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Abstract Background Polymerase delta-interacting protein 2 (Poldip2) is a novel regulator of vascular permeability that has been shown to be involved in aggravating blood–brain barrier (BBB) disruption following stroke; however, the underlying mechanisms are unknown. While endothelial tight junctions (TJ) are critical mediators of BBB permeability, the effect of Poldip2 on TJ function has not been elucidated yet. Here, we aim to define the mechanism by which Poldip2 mediates BBB disruption, specifically focusing on phosphorylation and stabilization of the TJ integral protein ZO-1. Methods and Results Cerebral ischemia was induced in endothelial-specific Poldip2 knockout mice and controls. Cerebral vascular permeability was assessed by Evans blue dye extravasation. Endothelial-specific Poldip2 deletion abolished Evans blue dye extravasation after ischemia induction. In vitro permeability assays demonstrated that Poldip2 knockdown suppressed TNF-α-induced endothelial cell (EC) permeability. Immunofluorescence staining showed that Poldip2 depletion prevented TNF-α-induced ZO-1 disruption at interendothelial junctions. Conversely, Poldip2 overexpression increased endothelial permeability, loss of ZO-1 localization at cell–cell junctions and enhanced reactive oxygen species (ROS) production. Treatment with the antioxidant N-acetyl cysteine (NAC) reduced Poldip2-induced ZO-1 disruption at inter interendothelial junctions. Immunoprecipitation studies demonstrated Poldip2 overexpression induced tyrosine phosphorylation of ZO-1, which was prevented by treatment with NAC or MitoTEMPO, a mitochondrial ROS scavenger. Conclusions These data reveal a novel mitochondrial ROS-driven mechanism by which Poldip2 induces ZO-1 tyrosine phosphorylation and promotes EC permeability following cerebral ischemia. Graphical Abstract

ABSTRACT 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

Abstract Nocturnal hypertension is highly prevalent among Chinese and Asian populations, which is mainly attributed to high salt intake and high salt sensitivity. Nocturnal hypertension increases the risk of cardiovascular and all‐cause mortality, independent of daytime blood pressure (BP). However, it can usually be detected by 24‐h ambulatory BP monitoring, rather than routine office or home BP measurement, thus is often underdiagnosed in clinical practice. Currently, no specific guidance is available for the management of nocturnal hypertension in China or worldwide. Experts from the Chinese Hypertension League summarized the epidemiologic and pathophysiologic characteristics and clinical phenotype of nocturnal hypertension and provided consensus recommendations on optimal management of nocturnal hypertension, with the goal of maximally reducing the cardiovascular disease risks. In this consensus document, 24‐h ABPM is recommended for screening and diagnosis of nocturnal hypertension, especially in the elderly, patients with diabetes, chronic kidney diseases, obstructive sleep apnea and other conditions prone to high nocturnal BP. Lifestyle modifications including salt intake restriction, exercise, weight loss, sleep improvement, and mental stress relief are recommended. Long‐acting antihypertensive medications are preferred for nocturnal and 24‐h BP control. Some newly developed agents, renal denervation, and other device‐based therapy on nocturnal BP reduction are evaluated.

Abstract Recent studies have reported the role of the M3 muscarinic acetylcholine receptor (M3R), a member of the G‐protein coupled receptor superfamily, encoded by the CHRM3 gene, in cardiac function and the regulation of blood pressure (BP). The aim of this study was to investigate the associations of CHRM3 genetic variants with salt sensitivity, longitudinal BP changes, and the development of hypertension in a Chinese population. We conducted a chronic dietary salt intervention experiment in a previously established Chinese cohort to analyze salt sensitivity of BP. Additionally, a 14‐year follow‐up was conducted on all participants in the cohort to evaluate the associations of CHRM3 polymorphisms with longitudinal BP changes, as well as the incidence of hypertension. The single nucleotide polymorphism (SNP) rs10802811 within the CHRM3 gene displayed significant associations with low salt‐induced changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), while rs373288072, rs114677844, and rs663148 exhibited significant associations with SBP and MAP responses to a high‐salt diet. Furthermore, the SNP rs58359377 was associated with changes in SBP and pulse pressure (PP) over the course of 14 years. Additionally, the 14‐year follow‐up revealed a significant association between the rs619288 polymorphism and an increased risk of hypertension (OR = 1.74, 95% CI: 1.06‐2.87, p = .029). This study provides evidence that CHRM3 may have a role in salt sensitivity, BP progression, and the development of hypertension.

Abstract Sodium intake shows a positive correlation with blood pressure, resulting in an increased risk for cardiovascular diseases (CVD). Salt reduction is a key step toward the WHO's goal of 25% reduction in mortality from non‐communicable diseases (NCDs) by 2025. This study aims to assess the current condition and temporal changes of the global CVD burden due to high sodium intake (HSI). We extracted data from the Global Burden of Disease (GBD) study 2019. The numbers and age‐standardized rates of mortality and disability‐adjusted life‐years (DALYs), stratified by location, sex, and socio‐demographic Index (SDI), were used to assess the high sodium intake attributable CVD burden from 1990 to 2019. The relationship between the DALYs rates and related factors was evaluated by stepwise multiple linear regression analysis. Globally, in 2019, the deaths and DALYs of HSI‐related CVD were 1.72 million and 40.54 million, respectively, increasing by 41.08% and 33.06% from 1990. Meanwhile, the corresponding mortality and DALYs rates dropped by 35.1% and 35.2%, respectively. The high‐middle and middle SDI quintiles bore almost two‐thirds of CVD burden caused by HSI. And the leading cause of HSI attributable CVD burden was ischemic heart disease. Universal health coverage (UHC) was associated with the DALYs rates after adjustment. From 1990 to 2019, the global CVD burden attributable to HSI has declined with spatiotemporal and sexual heterogeneity. However, it remains a major public health challenge because of the increasing absolute numbers. Improving UHC serves as an effective strategy to reduce the HSI‐related CVD burden.

Abstract Background Lipid management with a low-density lipoprotein cholesterol (LDL-C) goal of

Summary: Background: Limited data exists on how early-life weight changes relate to metabolic syndrome (MetS) risk in midlife. This study examines the association between long-term trajectories of body mass index (BMI), its variability, and MetS risk in Chinese individuals. Methods: In the Hanzhong Adolescent Hypertension study (March 10, 1987–June 3, 2017), 1824 participants with at least five BMI measurements from 1987 to 2017 were included. Using group-based trajectory modeling, different BMI trajectories were identified. BMI variability was assessed through standard deviation (SD), variability independent of the mean (VIM), and average real variability (ARV). Logistic regression analyzed the relationship between BMI trajectory, BMI variability, and MetS occurrence in midlife (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02734472). Findings: BMI trajectories were categorized as low-increasing (34.4%), moderate-increasing (51.8%), and high-increasing (13.8%). Compared to the low-increasing group, the odds ratios (ORs) [95% CIs] for MetS were significantly higher in moderate (4.27 [2.63–6.91]) and high-increasing groups (13.11 [6.30–27.31]) in fully adjusted models. Additionally, higher BMI variabilities were associated with increased MetS odds (ORs for SDBMI, VIMBMI, and ARVBMI: 2.30 [2.02–2.62], 1.22 [1.19–1.26], and 4.29 [3.38–5.45]). Furthermore, BMI trajectories from childhood to adolescence were predictive of midlife MetS, with ORs in moderate (1.49 [1.00–2.23]) and high-increasing groups (2.45 [1.22–4.91]). Lastly, elevated BMI variability in this period was also linked to higher MetS odds (ORs for SDBMI, VIMBMI, and ARVBMI: 1.24 [1.08–1.42], 1.00 [1.00–1.01], and 1.21 [1.05–1.38]). Interpretation: Our study suggests that both early-life BMI trajectories and BMI variability could be predictive of incident MetS in midlife. Funding: This work was supported by the National Natural Science Foundation of China No. 82070437 (J.-J.M.), the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University of China (No. XJTU1AF-CRF-2022-002, XJTU1AF2021CRF-021, and XJTU1AF-CRF-2023-004), the Key R&D Projects in Shaanxi Province (Grant No. 2023-ZDLSF-50), the Chinese Academy of Medical Sciences & Peking Union Medical College (2017-CXGC03-2), and the International Joint Research Centre for Cardiovascular Precision Medicine of Shaanxi Province (2020GHJD-14).

Abstract Background The new visceral adiposity index (NVAI) was superior to previous obesity indices in predicting cardiovascular diseases among Asians. Nevertheless, the utility of the NVAI for predicting chronic kidney disease is still unclear. The objective of this research was to explore the relationship between the NVAI and subclinical renal damage (SRD) and to investigate whether the NVAI outperforms other common obesity indices in predicting SRD in the Chinese population. Methods Participants in this cross-sectional study were from the Hanzhong Adolescent Hypertension Cohort. The NVAI and seven other common obesity indices were calculated, including body mass index, waist circumference, lipid accumulation product, visceral adiposity index, Chinese visceral adiposity index, a body shape index and metabolic score for visceral fat. Logistic regression models revealed the association between NVAI and SRD. The odds ratio (OR) and the 95% confidence interval (CI) were calculated to show the association between the two variables. The predictive power of eight obesity indices for SRD was evaluated through the receiver operating characteristic curve and area under the curve (AUC). In addition, the net reclassification index (NRI) and integrated discrimination improvement (IDI) were also applied to compare the incremental predictive value for SRD of different obesity indices. Results The median age of the 2358 subjects was 42.00 years. Across NVAI tertiles, the prevalence of SRD was 7.25%, 11.21%, and 21.60%, respectively. After adjusting for confounders, a high level of NVAI remained a risk factor for SRD. The ORs of the middle and top NVAI tertiles for SRD were 1.920 (95% CI: 1.322, 2.787) and 4.129 (95% CI: 2.750, 6.202), respectively. The AUC of the NVAI was 0.666 (95% CI: 0.647, 0.685), which was significantly larger than the AUC of any of the other obesity indicators. Moreover, the NRI and IDI were significantly improved when NVAI was added to the basic model for predicting SRD. Among eight obesity indices, NVAI had the highest NRI (0.392; 95% CI: 0.280, 0.503), and its IDI (0.021; 95% CI: 0.014, 0.027) was second only to that of the body mass index (0.023; 95% CI: 0.014, 0.032). Conclusions NVAI is independently and positively associated with SRD. Among the eight obesity indices, the NVAI shows the strongest predictive power for SRD in the Chinese population. The NVAI may be useful as an effective warning indicator of chronic kidney disease in Chinese adults.

Abstract Background The triglyceride-glucose index (TyG index) has emerged as a reliable surrogate marker of insulin resistance associated with arterial stiffness. However, most studies were based on a cross-sectional design, and few studies have evaluated the longitudinal impact of the TyG index on arterial stiffness. This study aimed to investigate the associations of single time point measurement and the long-term trajectory of the TyG index with arterial stiffness in a Chinese cohort. Methods Data are derived from the Hanzhong Adolescent Hypertension Cohort study. A total of 2480 individuals who participated in the 2017 survey was included in the cross-sectional analysis. A sample of 180 individuals from the sub-cohort with follow-up data in 2005, 2013, and 2017 was enrolled in the longitudinal analysis. The TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2), and arterial stiffness was determined using brachial-ankle pulse wave velocity (baPWV). The latent class growth mixture modeling method was used to identify the TyG index trajectories from 2005 to 2017. Results In the cross-sectional analysis, the median age of the study population was 42.8 (39.8, 44.9) years, and 1351 (54.5%) were males. Each one-unit increment in TyG index was associated with a 37.1 cm/s increase (95% confidence interval [CI] 23.7–50.6 cm/s; P

Abstract Sodium and potassium intake in hypertensive patients in China is not clear. The authors aimed to investigate the distribution of sodium and potassium intake in hypertensive patients in China, and to analyze the relationship between sodium and potassium intake and blood pressure. The study was performed in 130 hospitals from 23 provinces across China from 2016 to 2019. Finally, 9501 hypertensive patients average aged 54 years were included. 24 h urinary sodium and potassium excretion were measured. Distribution of urinary electrolytes were described according to age, gender and region. The association between urinary electrolytes and blood pressure was analyzed by multivariate linear regression. Hypertensive patients exhibited an average 24 h urinary sodium and potassium excretion of 156.7 ± 81.5 mmol/d and 39.2 ± 20.2 mmol/d (equivalent to sodium chloride of 9.2 g/d, potassium chloride of 2.9 g/d), sodium/potassium ratio (median) of 4.14 (2.92,5.73). Urinary electrolytes were lower in women than men (sodium: 171.1 vs 138.7, p

Abstract The pulsatile stress in the microcirculation may contribute to development or progression of chronic kidney disease. However, there is no prospective data confirming whether pulsatile stress in early life affect renal function in middle age. The authors performed a longitudinal analysis of 1738 participants aged 6–15 years at baseline, an ongoing Adolescent Prospective Cohort with a follow‐up of 30 years. The authors evaluated the association between pulsatile stress in childhood and adult subclinical renal damage (SRD), adjusting for related covariates. Pulsatile stress was calculated as resting heart rate × pulse pressure. Renal function was assessed with estimated glomerular filtration rate (eGFR) and urine albumin‐to‐creatinine ratio (uACR). The results showed that pulsatile stress in childhood was associated with adult SRD (Relative Risk, 1.43; p = .032), and the predictive value of combined pulse pressure and heart rate for SRD was higher than either of them alone. The high pulsatile stress in childhood increased the risk of adult SRD in males (RR, 1.92; p = .003), but this association was not found in females (RR, 0.91; p = .729). Further, the participants were categorized into four groups on the basis of pulsatile stress status in childhood and adulthood. Male patients with high pulsatile stress during childhood but normal pulsatile stress as adults still had an increased risk of SRD (RR, 2.04; 95% CI, 1.18–3.54), while female patients did not (RR, 0.96; 95% CI, 0.46–1.99). The study demonstrated that high pulsatile stress in childhood significantly increased the risk of adult SRD, especially in males. Adequate control of pulse pressure and heart rate from childhood, in the long‐term, is very important for preventing kidney damage.

Abstract Stage 1 hypertension, newly defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guideline, has been the subject of significant interest globally. This study aims to assess the impact of the new blood pressure (BP) stratum on subsequent subclinical cardiovascular outcomes in low‐risk young adults. This longitudinal study consisted of 1020 young adults (47.7% female; ages 18–23 years) free of cardiovascular disease from the Hanzhong Adolescent Hypertension Cohort with up to 25‐year follow‐up since 1992–1995. Outcomes were available through June 2017. Young adults with stage 1 hypertension accounted for 23.7% of the cohort. When it comes to middle adulthood, subjects with early life stage 1 hypertension were more likely to experience BP progression, and they had a 1.61‐fold increased risk of high‐risk brachial‐ankle pulse wave velocity (baPWV) and a 2.92‐fold risk of left ventricular hypertrophy (LVH) comparing with their normotensive counterparts. Among participants without any active treatment in midlife, the risk associated with stage 1 hypertension for BP progression was 2.25 (95% confidence interval [CI] = 1.41–3.59), high‐risk baPWV was 1.58 (95% CI = 1.09–2.79), LVH was 2.75 (95% CI = 1.16–6.48), and subclinical renal damage (SRD) was 1.69 (95% CI = 1.02–2.82) compared with the normal BP group. Overall, young adults with stage 1 hypertension had significantly higher risks for midlife subclinical cardiovascular outcomes than normotensive subjects. BP management targeting low‐risk young adults is of importance from both clinical and public health perspectives.

Abstract Aims/Introduction Excessive dietary salt or low potassium intakes are strongly correlated with insulin resistance (IR) and type 2 diabetes mellitus. In epidemiological and experimental studies, increased serum retinol‐binding protein 4 (RBP4) contributes to the pathogenesis of type 2 diabetes mellitus. Herein, we hypothesized that RBP4 might be an adipocyte‐derived “signal” that plays the crucial role in salt‐related insulin resistance or type 2 diabetes mellitus. This study aimed to assess whether salt consumption and potassium supplementation influence serum RBP4 levels in healthy individuals. Materials and Methods A total of 42 participants (aged 25–50 years) in a rural area of Northern China were successively provided normal (3 days at baseline), low‐salt (7 days; 3 g/day NaCl) and high‐salt (7 days; 18 g/day) diets, and a high‐salt diet with potassium additive (7 days; 18 g/day NaCl and 4.5 g/day KCl). Urinary sodium and potassium were measured to ensure compliance to dietary intervention. Then, RBP4 levels were evaluated by enzyme‐linked immunosorbent assay. Results High salt intake significantly raised serum RBP4 levels in healthy participants (17.5 ± 0.68 vs 28.6 ± 1.02 µg/mL). This phenomenon was abrogated by potassium supplementation (28.6 ± 1.02 vs 17.6 ± 0.88 µg/mL). In addition, RBP4 levels presented positive (r = 0.528, P

BackgroundHigh salt diet is one of the important risk factors of hypertension and cardiovascular diseases. Increasingly strong evidence supports epigenetic mechanisms' significant role in hypertension. We aimed to explore associations of epigenetics with high salt diet, salt sensitivity (SS), and SS hypertension.MethodsWe conducted a dietary intervention study of chronic salt loading in 339 subjects from northern China in 2004 and divided the subjects into different salt sensitivity phenotypes. A total of 152 participants were randomly selected from the same cohort for follow-up in 2018 to explore the effect of a high-salt diet on serum monomethylation of H3K4 (H3K4me1), histone methyltransferase Set7, and lysine-specific demethylase 1 (LSD-1).ResultsAmong SS individuals, the blood pressure (SBP: 140.8 vs. 132.9 mmHg; MAP: 104.2 vs. 98.7 mmHg) and prevalence of hypertension (58.8 vs. 32.8%) were significantly higher in high salt (HS) diet group than in normal salt (NS) diet group, but not in the salt-resistant (SR) individuals (P > 0.05). Serum H3K4me1 level (287.3 vs. 179.7 pg/ml, P < 0.05) significantly increased in HS group of SS individuals, but not in SR individuals. We found daily salt intake in SS individuals was positively correlated with serum H3K4me1 (r = 0.322, P = 0.005) and Set7 (r = 0.340, P = 0.005) levels after adjusting for age and gender, but not with LSD-1 (r = −0.137, P = 0.251). In addition, positive correlation between the serum H3K4me1 level and Set7 level (r = 0.326, P = 0.007) was also found in SS individuals. These correlations were not evident in SR individuals.ConclusionOur study indicates that high salt diet increases the serum H3K4me1 and Set7 levels in SS individuals.

This study aimed to develop a noninvasive, economical and effective subclinical renal damage (SRD) risk assessment tool to identify high-risk asymptomatic people from a large-scale population and improve current clinical SRD screening strategies. Based on the Hanzhong Adolescent Hypertension Cohort, SRD-associated variables were identified and the SRD risk assessment score model was established and further validated with machine learning algorithms. Longitudinal follow-up data were used to identify child-to-adult SRD risk score trajectories and to investigate the relationship between different trajectory groups and the incidence of SRD in middle age. Systolic blood pressure, diastolic blood pressure and body mass index were identified as SRD-associated variables. Based on these three variables, an SRD risk assessment score was developed, with excellent classification ability (AUC value of ROC curve: 0.778 for SRD estimation, 0.729 for 4-year SRD risk prediction), calibration (Hosmer—Lemeshow goodness-of-fit test p = 0.62 for SRD estimation, p = 0.34 for 4-year SRD risk prediction) and more potential clinical benefits. In addition, three child-to-adult SRD risk assessment score trajectories were identified: increasing, increasing-stable and stable. Further difference analysis and logistic regression analysis showed that these SRD risk assessment score trajectories were highly associated with the incidence of SRD in middle age. In brief, we constructed a novel and noninvasive SRD risk assessment tool with excellent performance to help identify high-risk asymptomatic people from a large-scale population and assist in SRD screening.

Abstract Background Intestinal microflora has been shown to play essential roles in the clinical therapies of metabolic diseases. The present study is aiming to investigate the potential roles and mechanisms of how intestinal microflora mediates lipid-reduction efficacy of Rosuvastatin. Methods To investigate the correlation between the intestinal microflora and efficacy of Rosuvastatin, we analyzed the diversity of intestinal microflora using PCR-DGGE analysis and 16S rDNA sequencing approaches. Furthermore, we compared the blood lipid levels of rat models with dysbiosis of intestinal microflora and control rats upon the Rosuvastatin administration. Results The diversity of the intestinal flora was obviously decreased upon the antibiotic treatment, this effect could be maintained for 2 weeks after establishment of the models. Importantly, the results from 16S rDNA sequencing demonstrated that the abundance of Lactobacillus and Bifidobacterium was remarkably diminished upon the antibiotic treatment in antibiotic+Rosuvastatin-treated group compared to that of Rosuvastatin-treated group and control group. Correspondently, the lipid-reduction efficacy of Rosuvastatin was significantly compromised. However, the diversity of the intestinal flora was recovered 4 weeks after the antibiotic treatment. Subsequently, the lipid-reduction efficacy of Rosuvastatin was also recovered to level of the control rats treated with Rosuvastatin alone. Conclusion Intestinal flora could play an essential role in mediating the lipid-reduction efficacy of Rosuvastatin.

The mechanism by which high-salt and low-potassium diet contributes to hypertension remains poorly understood. Plasma homocysteine (Hcys) is recognized as a primary mediator of blood pressure (BP) response to some diets. Therefore, the present study tried to investigate whether plasma Hcys and BP could be regulated by salt loading in normotensive salt-sensitive (SS) persons, and further explored whether potassium supplementation could reverse the effect. We enrolled 47 normotensive subjects, aged 29–65 years. The protocol included 7 days on a low-salt diet (3g/day, NaCl), 7 days on a high-salt diet (18g/day), and then a high-salt diet with potassium supplementation (4.5g/day) for 7 days. After high-salt intake, BP was significantly increased and potassium supplementation lowered it in the SS group. Plasma Hcys were higher in SS subjects than in salt-resistant (SR) subjects after salt loading (34.4 ± 17.0 μmol/L versus 19.16 ± 6.4 μmol/L, P < 0.01). Plasma Hcys in SS subjects was increased on a high-salt diet than on a low-salt diet (34.4 ± 17.0 μmol/L versus 16.5 ± 8.3 μmol/L, P < 0.01), but plasma Hcys was ameliorated by potassium supplementation (34.4 ± 17.0 μmol/L versus 20.9 ± 10.4 μmol/L, P < 0.01). In SS subjects, the change of mean arterial blood pressure (MBP) correlated significantly and positively with the alteration of plasma Hcys during low-salt to high-salt intake and high-salt to high-salt with potassium supplementation (r = 0.75, P < 0.001; r = 0.74, P < 0.001, respectively). Our results indicate that Hcys may partly mediate the impact of high-salt intake and potassium supplementation on BP in SS subjects.