5.49%-9.96% of the positive correlation between depression and DBP. No mediating effect of working hours was found between depression and obesity or blood pressure (P = 0.500-0.936). Conclusion: In the post-COVID-19 pandemic era, this study advocates for increased attention to lifestyle factors. Moderate extensions in sleep duration, reductions in working hours, and increased physical activity may help alleviate the burdens of depression, obesity, and blood pressure.

Childhood blood pressure (BP) is associated with increased arterial stiffness later in life. This study aimed to investigate the contributions of BP across different life stages to midlife arterial stiffness and the mediating role of metabolic factors. Using data from the Hanzhong Adolescent Hypertension Study, 1448 participants aged 6-18 years at baseline were prospectively followed for 30 years into adulthood. We used linear regression models to examine the associations between BP at different life stages and brachial-ankle pulse wave velocity (baPWV). In addition, parallel multiple mediation analyses were conducted to evaluate the mediating roles of blood glucose and lipid metabolism in these associations. Significant associations between BP and adult baPWV were observed across childhood, adulthood, and cumulative long-term BP burden, with BP in adulthood showing the strongest association. Additionally, the triglyceride-glucose index was identified as a mediator in the relationship between adult BP and midlife baPWV, with the mediation effects more pronounced among males. Our findings suggest that the detrimental impact of elevated BP on arterial stiffness begins early in life and intensifies over the lifespan, particularly during adulthood. Furthermore, the association between adult BP and arterial stiffness appears to be partially mediated by insulin resistance.

Nuclear receptor subfamily 3 group C member 2 (NR3C2) encodes the mineralocorticoid receptor (MR), which plays a pivotal role in the regulation of electrolyte and fluid homeostasis by mediating the physiological actions of mineralocorticoids, primarily aldosterone. In this study, we analyzed data from the Baoji Salt-Sensitivity Study, a population-based dietary intervention conducted in 2004 in northern China. A total of 514 adults from 124 families were enrolled and underwent a controlled salt intake protocol consisting of a 3-day baseline diet, followed by sequential 7-day low-salt (3.0 g/day) and high-salt (18.0 g/day) phases. Participants were prospectively followed for 14 years to evaluate the long-term incidence of hypertension. Our results demonstrated a significant negative association between the NR3C2 single nucleotide polymorphism (SNP) rs5522 and pulse pressure (PP) response during the low-salt intervention. During the high-salt phase, rs5522 was significantly associated with systolic blood pressure (SBP), while SNP rs3910053 showed significant negative correlations with SBP, diastolic blood pressure (DBP), and mean arterial pressure (MAP). Furthermore, rs3910053 was significantly associated with the incidence of hypertension over 14 years. These findings highlight the important role of NR3C2 in salt sensitivity (SS) and the risk of developing hypertension in the Chinese population. Trial Registration: ClinicalTrials.gov. registration number: NCT02734472.