bluuebunny/crossref_metadata_2025_split huggingface dataset:
ASSOCIATION OF CARDIOVASCULAR ENDPOINTS AND MORTALITY WITH CENTRAL AND PERIPHERAL PULSATILE BLOOD PRESSURE COMPONENTS
Authors: Huang Qifang , Aparicio Lucas , Thijs Lutgarde , Wei Fang -Fei , Melgarejo Jesus , Cheng Yi -Bang , Sheng Chang -Sheng , Yang Wen -Yi , Gilis-Malinowska Natasza , Boggia José , Niiranen Teemu , Wojciechowska Wiktoria , Stolarz-Skrzype Katarzyna , Barochiner Jessica , Tikhonoff Valérie , Casiglia Edoardo , Narkiewicz Krzysztof , Filipovský Jan , Czarnecka Danuta , Kawecka-Jaszcz Kalina , Jula Antti , Vanassche Thomas , Verhamme Peter , Struijker-Bouder Harry , Wang Ji -Guang , Zhang Zhen -Yu , Li Yan , Staessen Jan 
Published: April 2021

Objective:
Pulsatile blood pressure (pBP) confers cardiovascular risk. Whether associations of cardiovascular endpoints are tighter for central than peripheral systolic or pulse pressure (cSBP, pSBP, cPP, pPP) is uncertain.

Design and method:
We constructed the International Database of Central Arterial Properties for Risk Stratification (IDCARS), allowing a subject-level meta-analysis. IDCARS cohorts qualified for inclusion in the present analysis, if peripheral and central BP and cardiovascular risk factors had been measured at baseline, and if follow-up included both fatal and non-fatal outcomes.

Results:
Among 5608 participants (54.1% women; mean age, 54.2 years) enrolled in nine studies, median follow-up was 4.1 years. pSBP and pPP averaged 134.1 and 53.9 mmHg, and cSBP and cPP, estimated tonometrically from the radial waveform, 123.7 and 42.5 mmHg. The primary composite cardiovascular endpoint occurred in 317 participants (5.7%). Across fourths of the cPP distribution, rates increased exponentially (2.9, 5.7, 9.7, and 26.1 per 1000 person-years) with comparable estimates for cSBP, pSBP and pPP. The multivariable-adjusted hazard ratios, expressing the risk per 1-SD increment in blood pressure (HR), were 1.33 (95% confidence interval, 1.19–1.50) for cPP, 1.47 (1.31–1.64) for cSBP, 1.31 (1.17–1.46) for pPP, and 1.45 (1.30–1.62) for pSBP (P < 0.001). Further adjustment of cPP and cSBP, respectively for pPP and pSBP, and vice versa, removed the significance of all HRs. Adding cPP, cSBP, pSBP, pPP to a base model including covariables increased model fit (P < 0.001) with generalised R2 increments ranging from 0.40 to 0.77%, but adding a second pBP to a model including already one did not. Analyses of total mortality (204 deaths) and 106 cerebrovascular endpoints and sensitivity analyses across various subgroups produced consistent results.

Conclusions:
In this subject-level meta-analysis, the primary endpoint, mortality and cerebrovascular events were similarly associated with central than peripheral pBP.
RELATIONSHIP BETWEEN ARTERIAL STIFFNESS, PHYSICAL ACTIVITY & SEDENTARY TIME IN A YOUNG MIDDLE-EASTERN POPULATION
Authors: Mahmud Azra , Dalton Teigh , Nalin Jay , Nalin M. , Merrigan Orla , Saud Anas , Hamadah Randah 
Published: April 2021

Objective:
Arterial stiffness (AS) and physical activity are independent cardiovascular(CV) risk factors and predict outcome. We and others have shown that PA is associated with AS; however, the data is largely derived from older, Caucasian populations assessing PA with questionaires. The aim of this study was to explore the relationship between AS and PA using actigraphy in a young Middle-Eastern population, hitherto not studied.

Design and method:
Four-hundred and two apparently healthy subjects (mean age 20.7 ± 3 years, 52% females) were enrolled in this cross-sectional study. Anthropometric measurements performed included weight, height, waist and hip, total body fat, visceral fat and muscle mass.
Participants received an accelerometer (ActiGraph™) to wear on the wrist for 7 consecutive days. The average minutes/day spent at different PA intensities (min/day) was determined according to established cut-points as well as metabolic equivalents (METS). Arterial stiffness was measured using the SphygmoCor™ and Mibilograph® as pulse wave velocity (PWV), central BP and augmentation index(AIx), after fifteen minutes of supine rest. The data was analysed using JMP Pro version 13 (SAS for Windows, NC, USA).

Results:
30% of the population met the AHA Guidelines for PA with no gender difference. None of the subjects achieved moderate-vigorous or very vigorous activity with almost 50% of the time spent in being sedentary. There was a significant association between daily step count and body fat and body muscle content (p < 0.001). PWV was associated with age (r = 0.25, p < 0.001), brachial systolic BP(r = 0.57, p < 0.0001), aortic systolic BP(r = 0.65, p < 0.0001), cardiac output(r = 0.39, p < 0.0001), METS achieved(r = -0.42, p < 0.0001), light activity (r = -0.25, p < 0.001), moderate-to-vigorous (r = -0.29, p < 0.001), sedentary time (r = 0.45, P < 0.0001), waist(r = 0.47, p < 0.0001), visceral fat(r = 0.39, p < 0.001) and muscle mass(r = -0.31, p < 0.01). In a stepwise regression model with PWV as the dependent variable, age, MAP, gender, METS achieved and sedentary time emerged as independent determinants of PWV (R2 = 0.39, p < 0.0001).

Conclusions:
Unhealthy life-style is a strong risk factor for CVD, partly through the development of premature arterial stiffening. Our results highlight the deleterious effects of sedentary time on vascular function, independent of physical activity and energy consumption in a young, healthy population.
EARLY DETERMINANTS OF CHILDHOOD BLOOD PRESSURE AT AGE 6: THE GECKO DRENTHE AND ABCD BIRTH COHORTS
Authors: Xie Tian , Falahi Fahimeh , Schmidt-Ott Tabea , Vrijkotte Tanja , Corpeleijn Eva , Snieder Harold 
Published: April 2021

Objective:
The study aimed to explore the association between early determinants and childhood blood pressure at age 6.

Design and method:
From the population-based GECKO Drenthe birth cohort, 1663 Dutch children were included in the analyses. Birth weight was standardized (std-BW) for sex and gestational age, blood pressure was measured, and prenatal factors, pregnancy outcome and participants characteristics were derived from gynecologist/midwives or from parents by questionnaire. Hierarchical multiple linear regression models were used to test whether prenatal factors, std-BW, gestational age, breastfeeding independently contribute to childhood blood pressure at age 6. The models were further replicated in 2052 Dutch children from the Amsterdam Born Children and their Development (ABCD) study, and meta-analyses were performed to combine the results of the two cohorts. Next the effect of child's postnatal weight gain (the weight for age z-score change from age 2 to 6) on childhood BP was evaluated after adjustment for covariates only in the GECKO Drenthe cohort.

Results:
In the meta-analyses results of multiple linear regression, maternal prepregnancy BMI was positively associated with SBP (beta=0.09 mmHg; 95% confidence interval (CI), 0.02–0.15) and DBP (beta=0.11 mmHg; 95% CI, 0.05–0.17) at age 6. Children of women with hypertension during pregnancy had higher SBP (beta=0.91 mmHg, 95% CI, 0.14–1.68) and DBP (beta=0.71 mmHg, 95% CI, 0.04–1.39). Higher std-BW was associated with lower SBP (Per unit std BW, beta=-7.20 mmHg, 95% CI, -9.41--4.99) and lower DBP (beta=-4.00 mmHg, 95% CI, -5.94--2.07). Longer gestational age was not associated with DBP, only with lower SBP (per extra gestational week, beta=-0.23 mmHg, 95% CI, -0.43--0.02). The direction of effect sizes of these perinatal factors on childhood blood pressure were consistent in the two cohorts. Furthermore in the GECKO Drenthe cohort, higher postnatal weight gain was associated with higher SBP (beta=0.78 mmHg, 95% CI, 0.24–1.32) and higher DBP (beta=0.57 mmHg, 95% CI, 0.08–1.05).

Conclusions:
Higher maternal prepregnancy BMI, maternal pregnancy hypertension, a relatively lower birth weight for gestational age, shorter gestational age and faster postnatal weight gain independently contribute to higher childhood blood pressure at age 6.
IS BP LOAD ON AMBULATORY MONITORING A PREDICTOR OF TARGET ORGAN DAMAGE IN YOUTH? THE SHIP AHOY STUDY
Authors: Hamdani Gilad , Ferguson Michael , Lande Marc , Meyers Kevin , Samuels Joshua , Flynn Joseph T. , Urbina Elaine M. 
Published: April 2021

Objective:
Ambulatory BP monitoring (ABPM) is increasingly utilized for the diagnosis of hypertension (HTN). Pediatric guidelines consider BP load (% of reading above the ‘normal’ threshold) in risk-stratification of the ABPM phenotype. We sought to determine if load was an independent predictor of target organ damage (TOD) in youth.

Design and method:
Casual BP, ABPM, anthropometrics, echo for LV mass index (LVMI), systolic strain, diastolic function (E’/e’ ratio) and pulse wave velocity (PWV) for arterial stiffness (PWV) were measured in 367 adolescents (mean 15.6 + 1.7 years, 63% white, 58% male). ABPM was performed with Ontrak device (Spacelabs Inc., Snoqualmie, WA). Subjects were stratified by load (low <25% = 215, mid 25-<50% = 62, high >=50% =47) according to sex- and height-specific pediatric cut points. ANOVA was used to evaluate differences in CV risk factors and TOD across load groups. General linear models were used to evaluate load as an independent predictor of TOD after adjusting age, demographics, body mass index (BMI), and mean daytime SBP on ABPM.

Results:
There was a graded increase in most clinic and ambulatory BP means and loads across load groups (all p < 0.05). There was only a trend for higher LVMI (p = 0.06) and reduced strain (p = 0.05) in low vs high load groups. Diastolic function (E/e’) was lower in high vs low and mid groups and there was a graded increase in arterial stiffness (PWV) across load groups. Daytime SBP load was an independent determinant of all forms of TOD after adjusting for age and sex but lost significance for LVMI after adjusting for BMI%. Load remained a significant determinant of PWV & E/e’ after adjusting for BMI% and mean daytime ambulatory SBP. Load group was also a significant determinant of PWV and E/e’ even after adjustment for age, sex, BMI% and daytime ambulatory SBP (all p < 0.0001).

Conclusions:
Daytime SBP load adds to prediction of diastolic dysfunction and arterial stiffness but not LVMI or systolic function. Increased load on ABPM may indicate need for advanced imaging to detect early TOD in youth with HTN.
EXCESS ALDOSTERONE RELATIVE TO PLASMA RENIN AND ANGIOTENSIN II ASSOCIATES POSITIVELY WITH CENTRAL SYSTOLIC BLOOD PRESSURE IN YOUNG BLACK AFRICANS
Authors: Gafane-Matemane Lebo , Mokae Nametsegang , Breet Yolandi , Schutte Aletta E. 
Published: April 2021

Objective:
Populations of African ancestry usually present with a suppressed renin-angiotensin-aldosterone system (RAAS) attributed to excessive sodium retention and subsequently experience early and severe forms of hypertension-mediated organ damage. Central systolic blood pressure (cSBP) was previously found to be higher in young black adults as compared to their white counterparts. In the current study, we investigated associations of cSBP with a detailed RAAS profile in a healthy young population stratified according to ethnicity and sex.

Design and method:
This study included apparently healthy black men (N = 285) and women (N = 304), white men (N = 278) and women (N = 305) aged 20–30 years old. The SphygmoCor XCEL was used to derive cSBP. Aldosterone and equilibrium angiotensin levels were measured by LC-MS/MS and used for calculating angiotensin derived markers for plasma renin activity (PRA-S, Angiotensin I + Angiotensin II), angiotensin-converting enzyme (ACE-S, Angiotensin II/Angiotensin I), and two markers for adrenal effects of angiotensin II, the aldosterone-to-renin ratio (ARR-S, Aldosterone/PRA-S) and the aldosterone-to-angiotensin II-ratio (AA2-R, Aldosterone/Angiotensin II). Sodium and potassium were determined from 24-hour urine and then used to calculate sodium-to-potassium ratio.

Results:
Young black men and women presented with lower RAAS components and higher cSBP and urinary sodium-to-potassium ratio as compared to their white counterparts (all P < = 0.001). In forward stepwise multiple regression analyses, we observed the following associations: In black women, cSBP associated positively with ARR-S (β=0.269; P = 0.001) and AA2-R (β=0.263; P = 0.001), and negatively with PRA-S (β=-0.311; P < 0.001) and angiotensin II (β=-0.311; P < 0.001). In black men we observed a negative association between cSBP and PRA-S (β=-0.181; P = 0.047). None of the associations were present in white men and women.

Conclusions:
Positive associations of cSBP with the ratio of aldosterone to both PRA-S and angiotensin II in healthy young black women suggest that excess aldosterone may have deleterious effects on central blood pressure in this population group, which may lead to early target organ damage. The absence of any association between cSBP and RAAS components in white adults indicates an ethnic disparity in central pressure regulation.
GENES MEDIATING CELL GROWTH IN ALDOSTERONE-PRODUCING ADENOMAS
Authors: Yang Yuhong , Tetti Martina , Mulatero Paolo , Schneider Holger , Reincke Martin , Williams Tracy Ann 
Published: April 2021

Objective:
Aldosterone-producing adenomas (APA) are a major cause of primary aldosteronism. Somatic mutations explain the excess aldosterone production in the majority of patients with APA with mutations in KCNJ5 encoding a potassium channel the most prevalent in most reported populations. Mechanisms driving cell proliferation are largely undefined.

Design and method:
Quantitative transcriptome analysis using RNA-seq was used to identify differentially expressed genes between macro-APAs (n = 9, diameter >= 30 mm) and micro-APAs (n = 12, diameter <= 10 mm). Validation of RNA-seq data by TaqMan real-time PCR was performed for 14 genes in a broader cohort of APAs (NMD, no mutation detected, n = 28; KCNJ5-mutated, n = 43).

Results:
Hierarchical cluster analysis of the 500 genes with largest coefficient of variation indicated sample clustering based on genotype (KCNJ5 or NMD) and APA diameter. Differential expression of 155 and 348 genes was found between micro- and macro-APAs with KCNJ5 mutations and NMD, respectively. Among the top 5 overrepresented Gene Ontology terms (biological process), cell death was exclusively enriched in NMD micro- vs NMD macro-APAs. The expression levels of 10 genes were validated with a potential function related to cell growth. Expression of BEX1 (a reported tumour suppressor) was 2.8-fold down regulated in macro-APAs relative to micro-APAs (P < 0.001), and a linear negative correlation of BEX1 expression with APA diameter was observed in NMD APAs (r = -0.501, P = 0.007). Genes involved in beta-catenin signalling, SFRP2, DKK1 and TSPAN12 were 5.9-fold (P < 0.001), 1.8-fold (P = 0.007) and 8.3-fold (P < 0.0001) down regulated, respectively, in macro-APAs compared with micro-APAs. BAI1 and CCL21 were also down regulated in macro-APAs relative to micro-APAs (3.3-fold, P = 0.026; 2.6-fold, P = 0.145, respectively). Additionally, the expression of TMPRSS3 (r = 0.727, P < 0.001), BMP4 (r = 0.389, P = 0.041) and FBXL21 (r = 0.761, P < 0.001) showed a linear positive correlation with adenoma diameter in NMD subgroup.

Conclusions:
APA display distinct transcriptome profiles according to adenoma diameter which may help identify genes involved in APA tumour cell growth.
TELMISARTAN IMPROVES MYOCARDIAL REMODELING IN RATS WITH HYPERTENSIVE LEFT VENTRICULAR HYPERTROPHY THROUGH INHIBITING LEPTIN AUTOCRINE INDUCED BY ANGII AND ACTIVATING PPARGAMMA
Authors: Chen Hui , Li Min , Liu Lei , Zh Danjun , Tian Gang 
Published: April 2021

Objective:
The mechanism of left ventricular hypertrophy (LVH) in hypertension is complex. This study was to investigate the role of telmisartan in improving myocardial remodeling in hypertensive LVH and explore the potential molecular mechanism.

Design and method:
Eight-week male Sprague-Dawley (SD) rats were used to establish hypertensive LVH model through abdominal aortic constriction. Telmisartan was intragastrically administered 6weeks after surgery. Cardiac fibroblasts were used in vitro experiments under the treatment of angiotensin II (AngII), leptin or different inhibitors. The cardiac function and myocardial remodeling level were evaluated in rats, and the AngII-AT1R-ROS-ERK1/2-AP-1 pathway, leptin-JAK2/STAT3-TGF-β1/Smad3 pathway, and the metabolism-related parameters of collagen fibers were detected in cardiac fibroblasts.

Results:
Telmisartan treatment could alleviate left ventricular diastolic dysfunction (Table 1), reduce myocardial local RAAS and leptin level (Table 2), improve myocardial fibrosis and inhibit the activation of leptin-JAK2/STAT3-TGF-β1/Smad3 pathway in hypertensive LVH rats (Figure 1). AngII could increase the expression of leptin and induce AP-1 nuclear transposition in cardiac fibroblasts, and AT1R antagonist telmisartan, ROS scavenger NAC, ERK1/2 inhibitor PD98059 or AP-1 inhibitor SR11302 could inhibit leptin synthesis and secretion induced by AngII (Figure 2). Leptin could induce collagen metabolic disorders in cardiac fibroblasts, which could be partly restored by JAK2 inhibitor AG-490, STAT3 inhibitor S3I-201 or telmisartan. Telmisartan could reduce leptin synthesis and secretion as good as leptin antagonist, and improve collagen metabolism disorder induced by AngII better than leptin antagonist (Figure 3). Telmisartan could increase the expression of PPAR-γ to almost 3-fold of the control group. When pretreated with PPAR-γ inhibitor GW9662, telmisartan couldn’t restore the collagen metabolic disorders and the increased expression of P-STAT3 stimulated by leptin (Figure 4).

Conclusions:
Telmisartan can improve myocardial remodeling in hypertensive LVH rats via two ways: one is inhibiting leptin autocrine induced by local AngII as AT1R antagonist, the other is inhibiting leptin downstream signaling molecular STAT3 phosphorylation as PPAR-γ agonist (Figure 5). These findings demonstrate the crosstalk between myocardial local RAAS and leptin, and reveal a new molecular mechanism of telmisartan in improving myocardial remodeling in hypertensive LVH.
PROXIMAL TUBULE-SPECIFIC DELETION OF AT1A RECEPTORS ATTENUATES ANGIOTENSIN II-INDUCED HYPERTENSION BY INCREASING GLOMERULAR FILTRATION AND THE PRESSURE-NATRIURESIS RESPONSE
Authors: Li Xiao , Leite Ana , Zheng Xiaowen , Zhao Chunling , Zhuo Jia 
Published: April 2021

Objective:
The present study tested the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and full development of Ang II-induced hypertension.

Design and method:
Six groups (n = 7–12 per group) of adult male wild-type (WT) and PT-Agtr1a-/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg/day, i.p.). Glomerular filtration rate (GFR) was measued using fluorescein-labeled sinistrin, and natriuretic responses were determined under basal conditions and after Ang II infusion.

Results:
Basal systolic blood pressure were ∼13 ± 3 mmHg lower in PT-Agtr1a-/- than WT mice (P < 0.01). However, basal GFR was higher in PT-Agtr1a-/- mice (WT: 160.4 ± 7.0 μl/min vs. PT-Agtr1a-/-: 186.0 ± 10 μl/min, P < 0.01). Basal 24 h urinary Na+ excretion (UNaV) was higher in PT-Agtr1a-/- than WT mice (P < 0.01). In response to Ang II infusion, both WT and PT-Agtr1a-/- mice developed hypertension with similar pressor response to Ang II in WT (43 ± 3 mmHg, P < 0.01) and PT-Agtr1a-/- mice (39 ± 5 mmHg, P < 0.01). However, systolic blood pressure was still 16 ± 3 mmHg lower in PT-Agtr1a-/- mice (P < 0.01). Ang II decreased GFR to 132.2 ± 7.0 μl/min in WT mice (P < 0.01), and to 129.4 ± 18.6 μl/min in PT-Agtr1a-/- mice (P < 0.01), respectively. In WT mice, UNaV increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group (P < 0.01). In PT-Agtr1a-/- mice, UNaV increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group (P < 0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT-Agtr1a-/- mice (P < 0.01). Finally, proximal tubule-specific deletion of AT1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion (P < 0.01) or a 2% high salt diet for 2 weeks (P < 0.01).

Conclusions:
The present study supports the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and the development of Ang II-induced hypertension.
EPIDEMIOLOGICAL CHARACTERISTICS AND RELATED FACTORS OF FRAILTY IN CHINESE OLDER ADULTS WITH HYPERTENSION
Authors: Ma Lina , Li Yun , Tang Zhe 
Published: April 2021

Objective:
Hypertension and frailty are associated and often coexist in older adults. We have previously showed that frailty is associated with poorer physical function and higher mortality in community-dwelling hypertensive older adults in Beijing Longitudinal Study of Aging. However, little is known about the effect of frailty on hypertension prevalence, treatment, and control in Chinese older adults. We aimed to explore the epidemiological characteristics and related factors of frailty in Chinese older adults with hypertension in a nationwide survey.

Design and method:
Data were from China Comprehensive Geriatric Assessment Study (CCGAS, 2011–2012) using stratified, multiple-stage, random, and cluster sampling methods. A total of 6867 community-dwelling older adults were included. Comprehensive Geriatric Assessment frailty index (CGA-FI) was measured on the basis of six variables: demographic characteristics, physical health, physical function, living behavior and social function, mental health, and cognitive function. Frailty was defined as a score lower than 0.25.

Results:
The FI was positively correlated with age in both Non-HT group (male: r = 0.375, p < 0.001, female: r = 0.340, p < 0.001) and HT group (male: r = 0.273, p < 0.001, female: r = 0.340, p < 0.001). The prevalence of hypertension in older adults with frailty was higher than those without frailty (78.3% vs 64.1%, p < 0.001). However, the awareness and treatment rates of hypertension were higher in participants with frailty than those without frailty (awareness rate: 82.9% vs 67.9%, p < 0.001; treatment rate: 68.4% vs 57.8%, p < 0.001). There was no significant difference in control rate of hypertension between HT group and Non-HT group (73.9% vs 74.2%, p = 0.872). The prevalence of frailty was significantly higher in HT than in Non-HT (13.8% vs 7.4%, p < 0.001). Logistic analysis shows that age, marriage, coronary heart disease, chronic obstructive pulmonary disease, diabetic mellitus, osteoporosis, hearing loss, exercise, depression, cognitive impairment and white blood cells were independently related factors with frailty in older participants with hypertension.

Conclusions:
The prevalence, awareness and treatment rates of hypertension were higher in older adults with frailty than those without frailty in China.