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Background and Aims: Insulin resistance (IR) has previously been associated with hypertension, and obesity is a risk factor for IR and hypertension. There is likely an association between body mass index (BMI) and risk for hypertension through the triglyceride-glucose (TyG) index but this relationship remains uncharacterized., Methods and Results: This study is based on the Hanzhong Adolescent Hypertension Cohort, which is an ongoing prospective study established in 1987. The TyG index was calculated as ln [fasting triglyceride (mg/dl) × fasting plasma glucose (mg/dl)/ 2 ]. The total area under the curve (AUCt) and incremental AUC (AUCi) were calculated as the long-term burden and trend of BMI, respectively. We found that BMI AUCt and BMI AUCi were significantly associated with the risk of adult hypertension, both without (RR = 1.30/1.31 for BMI AUCt/AUCi) and with (RR = 1.25/1.26 for BMI AUCt/AUCi) the inclusion of the TyG index as a covariate. Importantly, mediation analysis revealed that the TyG index mediated the BMI AUCt-SBP association (19.3%), the BMI AUCt-DBP association (22.7%), the BMI AUCi-SBP association (18.5%) and the BMI AUCi-DBP association (21.3%). Furthermore, the TyG index had a significant mediating effect of 15.9% on the BMI AUCt-hypertension association and 14.9% on the BMI AUCi-hypertension association., Conclusion: These findings suggest that the TyG index plays an important mediating role in the association between the cumulative burden and increasing trends of BMI originating in childhood and the risk of hypertension in midlife. We emphasize that early weight management has the potential to reduce the burden of hypertension caused by IR., Trial Registration: The study was clinically registered at the ClinicalTrials.gov (NCT02734472) and approved by the Academic Committee of the First Affiliated Hospital of Xi'an Jiaotong University (XJTU1AF2015LSL-047)., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Normoalbuminuria has recently been associated with increased cardiovascular risk, and vascular aging is proposed as the early manifestation of cardiovascular disease. Here, the authors aimed to examine the association of high-normal albuminuria and vascular aging in a Chinese cohort. From our previously established cohort, 1942 participants with estimated glomerular filtration rate ≥60 mL/min/1.73 m 2 or urinary albumin-creatinine ratio (UACR) <30 mg/g were enrolled. Brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s and/or carotid intima-media thickness (CIMT) ≥0.9 mm were used as indicators of vascular aging. Multivariate regression and receiving operating characteristic curve analysis were performed to examine the relationship between continuous and categorical UACR with vascular aging. We found an average UACR value of 8.08 (5.45-12.52) mg/g in this study. BaPWV and CIMT demonstrated positive correlations with lg-UACR (p < .05). High-normal albuminuria (10-29 mg/g) was significantly associated with the presence of vascular aging after adjusting for multiple cardiovascular confounders (OR = 1.540, 95% CI = 1.203-1.972, p = .001). In addition, a lg-UACR cutoff point of 0.918 lg(mg/g) (equal to UACR of 8.285 mg/g) was significantly associated with the presence of vascular aging and its components for all participants and those without hypertension or diabetes and without medication (p < .05). Briefly, high-normal albuminuria was significantly associated with vascular aging in this sample of Chinese adults. These findings implied the warning of elevated UACR even within normal range in clinical practice and the importance of UACR screening in normoalbuminuria for early detection and prevention of cardiovascular disease in otherwise healthy participants., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lowers blood pressure (BP) and exert a salutary effect on the salt sensitivity of BP. This study aimed to examine the associations of SGLT2 genetic variants with salt sensitivity, longitudinal BP changes and the risk of incident hypertension in Baoji Salt-Sensitive Study. A total of 514 participants were recruited when the cohort was established in 2004, and 333 participants received a dietary intervention that consisted of a 3-day usual diet followed sequentially by a 7-day low-salt diet and a 7-day high-salt diet. The cohort was then followed up for 14 years to evaluate the longitudinal BP changes and development of hypertension. We found that SGLT2 SNP rs3813007 was significantly associated with the systolic BP (SBP) responses to the low-salt diet. Over the 14 years of follow-up, SNPs rs3116149 and rs3813008 were significantly associated with the longitudinal SBP changes, and SNPs rs3116149, rs3813008, rs3813007 in SGLT2 were significantly associated with incidence of hypertension. Furthermore, gene-based analyses revealed that SGLT2 was significantly associated with hypertension incidence. Our study suggests that SGLT2 genetic polymorphisms may be involved in salt sensitivity and development of hypertension., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), a member of the E3 ubiquitin-protein ligases, encoded by NEDD4L gene, was found to be involved in in salt sensitivity by regulating sodium reabsorption in salt-sensitive rats. The authors aimed to explore the associations of NEDD4L genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in Chinese adults. Participants from 124 families in Northern China in the Baoji Salt-Sensitive Study Cohort in 2004, who received the chronic salt intake intervention, including a 7-day low-salt diet (3.0 g/day) and a 7-day high-salt diet (18 g/day), were analyzed. Besides, the development of hypertension over 14 years was evaluated. NEDD4L single nucleotide polymorphism (SNP) rs74408486 was shown to be significantly associated with systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) responses to low-salt diet, while SNPs rs292449 and rs2288775 were significantly associated with pulse pressure (PP) response to high-salt diet. In addition, SNP rs4149605, rs73450471, and rs482805 were significantly associated with the longitudinal changes in SBP, DBP, MAP, or PP at 14 years of follow-up. SNP rs292449 was significantly associated with hypertension incidence over the 14-year follow-up. Finally, this gene-based analysis found that NEDD4L was significantly associated with longitudinal BP changes and the incidence of hypertension over the 14-year follow-up. This study indicated that gene polymorphism in NEDD4L serve an important function in salt sensitivity, longitudinal BP change and development of hypertension in the Chinese population., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Recent evidence indicates that long-term visit-to-visit blood pressure variability (BPV) may be associated with risk of cardiovascular disease. We, therefore, aimed to determine the potential associations of long-term BPV from childhood to middle age with subclinical kidney damage (SKD) and albuminuria in adulthood., Methods: Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, which recruited children and adolescents aged 6 to 18 years at baseline, we assessed BPV by SD and average real variability (ARV) for 30 years (6 visits). Presence of SKD was defined as estimated glomerular filtration rate between 30 and 60 mL/min per 1.73 m 2 or elevated urinary albumin-to creatinine ratio at least 30 mg/g. Albuminuria was defined as urinary albumin-to creatinine ratio ≥30 mg/g., Results: During 30 years of follow-up, of the 1771 participants, 204 SKD events occurred. After adjustment for demographic, clinical characteristics, and mean BP during 30 years, higher SD SBP , ARV SBP , SD DBP , ARV DBP , SD MAP , ARV MAP , and ARV PP were significantly associated with higher risk of SKD. When we used cumulative exposure to BP from childhood to adulthood instead of mean BP as adjustment factors, results were similar. In addition, greater long-term BPV was also associated with the risk of albuminuria. Long-term BPV from childhood to middle age was associated with higher risk of SKD and albuminuria in adulthood, independent of mean BP or cumulative exposure to BP during follow-up., Conclusions: Identifying long-term BPV from early age may assist in predicting kidney disease and cardiovascular disease in later life.

Corin, a transmembrane serine protease that can cleave pro-atrial natriuretic peptide (Pro-ANP) into smaller bioactive molecule atrial natriuretic peptide, has been shown to be involved in the pathophysiology of hypertension, cardiac hypertrophy. We sought to examine the associations of corin genetic variations with salt sensitivity, blood pressure (BP) changes and hypertension incidence. We studied participants of the original Baoji Salt-Sensitive cohort, recruited from 124 families from seven Chinese villages in 2004 who sequentially received a usual baseline salt diet, a 7-day low salt diet (3 g/day) and a 7-day high salt diet (18 g/day), respectively. They were followed up for 8 years (in 2009, 2012) to evaluate the development of hypertension. Corin SNP rs3749584 was significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) response to low-salt diet, while rs4695253, rs17654278 were associated with pulse pressure (PP) response to low-salt diet. SNPs rs4695253, rs12509275, rs2351783, rs2271036, rs2271037 were significantly associated with systolic BP (SBP), DBP, and MAP responses to high-salt diet. In addition, SNPs rs12641823, rs6834933, rs2271036, and rs22710367 were significantly associated with the longitudinal changes in SBP, DBP, MAP, or PP over 8 years of follow-up. SNP rs73814824 was significantly associated with the incidence of hypertension over 8 years. Gene-based analysis showed that corin gene was significantly associated with longitudinal BP changes and hypertension incidence after 8-year follow-up. This study suggests that corin may play a role in salt sensitivity, BP progression, and development of hypertension., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Uromodulin, also named Tamm Horsfall protein, have been associated with renal function and sodium homeostasis regulation. The authors sought to examine the effects of salt intake on plasma and urinary uromodulin levels and the association of its genetic variants with salt sensitivity in Chinese adults. Eighty patients from our natural population cohort were maintained sequentially either on a usual diet for 3 days, a low-salt diet (3.0 g) for 7 days, and a high-salt diet (18.0 g) for an additional 7 days. In addition, the authors studied 514 patients of the Baoji Salt-Sensitive Study, recruited from 124 families who received the same salt intake intervention, and investigated the association of genetic variations in uromodulin gene with salt sensitivity. Plasma uromodulin levels were significantly lower on a high-salt diet than on a baseline diet (28.3 ± 4.5 vs. 54.9 ± 8.8 ng/ml). Daily urinary excretions of uromodulin were significantly decreased on a high-salt diet than on a low-salt diet (28.7 ± 6.7 vs. 157.2 ± 21.7 ng/ml). SNPs rs7193058 and rs4997081 were associated with the diastolic blood pressure (DBP), mean arterial pressure (MAP) responses to the high-salt diet. In addition, several SNPs in the uromodulin gene were significantly associated with pulse pressure (PP) response to the low-salt intervention. This study shows that dietary salt intake affects plasma and urinary uromodulin levels and that uromodulin may play a role in the pathophysiological process of salt sensitivity in the Chinese populations., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Pentraxin 3 (PTX3) is synthesized locally and released into the circulation, reflecting local inflammation in the cardiovascular system. Therefore, we conducted a study to explore the effect of PTX3 in spontaneously hypertensive heart failure (SHHF) rats. Sprague Dawley (SD) and SHHF rats were treated with recombinant PTX3 protein, and the blood pressure (BP) and echocardiographic parameters were collected. Radioimmunoassay, enzyme immunoassay and enzyme-linked immunosorbent assay (ELISA) were applied to detect plasma levels of atrial/B-type natriuretic peptide (ANP/BNP) and PTX3. The pathological changes in the myocardial tissues were observed by hematoxylin and eosin (HE) and Masson stainings. The mRNA and protein expressions were detected by quantitative real-time reverse-transcription polymerase chain reaction (qPCR) and western blotting. Cardiomyocyte apoptosis was evaluated by TUNEL staining and DNA fragmentation test. Increased plasma concentrations of PTX3 were found in SHHF rats compared with SD rats, which was further enhanced by recombinant PTX3 protein. After injection with recombinant PTX3 protein, the heart function was improved in SHHF rats with the decreased systolic and diastolic BP, and the reduced plasma levels of ANP and BNP. Moreover, PTX3 improved the myocardial damage and interstitial fibrosis in SHHF rats with reduced cardiomyocyte apoptosis and decreased mRNA expressions of pro-inflammatory factors in myocardial tissues. PTX3 could decrease the BP and plasma levels of ANP and BNP in SHHF rats, as well as improve the inflammation, cardiomyocyte apoptosis, and pathological changes of myocardial tissues, suggesting it may be a useful intervention in the treatment of SHHF., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Pregnancy-associated plasma protein-A2 (PAPP-A2) is the homolog of PAPP-A in the vertebrate genome and its role in protecting against salt-induced hypertension in salt-sensitive rats has been confirmed. We sought to examine the associations of plasma PAPP-A2 levels and its genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in humans., Methods: Eighty participants (18-65 years old) sequentially consuming a usual diet, a 7-day low-salt diet (3.0 g/day) and a 7-day high-salt diet (18 g/day). In addition, we studied participants of the original Baoji Salt-Sensitive Study, recruited from 124 families in Northern China in 2004 who received the same salt intake intervention, and evaluated them for the development of hypertension over 14 years., Results: The plasma PAPPA2 levels significantly decreased with the change from baseline to a low-salt diet and decreased further when converting from the low-salt to high-salt diet. SNP rs12042763 in the PAPP-A2 gene was significantly associated with systolic BP responses to both low-salt and high-salt diet while SNP rs2861813 showed a significant association with the changes in SBP and pulse pressure at 14-year follow-up. Additionally, SNPs rs2294654 and rs718067 demonstrated a significant association with the incidence of hypertension over the 14-year follow-up. Finally, the gene-based analysis found that Pappa2 was significantly associated with longitudinal SBP changes and the incidence of hypertension over the 14-year follow-up., Conclusions: This study shows that dietary salt intake affects plasma PAPP-A2 levels and that PAPP-A2 may play a role in salt sensitivity, BP progression and development of hypertension in the Chinese populations., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The relationship between child-to-adult blood pressure (BP) trajectories and metabolic syndrome (MetS) is unknown. We aimed to determine the predictive role of BP trajectories for incident MetS and its components., Methods: The prospective Hanzhong Adolescent Hypertension study began in 1987 and included 2692 participants free of MetS at baseline with at least 3 BP measurements available from 1987 to 2017., Results: The systolic BP (SBP) trajectory patterns were grouped as normal (class 1, 18.7%), high normal (class 2, 60.3%), prehypertensive (class 3, 13.1%), stage 1 hypertensive (class 4, 5.7%), and stage 2 hypertensive (class 5, 2.2%). Compared with those in the normal group, individuals in classes 2 to 5 had significantly higher risks of MetS (all Ps < .05), and those with hypertension had more than an 8-fold higher risk of MetS (both P < .05). The fully adjusted risk ratios (RRs) of central obesity increased significantly in a stepwise manner as the SBP trajectory group increased from class 1 to class 5 (P < .05). Compared with those with a normal SBP trajectory, participants in the prehypertensive group and stage 1 and stage 2 hypertensive groups had significantly higher RRs for high-risk triglycerides after full adjustment (RR = 1.89 [1.22-2.94]; RR = 3.61 [2.16-6.02]; and RR = 3.22 [1.52-6.84], respectively)., Conclusion: Our study suggests that BP trajectories are predictive of incident MetS outcomes. Early detection of hypertension or modest elevations in BP is crucial. The stage of hypertension based on SBP level showed a greater association with central obesity., (Copyright © 2020 AACE. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Chronic kidney disease (CKD) is a global public health problem, including in China. The aim of this study was to identify the risk factors for the development and progression of subclinical renal disease (SRD) in a Chinese population. We also examined whether the impact of the risk factors on SRD changed over time., Subjects/methods: To identify the predictors of SRD, we performed a cross-sectional study of the 2432 subjects in our Hanzhong Adolescent Hypertension Cohort. A subgroup of 202 subjects was further analyzed over a 12-year period from 2005 to 2017 to determine the risk factors for the development and progression of SRD., Results: In cross-sectional analysis, elevated blood pressure, male gender, diabetes, body mass index, and triglyceride were independently associated with a higher risk of SRD. In longitudinal analysis, an increase in total cholesterol over a 4-year period and an increase in serum triglyceride over a 12-year period were independently associated with progression of albuminuria. Finally, increases in both total cholesterol and serum uric acid over a 4-year follow-up showed an independent association with a modest reduction in estimated glomerular filtration rate (eGFR)., Conclusions: In this study of a Chinese cohort, we show several metabolic abnormalities as independent risk factors for subclinical renal disease in a Chinese cohort. In addition, we demonstrate that the effects of total cholesterol, triglycerides and uric acid on the development and progression of albuminuria or the decline in eGFR vary at different points of follow-up. These findings highlight the importance of early detection of metabolic abnormalities to prevent SRD.

Objective: Cyclooxygenase (COX)-2, an inducible isoform of the major rate-limiting enzymes that regulate the production of prostaglandins is associated with injury, inflammation and proliferation. We sought to examine whether plasma COX-2 levels and its genetic variants is associated with salt sensitivity, BP changes and/or hypertension in humans., Methods: Eighty participants (aged 18-65 years) were maintained sequentially either on a usual diet for 3 days, a low-salt diet (3.0 g) for 7 days, and a high-salt diet (18.0 g) for an additional 7 days. In addition, we studied participants of the original Baoji Salt-Sensitive Study, recruited from 124 families from seven Chinese villages in 2004 who received the same salt intake intervention, and evaluated them for the development of hypertension., Results: Plasma COX-2 levels were significantly decreased with reduction of salt intake from the usual to a low-salt diet and decreased further when converting from the low-salt to the high-salt diet. SNPs rs12042763 in the COX-2 gene was significantly associated with SBP responses to both low-salt and high-salt diet. SNPs rs689466 and rs12042763 were significantly associated with longitudinal changes in BPs. In addition, several COX-2 SNPs were significantly associated with incident hypertension over an 8-year follow-up. Gene-based analyses also supported the overall association of COX-2 with longitudinal changes in SBP and hypertension incidence., Conclusion: This study shows that dietary salt intake affects plasma COX-2 levels and that COX-2 may play a role in salt sensitivity, BP progression and development of hypertension in the Chinese populations studied.

Background: A high atherogenic index of plasma (AIP) is associated with increased cardiovascular risk and higher serum uric acid levels, but whether AIP is a strong risk factor for developing subclinical renal damage (SRD) is unknown. This study aimed to explore the effect of AIP variations on the prevalence of SRD in a 12-year follow-up study., Methods: (1) The cross-sectional study enrolled 2485 participants from the Hanzhong cohort in 2017; (2) A total of 202 participants were included in the small longitudinal cohort from 2005 to 2017. Longitudinal analysis was used to determine whether an elevated AIP predicts the development of SRD., Results: In the cross-sectional analysis, the AIP level was correlated with the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatine ratio (uACR) (P < 0.05). The age-adjusted odds ratio (OR) for prevalent SRD in men in the high AIP group was 1.924 (1.355-2.732) (P < 0.001), while in women, the OR was 1.616 (1.049-2.490) (P = 0.030) in the high AIP group. In the longitudinal analysis, significantly higher uACR levels were found in participants with normal AIP at baseline and elevated AIP in 2013 (P < 0.05). The adjusted OR for prevalent SRD in the incident AIP group was 4.741 (1.668-13.472) (P = 0.003) compared with the control group., Conclusions: Our study indicates that elevated AIP increased the risk of developing SRD and was associated with uACR and eGFR. As a simple marker of CVD risk, AIP may emerge as a novel and reliable indicator of SRD.

Background and Objectives: The aim of the study was to examine the associations of uric acid (UA) in blood and urine with subclinical renal damage (SRD) and its progression in a Chinese cohort., Methods: 1) 2342 participants from our previously established cohort who were followed up in 2017 were included. Cross-sectional analysis was used to examine the relationships between serum and urinary UA and the risk of SRD. 2) A total of 266 participants were recruited from the same cohort in 2013, and followed up in 2017. Longitudinal analysis was used to determine the relationships of serum and urinary UA with progression of SRD, which was defined as urinary albumin-to-creatinine ratio (uACR) progression or estimated glomerular filtration rate (eGFR) decline., Results: In cross-sectional analysis, higher levels of uACR were associated with higher levels of serum uric acid (SUA) and urinary uric acid/creatinine ratio (uUA/Cre). Lower eGFR was associated with higher levels of SUA and fractional excretion of uric acid (FEUA) but lower uUA/Cre levels in all subjects. In addition, the multivariate-adjusted odds ratios for SRD compared with non-SRD were 3.574 (2.255-5.664) for uUA/Cre. Increasing uUA/Cre levels were associated with higher risk of SRD. In longitudinal analysis, 4-year changes of uUA/Cre and SUA were significantly associated with eGFR decline., Conclusions: This study suggested that urinary UA excretion was significantly associated with the risk of SRD in Chinese adults. Furthermore, 4-year changes of serum and urinary UA were associated with SRD progression. These findings suggest that UA, especially urinary UA, may be used as a simple, noninvasive marker for early detection of decreased renal function in otherwise healthy subjects., Competing Interests: The authors have declared that no competing interests exist.

Currently, the prevention and treatment of hypertensive crises especially when it occurs with serious adverse outcomes have led to worldwide controversy. Despite of clinical possibilities of multiple agents, clinical failures still occur frequently. Therefore, early evaluations and observations of different therapies on appropriate animals should be emphasized. In the present study, an animal model for hypertensive crises emergencies was firstly established and experimentally testified. Five-month-male spontaneously hypertensive rat was consecutively fed with 60%-Kcal fat diet for four, six, and eight weeks with body weight and blood pressure monitored every two weeks, and then followed by an acute vasoconstriction stress of 5-min ice-bath treatment in the 4-h time interval of two adrenaline injections (0.8 mg/kg). Forty-four biochemical parameters were detected, covering hepatic and renal function, blood glucose and lipid levels, myocardial enzymes and energy metabolisms, blood coagulative and anti-coagulative system, oxidative stress and anti-inflammatory cytokine, blood viscosity, and RAAS system. Six tissues including heart, brain, liver, kidney, coronary arteries, and mesenteries were removed for pathological observations with hematoxylin-eosin staining. As a result, multi-organ dysfunctions in the heart, brain, liver, kidney, vascular endothelium, and blood system were testified in the modeling rats at weeks 6 and 8. In conclusion, severe consequences of this animal model were highly similar to those in hypertensive crises emergencies, which could be further utilized in the early intervention of hypertensive crises emergencies including the possible risk factors control and efficient therapies assessment. Impact statement In the late 90s, numerous reports predicted that 1-2% of hypertensive individuals would undergo hypertensive crises (HPC) and figures reached as high as 7% when no antihypertensive therapies were administrated. Currently, clinical failures appear frequently due to the improper or excessive medication regimen instead of the illness itself. Therefore, early evaluations and observations of HPC on appropriate animal models ahead of patients should be discussed and emphasized more widely. In the present study, an appropriate animal model for HPC emergencies was firstly established, in which the consequences of long-term high-fat diet feeding followed by an acute vasoconstriction stress on the spontaneously hypertensive rats were experimentally testified. The proposed model would have a wide application prospects in early intervention of HPC emergencies including the controls of possible risk factors and assessments of efficient therapies.