Associations of ultra long-term visit-to-visit blood pressure variability, since childhood with vascular aging in midlife: a 30-year prospective cohort study.

OBJECTIVE: Vascular aging, as assessed by structural and functional arterial properties, is an independent predictor of cardiovascular outcomes. In this study, we aimed to investigate the associations of ultra long-term blood pressure (BP) variability from childhood to midlife with vascular aging in midlife. METHODS: Using data from the longitudinal cohort of Hanzhong Adolescent Hypertension Study, 2065 participants aged 6-18 years were enrolled and followed up with seven visits over 30 years. Ultra long-term BP variability (BPV) was defined as the standard deviation (SD) and average real variability (ARV) of BP over 30 years (seven visits). Vascular aging included arterial stiffness, carotid hypertrophy, and carotid plaque. RESULTS: After adjusting for demographic variables, clinical characteristics and mean BP over 30 years, higher SD SBP , ARV SBP , SD DBP and ARV DBP since childhood were significantly associated with arterial stiffness in midlife. Additionally, higher SD DBP and ARV DBP were significantly associated with carotid hypertrophy and the presence of carotid plaque in midlife. When we used cumulative exposure to BP from childhood to midlife instead of mean BP as adjustment factors, results were similar. Furthermore, we found a significant association between long-term BPV from childhood to adolescence and the presence of carotid plaque, whereas long-term BPV from youth to adulthood is associated with arterial stiffness. CONCLUSION: Higher BPV from childhood to adulthood was associated with vascular aging in midlife independently of mean BP or cumulative BP exposure. Therefore, long-term BPV from an early age may serve as a predictor of cardiovascular diseases (CVDs) in later life.

Renalase alleviates salt-induced kidney necroptosis and inflammation.

Recent evidence suggests that necroptosis may contribute to the development of kidney injury. Renalase is a novel secretory protein that exerts potent prosurvival and anti-inflammatory effects. We hypothesized that renalase could protect the kidney from salt-induced injury by modulating necroptosis. High salt and renalase treatments were administered to Dahl salt-sensitive (SS) rats, renalase knockout (KO) mice, and HK-2 cells. Furthermore, a cohort of 514 eligible participants was utilized to investigate the association between single nucleotide polymorphisms (SNPs) in the genes RIPK1, RIPK3, and MLKL, and the risk of subclinical renal damage (SRD) over 14 years. A high-salt diet significantly increased the expression of key components of necroptosis, namely RIPK1, RIPK3, and MLKL, as well as the release of inflammatory factors in SS rats. Treatment with recombinant renalase reduced both necroptosis and inflammation. In renalase KO mice, salt-induced kidney injury was more severe than in wild-type mice, but supplementation with renalase attenuated the kidney injury. In vitro experiments with HK-2 cells revealed high salt increased necroptosis and inflammation. Renalase exhibited a dose-dependent decrease in salt-induced necroptosis, and this cytoprotective effect was negated by the knockdown of PMCA4b, which is the receptor of renalase. Furthermore, the cohort study showed that SNP rs3736724 in RIPK1 and rs11640974 in MLKL were significantly associated with the risk of SRD over 14 years. Our analysis shows that necroptosis plays a significant role in the development of salt-induced kidney injury and that renalase confers its cytoprotective effects by inhibiting necroptosis and inflammation.

Associations of E-proteinoid 3 receptor genetic polymorphisms with salt sensitivity, longitudinal blood pressure changes, and hypertension incidence in Chinese adults.

The E-proteinoid 3 receptor (PTGER3), a member of the prostaglandin E2 (PGE2) subtype receptor, belongs to the G-protein-coupled superfamily of receptors. Animal studies have demonstrated its involvement in salt sensitivity by regulating sodium reabsorption. This study aimed to investigate the association between genetic variants of PTGER3 and salt sensitivity, longitudinal blood pressure (BP) changes, and the incidence of hypertension in Chinese adults. A chronic salt intake intervention was conducted involving 514 adults from 124 families in the 2004 Baoji Salt-Sensitivity Study Cohort in northern China. These participants followed a 3-day regular baseline diet, followed by a 7-day low-salt diet (3.0 g/d) and a 7-day high-salt diet (18 g/d), and were subsequently followed for 14 years. The findings revealed a significant relationship between the single nucleotide polymorphism (SNP) rs17482751 of PTGER3 and diastolic blood pressure (DBP) response to high salt intervention. Additionally, SNPs rs11209733, rs3765894, and rs2268062 were significantly associated with longitudinal changes in systolic blood pressure (SBP), DBP, and mean arterial pressure (MAP) during the 14-year follow-up period. SNP rs6424414 was significantly associated with longitudinal changes in DBP over 14 years. Finally, SNP rs17482751 showed a significant correlation with the incidence of hypertension over 14 years. These results emphasize the significant role of PTGER3 gene polymorphism in salt sensitivity, longitudinal BP changes, and the development of hypertension in the Chinese population.

Long-term burden and increasing trends of body mass index are linked with adult hypertension through triglyceride-glucose index: A 30-year prospective cohort study.

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).

Association of high-normal albuminuria and vascular aging: Hanzhong adolescent hypertension study.

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 m2 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.

Associations of lipid accumulation product, visceral adiposity index, and triglyceride-glucose index with subclinical organ damage in healthy Chinese adults.

Background and aims: Obesity is an independent risk factor for cardiovascular disease development. Here, we aimed to examine and compare the predictive values of three novel obesity indices, lipid accumulation product (LAP), visceral adiposity index (VAI), and triglyceride-glucose (TyG) index, for cardiovascular subclinical organ damage. Methods: A total of 1,773 healthy individuals from the Hanzhong Adolescent Hypertension Study cohort were enrolled. Anthropometric, biochemical, urinary albumin-to-creatinine ratio (uACR), brachial-ankle pulse wave velocity (baPWV), and Cornell voltage-duration product data were collected. Furthermore, the potential risk factors for subclinical organ damage were investigated, with particular emphasis on examining the predictive value of the LAP, VAI, and TyG index for detecting subclinical organ damage. Results: LAP, VAI, and TyG index exhibited a significant positive association with baPWV and uACR. However, only LAP and VAI were found to have a positive correlation with Cornell product. While the three indices did not show an association with electrocardiographic left ventricular hypertrophy, higher values of LAP and TyG index were significantly associated with an increased risk of arterial stiffness and albuminuria. Furthermore, after dividing the population into quartiles, the fourth quartiles of LAP and TyG index showed a significant association with arterial stiffness and albuminuria when compared with the first quartiles, in both unadjusted and fully adjusted models. Additionally, the concordance index (C-index) values for LAP, VAI, and TyG index were reasonably high for arterial stiffness (0.856, 0.856, and 0.857, respectively) and albuminuria (0.739, 0.737, and 0.746, respectively). Lastly, the analyses of continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) demonstrated that the TyG index exhibited significantly higher predictive values for arterial stiffness and albuminuria compared with LAP and VAI. Conclusion: LAP, VAI, and, especially, TyG index demonstrated utility in screening cardiovascular subclinical organ damage among Chinese adults in this community-based sample. These indices have the potential to function as markers for early detection of cardiovascular disease in otherwise healthy individuals.

Associations of SGLT2 genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

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.

Sex differences in impact of cumulative systolic blood pressure from childhood to adulthood on albuminuria in midlife: a 30-year prospective cohort study.

BACKGROUND AND OBJECTIVES: Albuminuria is recognized as being a predictor of cardiovascular and renal disease. We aimed to identify the impact of the long-term burden and trends of systolic blood pressure on albuminuria in midlife, as well as to explore sex differences concerning this relationship. METHODS: This longitudinal study consisted of 1,683 adults who had been examined 4 or more times for blood pressure starting in childhood, with a follow-up time period of 30 years. The cumulative effect and longitudinal trend of blood pressure were identified by using the area under the curve (AUC) of individual systolic blood pressure measurement with a growth curve random effects model. RESULTS: Over 30 years of follow-up, 190 people developed albuminuria, including 53.2% males and 46.8% females (aged 43.39 ± 3.13 years in the latest follow-up). The urine albumin-to-creatinine ratio (uACR) values increased as the total and incremental AUC values increased. Additionally, women had a higher albuminuria incidence in the higher SBP AUC groups than men do (13.3% for men vs. 33.7% for women). Logistic regression showed that the ORs of albuminuria for males and females in the high total AUC group were 1.34 (0.70-2.60) and 2.94 (1.50-5.74), respectively. Similar associations were found in the incremental AUC groups. CONCLUSIONS: Higher cumulative SBP was correlated with higher uACR levels and a risk of albuminuria in middle age, especially in women. The identification and control of cumulative SBP levels from an early age may assist in reducing the incidences of renal and cardiovascular disease for individuals in later life.

Early-Life Cardiovascular Risk Factor Trajectories and Vascular Aging in Midlife: A 30-Year Prospective Cohort Study.

BACKGROUND: Vascular aging, as assessed by structural and functional arterial properties, is an independent predictor of cardiovascular outcomes. We aimed to explore the associations of individual cardiovascular risk factors from childhood to midlife and their accumulation over a 30-year span with vascular aging in midlife. METHODS: Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, 2180 participants aged 6 to 18 years at baseline were followed for over 30 years. Distinct trajectories of systolic blood pressure (SBP), body mass index (BMI), and heart rate from childhood to midlife were identified by group-based trajectory modeling. Vascular aging was assessed by carotid intima media thickness or brachial-ankle pulse wave velocity. RESULTS: We identified 4 distinct SBP trajectories, 3 distinct BMI trajectories, and 2 distinct heart rate trajectories from childhood to midlife. Persistently increasing SBP, high-increasing BMI, and high-stable heart rate were all shown to have a positive association with brachial-ankle pulse wave velocity in midlife. For carotid intima-media thickness, similar associations were observed for persistently increasing SBP and high-increasing body mass index. After further adjustment for SBP, body mass index and heart rate at the time of vascular assessment in 2017, associations were also observed for cardiovascular risk factor trajectories accumulation with brachial-ankle pulse wave velocity (ß, 0.656 [95% CI, 0.265-1.047]) and with carotid intima media thickness (ß, 0.045 [95% CI, 0.011-0.079]) in adulthood. CONCLUSIONS: Longitudinal exposure to individual cardiovascular risk factors from childhood to midlife and cardiovascular risk factor accumulation were associated with an increased risk of vascular aging in midlife. Our study lends support for early targeting of risk factors in order to prevent cardiovascular disease later in life.

The prevalence of masked hypertension and masked uncontrolled hypertension in relation to overweight and obesity in a nationwide registry in China.

Masked hypertension is difficult to identify and is associated with adverse outcomes. How and to what extent masked hypertension is related to overweight and obesity remain unclear. In participants with a clinic blood pressure (BP) < 140/90 mmHg enrolled in a nationwide prospective registry in China, we performed ambulatory and home BP measurements and defined masked hypertension and masked uncontrolled hypertension as an elevated 24-h (≥130/80 mmHg), daytime (≥135/85 mmHg) or nighttime ambulatory BP (≥120/70 mmHg) or an elevated home BP (≥135/85 mmHg). Overweight and obesity were defined as a body mass index of 25.0-29.9 and ≥30.0 kg/m2, respectively. The 2838 participants had a mean (±SD) age of 54.9 ± 13.6 years and included 1286 (45.3%) men and 1065 (37.5%) and 173 (6.1%) patients with overweight and obesity, respectively. Multiple stepwise regression analyses identified that body mass index was significantly (P ≤ 0.006) associated with the prevalence of masked ambulatory and home hypertension in treated (n = 1694, 58.6% and 42.1%, respectively) but not untreated participants (n = 1144, 55.7% and 29.5%, respectively). In categorical analyses, significant associations were observed with overweight and obesity for the prevalence of masked uncontrolled ambulatory and home hypertension (P ≤ 0.02) but not masked ambulatory or home hypertension (P ≥ 0.08). The adjusted odds ratios (95% confidence intervals) for overweight and obesity relative to normal weight were 1.56 (1.27-1.92) and 1.34 (1.09-1.65) for masked uncontrolled ambulatory and home hypertension, respectively. In conclusion, overweight and obesity were associated with a higher prevalence of masked uncontrolled hypertension, indicating that clinic BP might overestimate antihypertensive treatment effects in patients with overweight and obesity.

Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

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.

Blood Pressure Trajectories From Childhood to Youth and Arterial Stiffness in Adulthood: A 30-Year Longitudinal Follow-Up Study.

Background: This study aimed to identify the subgroups of individuals sharing similar blood pressure (BP) trajectories from childhood to youth and explore the associations of these trajectories with arterial stiffness in adulthood. Methods: A group-based trajectory model was used to identify BP trajectories among 2,082 individuals in the Hanzhong adolescent hypertension cohort by using BP values repeatedly measured at four visits from childhood (6-15 years) to youth (14-23 years). The brachial-ankle pulse wave velocity (baPWV) was examined 30 years after the baseline survey. Mixed linear regression models were used to examine the associations of these trajectories with adult baPWV. Results: Among the 2,082 individuals, three trajectory groups of systolic BP were identified as follows: the low-level group (n = 889), medium-level group (n = 1,021), and high-level group (n = 172). The baPWV in adulthood was higher in medium-level and high-level groups compared with the low-level group (1271.4 ± 224.7 cm/s, 1366.1 ± 249.8 cm/s vs. 1190.1 ± 220.3 cm/s, all p < 0.001). After adjustment for potential confounding factors, the association between baPWV and systolic BP trajectories was statistically significant (adjusted ß = 49.4 cm/s; p < 0.001 for the medium-level group and ß = 107.6 cm/s; p < 0.001 for the high-level group compared with the low-level group). Similar results were obtained for the association of baPWV with the trajectories of diastolic BP and mean arterial pressure (MAP), except for pulse pressure. Conclusion: Our investigation demonstrates different BP trajectories from childhood to youth and shows the trajectories of systolic BP, diastolic BP, and MAP are significant predictors of arterial stiffness in adulthood.

Early life body mass index trajectories and albuminuria in midlife: A 30-year prospective cohort study.

Background: Albuminuria is a marker of vascular dysfunction and is associated with chronic renal and cardiovascular diseases. Data on the association between the longitudinal patterns of weight change early in life and albuminuria later in life are limited. We aimed to identify the body mass index (BMI) trajectory across a 30-year span and evaluate its association with middle-age albuminuria. Methods: Of the 4623 participants aged 6-18-year-old recruited by Hanzhong Adolescent Hypertension Study cohort in northern China from March 10, 1987 to June 3, 2017, a total of 1,825 participants followed up with 6 visits over 30 years were enrolled. Group-based trajectory modeling was used to identify distinct BMI trajectories in longitudinal analyses. Albuminuria was defined as a urinary albumin-to-creatinine ratio (uACR) ≥ 30 mg/g. Findings: Three distinct BMI trajectories were identified: low-increasing (n = 671, 36.8%), moderate-increasing (n = 940, 51.5%), and high-increasing (n = 214, 11.7%); male participants exhibited a steeper increase in BMI than females. The uACR was increased linearly from the low- to high-increasing group. A total of 201 individuals developed albuminuria, with an incidence of 11.0%. Compared with the low-increasing group, the odds ratio (OR) of albuminuria in middle age was 2.13(95% confidence interval [CI]: 1.26 to 3.61) for the high-increasing group after full adjustment for age, sex, smoking, alcohol consumption, marital status, systolic blood pressure, diabetes, and hyperlipidemia. The unadjusted ORs of the high-increasing BMI group were 5.08 (2.76-9.37) for males and 3.45 (1.78-6.69) for females, and the association remained significant in males in the fully adjusted models. Interpretation: Higher BMI trajectories are associated with higher uACR and an increased risk of albuminuria in middle age, especially in males. Identifying long-term BMI trajectories from an early age may assist in predicting the risk of renal diseases and cardiovascular disease later in life. Funding: This work was supported by the National Natural Science Foundation of China (81600327, 82070437, 81870319, 82070549, and 82170437), Natural Science Basic Research Program of Shaanxi Province (2021JM-257 and 2021JM-588), Institutional Foundation of the First Affiliated Hospital of Xi'an Jiaotong University (2019QN-06 and 2021ZXY-14), the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University of China (XJTU1AF-CRF-2019-004, XJTU1AF2021CRF-021, and XJTU1AFCRF-2017-021), Research Incubation Fund of Xi'an People's Hospital (FZ-61), Grants from the Major Chronic Non-communicable Disease Prevention and Control Research Key Project of the Ministry of Science and Technology of China (2017YFC1307604 and 2016YFC1300104).

Associations of Long-Term Visit-to-Visit Blood Pressure Variability With Subclinical Kidney Damage and Albuminuria in Adulthood: a 30-Year Prospective Cohort Study.

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 m2 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 SDSBP , ARVSBP , SDDBP , ARVDBP , SDMAP , ARVMAP , and ARVPP 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.

Associations of Renalase With Blood Pressure and Hypertension in Chinese Adults.

Objective: Renalase, a novel secretory flavoprotein with amine oxidase activity, is secreted into the blood by the kidneys and is hypothesized to participate in blood pressure (BP) regulation. We investigated the associations of renalase with BP and the risk of hypertension by examining renalase single nucleopeptide polymorphism (SNPs), serum renalase levels, and renal expression of renalase in humans. Methods: ① Subjects (n = 514) from the original Baoji Salt-Sensitive Study cohort were genotyped to investigate the association of renalase SNPs with longitudinal BP changes and the risk of hypertension during 14 years of follow-up. ② Two thousand three hundred and ninety two participants from the Hanzhong Adolescent Hypertension Study cohort were used to examine the association of serum renalase levels with hypertension. Renalase expression in renal biopsy specimens from 193 patients were measured by immunohistochemistry. ③ Renalase expression was compared in hypertensive vs. normotensive patients. Results: ① SNP rs7922058 was associated with 14-year change in systolic BP, and rs10887800, rs796945, rs1935582, rs2296545, and rs2576178 were significantly associated with 14-year change in diastolic BP while rs1935582 and rs2576178 were associated with mean arterial pressure change over 14 years. In addition, SNPs rs796945, rs1935582, and rs2576178 were significantly associated with hypertension incidence. Gene-based analysis found that renalase gene was significantly associated with hypertension incidence over 14-year follow-up after adjustment for multiple measurements. ② Hypertensive subjects had higher serum renalase levels than normotensive subjects (27.2 ± 0.4 vs. 25.1 ± 0.2 µg/mL). Serum renalase levels and BPs showed a linear correlation. In addition, serum renalase was significantly associated with the risk of hypertension [OR = 1.018 (1.006-1.030)]. ③ The expression of renalase in human renal biopsy specimens significantly decreased in hypertensive patients compared to non-hypertensive patients (0.030 ± 0.001 vs. 0.038 ± 0.004). Conclusions: These findings indicate that renalase may play an important role in BP progression and development of hypertension.

Association between Phenotypic Age and Mortality in Patients with Multivessel Coronary Artery Disease.

BACKGROUND: Chronological age (CA) is not a perfect proxy for the true biological aging status of the body. A new biological aging measure, phenotypic age (PhenoAge), has been shown to capture morbidity and mortality risk in the general US population and diverse subpopulations. This study was aimed at evaluating the association between PhenoAge and long-term outcome of patients with multivessel coronary artery disease (CAD). METHODS: A total of 609 multivessel CAD patients who received PCI attempt and with follow-up were enrolled. The clinical outcome was all-cause mortality on follow-up. PhenoAge was calculated using an equation constructed from CA and 9 clinical biomarkers. Cox proportional hazards regression models and receiver operating characteristic (ROC) curves were performed to evaluate the association between PhenoAge and mortality. RESULTS: Overall, patients with more diseases had older PhenoAge and phenotypic age acceleration (PhenoAgeAccel). After a median follow-up of 33.5 months, those with positive PhenoAgeAccel had a significantly higher incidence of all-cause mortality (P = 0.001). After adjusting for CA, Cox proportional hazards models showed that both PhenoAge and PhenoAgeAccel were significantly associated with all-cause mortality. Even after further adjusting for confounding factors, each 10-year increase in PhenoAge was also associated with a 51% increased mortality risk. ROC curves revealed that PhenoAge, with an area under the curve of 0.705, significantly outperformed CA, the individual clinical chemistry measure, and other risk factors. When reexamining the ROC curves using various combinations of variables, we found that PhenoAge provides additional predictive power to all models. CONCLUSIONS: In conclusion, PhenoAge was strongly associated with all-cause mortality even after adjusting for CA. Our findings suggest that PhenoAge measure may be complementary in predicting mortality risk for patients with multivessel CAD.

Association of Genetic Variants of Klotho with BP Responses to Dietary Sodium or Potassium Intervention and Long-Term BP Progression.

OBJECTIVES: Klotho (KL) plays pivotal roles in the progression of salt-sensitive hypertension. Salt-sensitive hypertension was associated with KL genotypes. We aimed to explore the association of common genetic variants of KL with individual blood pressure (BP) responses to sodium and potassium through a dietary intervention study as well as long-term BP progression. METHODS: We conducted family-based dietary interventions among 344 participants from 126 families in rural villages of northern China in 2004. Subjects sequentially underwent a baseline diet, a low-salt diet (51.3 mmol/day Na), a high-salt diet (307.8 mmol/day Na), and a high-salt + potassium supplementation diet (307.8 mmol/day Na + 60 mmol/day K). After dietary intervention, we followed up with these participants in 2009 and 2012. The associations between 6 single-nucleotide polymorphisms (SNPs) of KL and phenotypes were analyzed through a linear mixed-effects model. RESULTS: SNPs rs211247 and rs1207568 were positively correlated with the BP response to high-salt diet in the dominant model after adjusting for confounders (ß = 1.670 and 2.163, p = 0.032 and 0.005, respectively). BPs rs526906 and rs525014 were in a haplotype block. Block rs526906-rs525014 was positively correlated with diastolic BP response to potassium and potassium sensitivity in the additive model (ß = 0.845, p = 0.032). In addition, regression analysis indicated that rs211247 was associated with long-term systolic BP alterations after 8 years of follow-up in the recessive model (ß = 20.47, p = 0.032). CONCLUSIONS: Common variants of the KL gene might modify individual BP sensitivity to sodium or potassium and influence the long-term progression of BP, suggesting a potential role in the development of salt-sensitive hypertension. Thus, KL may be a new early intervention target for salt-sensitive hypertension.

Associations of Serum Uromodulin and Its Genetic Variants With Blood Pressure and Hypertension in Chinese Adults.

Background: Uromodulin, also named Tamm Horsfall protein, has been associated with renal function and regulation of sodium homeostasis. We aimed to examine the associations of serum uromodulin levels and its genetic variants with longitudinal blood pressure (BP) changes and hypertension incidence/risk. Methods: A total of 514 participants from the original Baoji Salt-Sensitive Study cohort were genotyped to examine the associations of genetic variations in uromodulin gene with the longitudinal BP changes and the incidence of hypertension over 8 years of follow-up. In addition, 2,210 subjects from the cohort of Hanzhong Adolescent Hypertension Study were used to investigate the relationships between serum uromodulin levels and the risk of hypertension. Results: SNPs rs12917707 and rs12708631 in the uromodulin gene were significantly associated with the longitudinal BP changes over 8 years of follow-up. SNP rs12708631 was significantly associated with the incidence of hypertension over 8 years. In addition, gene-based analyses supported the associations of uromodulin gene with the longitudinal BP changes and hypertension incidence in Baoji Salt-Sensitive Study cohort. Furthermore, serum uromodulin levels in the hypertensive subjects were lower than in the normotensive subjects (25.5 ± 1.1 vs. 34.7 ± 0.7 ng/mL). Serum uromodulin levels decreased gradually as BP levels increased (34.6, 33.2, 27.8, and 25.0 ng/mL for subjects with normotension, high-normal, grade 1 hypertension, and grade 2 hypertension, respectively). Serum uromodulin was significantly associated with the lower risk of hypertension [0.978 (0.972-0.984)] in Hanzhong Adolescent Hypertension Study cohort. Conclusion: This study shows that uromodulin is associated with blood pressure progression and development of hypertension.

Associations of corin genetic polymorphisms with salt sensitivity, blood pressure changes, and hypertension incidence in Chinese adults.

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.