bluuebunny/crossref_metadata_2025 huggingface dataset:
BODY MASS INDEX IS DIFFERENTLY ASSOCIATED WITH ISOLATED DIASTOLIC HYPERTENSION AND ISOLATED SYSTOLIC HYPERTENSION: INSIGHTS FROM THE UPDATE STUDY IN CHINA
Authors: Xie Kun , Bao Liwen , Gao Xiufang , Li Yong
Published: April 2021

Objective:

Hypertension is highly prevalent and body mass index (BMI) is one of the risk factors of hypertension. But little is known whether BMI is differently associated with isolated diastolic hypertension (IDH) and isolated systolic hypertension (ISH).

Design and method:

Patients with primary hypertension aged over 18 years were investigated from all over the country using convenience sampling during 2017–2019. IDH was defined as systolic blood pressure (SBP) < 140 mmHg and diastolic blood pressure (DBP) > = 90 mmHg with or without antihypertensive agents. ISH was defined as SBP > = 140 mmHg and DBP < 90mmHg with or without antihypertensive agents. Elevated BMI was defined as BMI > = 25 kg/m2.

Results:

Totally 8548 patients were screened. 73 of them were excluded due to missing covariates and 8475 participants were included. The average age was 63.67 ± 12.78 years and male accounted for 54.4%. 18.5% of them had a smoking history and 89.4% of them were using antihypertensive agents. Among them, 361 (4.3%) had IDH and 2096 (24.7%) had ISH. Patients with IDH were younger than those with ISH (54.84 ± 13.21 vs 66.87 ± 12.09, p < 0.001). Male accounted for more in IDH than in ISH (64.5% vs 50.7%, p < 0.001). BMI in IDH was higher than that in ISH (26.47 ± 6.53 vs 24.70 ± 3.77, p < 0.001). More patients had smoking history in IDH than in ISH (27.4% vs 17.1%, p < 0.001). Fewer patients were using antihypertensive agents in IDH than in ISH (82.0% vs 88.4%, p = 0.001). After adjusting for age, gender, smoking history and antihypertensive agents, multi-variate logistic analysis showed that elevated BMI remained significantly associated with the prevalence of IDH (OR = 1.30, 95% CI 1.05–1.61, p = 0.018) whereas no association was found in elevated BMI and ISH (OR = 1.05, 95% CI 0.95–1.16, p = 0.358).

Conclusions:

BMI was associated with the prevalence of IDH rather than ISH. Patients with elevated BMI were more likely to have IDH. BMI management could be particularly effective in IDH management.
FEASIBILITY OF HYPERTENSION AWARENESS AND CONTROL IN SWISS PHARMACIES DURING THE MMM17 CAMPAIGN
Authors: Polychronopoulou E. , Razafinjatovo C. , Tremblay S. , Wurzner A. , Ménétré G. , Burnier M. , Wuerzner G.
Published: April 2021

Objective:

May Measurement Month 2017 was an international screening campaign for hypertension organized by the International Society of Hypertension and the World Hypertension League conducted worldwide on adults over 18 years old. In Switzerland, the campaign was conducted almost exclusively in pharmacies. The objective was to assess the feasibility of a hypertension screening program in pharmacies.

Design and method:

40 pharmacies in the Canton of Vaud included participants from the 1st to the 31st May 2017. After obtaining written informed consent, three standardized blood pressure measurements using validated oscillometric devices were taken. A short questionnaire for basic demographic and clinical information was then completed. The BP results and the answers to the aforementioned questionnaire were directly uploaded to a safe data server via on online application. Descriptive statistics and chi-squared tests were used.

Results:

1045 participants (73.4% women, p < 0.05) were included in the study. Mean age and body mass index were respectively 48.5 ± 18.7years and 24.5 ± 4.5 kg/m2. The overall prevalence of hypertension was 28.5% using ESH2018 cut-off values for hypertension values and 50.7% using AHA2017 cut-off values. The prevalence was higher in men (42.5 vs 23.5%, p < 0.05 with ESH2018 and 70.5% vs 43.6% with AHA2017). Out of 298 hypertensive participants, 178 were treated and 120 (40.3%) were not treated. Uncontrolled hypertension was present in 36.0% of treated hypertensive participants (no difference between men and women). Systolic blood pressure decreased from the first to the second measurement (124 to 122 mm Hg, p < 0.05) and from the second to the third measurement (122 to 120 mm Hg, p < 0.05). No difference was observed for diastolic blood pressure.

Conclusions:

Screening program in pharmacies is feasible and enables the identification of untreated or unaware hypertensive patients (13.8%). Women are more likely to participate to hypertension screening programs in pharmacies.
ASSOCIATION BETWEEN QUALITY OF SLEEP AND THE DEVELOPMENT OF HYPERTENSION IN NORMOTENSIVE SUBJECTS
Authors: Takase Hiroyuki , Machii Masashi , Nonaka Daishi , Ohno Kazuto , Takayama Shin , Sugiura Tomonori , Ohte Nobuyuki , Dohi Yasuaki
Published: April 2021

Objective:

Although there are many reports on the relationship between sleep time and hypertension, definite conclusions have not been drawn yet. On the other hand, an influence of the feeling of satisfaction about the sleep on the incidence of hypertension remains unknown. We investigated effects of a sleep time and a feeling of satisfaction of sleep on the development of hypertension.

Design and method:

Normotensive 2162 subjects (male = 1316, 44.7 ± 8.0 year-old at baseline), who visited our hospital for a physical check-up between 2008 and 2015, were enrolled. Quality of sleep (satisfied or not satisfied) and sleep time (<6 hours or > = 6 hours) were assessed by a questionnaire. They were followed up until December 2016 (median 1540 day) with the endpoint being the development of hypertension. Hypertension was defined as blood pressure > = 140/90mmHg or the use of antihypertensive medications.

Results:

During the follow-up, hypertension developed in 846 subjects (42.0 per 1000 person-year), with the incidence being more frequent in male than female subjects (52.3 vs. 24.9 per 1000 person-year). The incident hypertension was higher in subjects who were satisfied with their sleep than those who were not (48.3 vs. 32.5 per 1000 person-year). Multivariate Cox-hazard analysis adjusted for possible risk factors revealed that feeling of satisfaction (hazard ratio [HR]:1.395, 95% confidence interval [CI]:1.120–1.738), but not the duration of sleep, was associated with the development of hypertension. Among subjects who feel their sleep time sufficient, HR (95%CI) was 1.921 (1.225–3.011) in subjects with a sleep time > = 6 hours and 1.387 (1.087–1.770) in those with a sleep time < 6 hours.

Conclusions:

A feeling of satisfaction of sleep rather than a sleep time may be an important factor that leads to the development of hypertension though the results should be interpreted with a caution because data on sleeping status were obtained from questionnaire. Further investigation is necessary to clarify the mechanism underlying the association between the development of hypertension and satisfaction of sleep.
BLOOD PRESSURE AND CHRONIC KIDNEY DISEASE INCIDENCE STRATIFIED BY SEX AND THE USE OF ANTIHYPERTENSIVE DRUGS
Authors: Satoh Michihiro , Hirose Takuo , Nakayama Shingo , Murakami Takahisa , Takabatake Kyosuke , Asayama Kei , Imai Yutaka , Ohkubo Takayoshi , Mori Takefumi , Metoki Hirohito
Published: April 2021

Objective:

The individuals treated by antihypertensive drugs potentially have a higher cardiovascular disease risk than those without the use of antihypertensive drugs regardless of blood pressure (BP) levels. However, the amount of increase in the risk for chronic kidney disease (CKD) incidence in treated individuals compared with untreated individuals with the same BP level is yet to be assessed. Furthermore, detailed information on sex-difference in the association of BP with CKD risk is scarce. To assess the association between BP and the risk for CKD incidence after the stratification by sex and the use of antihypertensive drugs, the present study involved a longitudinal analysis based on multiple measurements of serum creatinine from a large-scale health check-up.

Design and method:

We conducted a retrospective cohort study using the JMDC database, which contains the annual health check-up data of Japanese employees and their dependents aged < 75 years. We included 154,692 participants (men: 69.68%; mean age 44.74) without CKD, which was defined as an estimated glomerular filtration rate < 60 mL/min per 1.73 m2 or proteinuria.

Results:

During the mean follow-up period of 4.78 years, new onset of CKD occurred in 14,888 participants. When the normal BP group (systolic/diastolic BP < 120/ < 80 mmHg) without treatment was used as a reference, the hazard ratios (95% confidence intervals) of high BP (130–139/80–89 mmHg) and grade 1 (140–159/90–99 mmHg) and grade 2–3 hypertension (> = 160–179/ > = 100 mmHg) were 1.11 (1.06–1.56), 1.36 (1.28–1.45), and 1.76 (1.56–1.99) for untreated participants, respectively. However, in treated men, even normal BP was associated with a 1.5-times higher risk for CKD. The results were similar in women except for the hazard ratios of normal and high normal BP in treated women, which were 0.98 and 0.95, respectively.

Conclusions:

Treated individuals had higher risk for CKD incidence and sex differences existed in the association of BP with CKD risk in the present study. Kidney function in treated individuals should be followed carefully, especially in men.
ETHNIC DIFFERENCES IN THE ASSOCIATION BETWEEN HANDGRIP STRENGTH AND THE PREVALENCE OF HYPERTENSION
Authors: Lopez-Lopez Jose Patricio , Ney-Salazar Daniela , Parra-Gomez Laura Alejandra , Camacho Paul Anthony , Rangarajan Sumathy , Yusuf Salim , Lopez-Jaramillo Patricio
Published: April 2021

Objective:

Higher prevalence of hypertension among afro-descendants compared to other ethnic groups has been reported in high-income countries. Genetic, behavioral, and socioeconomic factors could explain these differences, and body composition could contribute. This study aims to assess the association between handgrip strength (HGS) and hypertension in different ethnicities in a middle-income country. We additionally evaluated the role of socioeconomic and behavioral factors to explain ethnic differences.

Design and method:

We evaluated the association between HGS measured by Jamar Dynamometer and the risk hypertension in 4102 adults aged 35 to 70 years from 3 ethnic groups (593 whites, 3001 mestizos, 508 afro-descendants) enrolled in the prospective population-based cohort study PURE-Colombia. We calculated unadjusted and adjusted odds ratios (95% CI) for the prevalence of hypertension across tertiles of HGS and the association with anthropometric, socioeconomic, and behavioral factors.

Results:

Results: The overall prevalence of hypertension was 39.2%, being greater in the afro-descendants (46.3%) than in whites (41.5%) and mestizos (37.6%). A higher prevalence of hypertension was found in mestizos and afro-descendants in tertile 1 of HGS (< 21 kg) compared to those in tertile 3 of HGS (> 29.7 kg) (OR = 1.48; 95% CI: 1.20 - 1.84 and OR = 1.70; 95% IC: 1.01 – 2.85, respectively). However, when adjusting by confounders, the association lost statistical significance. The prevalence of hypertension was positively associated with body mass index and waist circumference. There was a higher prevalence amongst individuals with a low educational level compared to those with a high educational level in whites (OR = 1.74; 95% CI: 1.08 - 2.78), mestizos (OR = 1.5 95% CI: 1.13 - 2.01), and afro-descendants (OR = 2.46; 95% CI: 1.11 - 5.45). Behavioral factors, such as alcohol and tobacco intake, protein, and fat consumption, were not associated with a higher prevalence of hypertension.

Conclusions:

HGS could partially contribute to explaining ethnic differences in the prevalence of hypertension. However, socioeconomic factors such as education level play a key role. Therefore, a greater focus on screening for low HGS, interventions aimed at attenuating age-related declines, and addressing social inequalities could positively impact these differences.
TRENDS IN STATUS OF HYPERTENSION IN SOUTH CHINA: RESULTS FROM TWO REPRESENTATIVE CROSS-SECTIONAL SURVEYS, 2012-2017
Authors: Liu Lin , Huang Yuqing , Huang Jiayi , Yu Yuling , Chen Chaolei , Shen Geng , Feng Yingqing
Published: April 2021

Objective:

This study aims to investigate the long-term natural trends in the status of hypertension in south China from 2012–2017.

Design and method:

Two successive cross-sectional surveys were conducted in Guangdong Province in 2012 and 2017, which include 10970 and 36376 participants aged 35 to 75 from different area, respectively. A multistage, stratified and cluster random sampling method was used to enroll the participants. Hypertension was defined as a mean systolic blood pressure at least 140mmHg and/or a mean diastolic blood pressure at least 90 mmHg, and/or self-reported use of antihypertensive medication within past 2 weeks, according to the 2010 Chinese guidelines for the management of Hypertension. The prevalence and control rates of hypertension were also estimated according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) high blood pressure guideline.

Results:

In 2012, 39.3% participants had hypertension, whereas 37.6% participants had hypertension in 2017. The age-standardized prevalence was 34.7% [95% confidence interval (CI): 34.1–35.2] and 31.9% (95% CI: 31.6–32.2) in 2012 and 2017, respectively. The prevalence of prehypertension decreased from 14.5 to 13.1% from 2012 to 2017. Over the two study periods, 45.6 and 51.2% of those with hypertension were aware of their diagnosis in 2012 and 2017, respectively, and 40.8 and 44.9% were taking antihypertensive medications, respectively; the control rates increase from 15.1 to 17.0% and among those who received medical treatment 36.9 and 37.9% achieved control of BP, respectively. Based on the 2017 ACC/AHA guideline, prevalence of hypertension was 64.5% in 2012 and 59.1% in 2017. The control rate increased from 3.0 to 4.4% during this period. And among participants who received medical treatment, only 12.2 and 15.2% of participants achieve the target of hypertensive management in 2012 and 2017, respectively.

Conclusions:

During 2012 to 2017, the prevalence of hypertension in South China trended to be stable, and the rate of awareness, treatment and control increased but still low.
TEN YEARS TREND OF HYPERTENSION AWARENESS, TREATMENT, AND CONTROL RATE IN KOREA
Authors: Kim Kwang Il , Choi Jungyeon , Kim Cheol-Ho
Published: April 2021

Objective:

We analyzed the Korean National Health and Nutrition Examination Survey (KNHANES) database to determine the trend of hypertension awareness, treatment, and control rate in Korea during the last 10 years. In addition, we tried to investigate the effect of chronic medical conditions such as diabetes mellitus, obesity, hypercholesterolemia, and chronic kidney disease on hypertension management.

Design and method:

The KNHANES, which was conducted by the Korea Centers for Disease Control and Prevention, was a cross-sectional, nationally representative survey in which a stratified multistage sampling design was used.

Results:

A total of 59,282 adults older than 20 years were included in the analysis. Mean age was 50.7 ± 16.4 years and male subjects were 42.6%. The prevalence of hypertension, hypercholesterolemia, diabetes mellitus, obesity, and chronic kidney disease (CKD) were significantly increased during the last 10 years. The prevalence of diabetes mellitus, hypercholesterolemia, obesity, and CKD was significantly higher in the hypertensive patients compared to normotensive subjects. Especially, there was a clustering of those cardiovascular risk factors, which was more prominent as people get older. During the last 10 years, the awareness, treatment, and control rate of hypertension have been significantly improved. The treatment and control rates of hypertension was higher in patients having multimorbidity, which imply the multimorbidity have a favorable effect on the treatment and control of hypertension in Korean population.

Conclusions:

Hypertension treatment, control rate have been improved during the last 10 years. Higher rate of awareness, treatment and control rate of hypertension in patients having multimorbidity suggest that more aggressive surveillance or treatment for the multimorbid hypertensive patients might be associated with the improvement of hypertension treatment and control rate in Korea.
THE EFFECTS OF MIDDAY NAP DURATION ON THE RISK OF HYPERTENSION IN CHINESE RURAL POPULATION
Authors: Huang Miao , Lu Yao , Yuan Hong
Published: April 2021

Objective:

Most previous epidemiological studies regarding sleep and risk of hypertension focused on the association between night sleep duration and hypertension. However, data on the effect of midday nap duration on hypertension are scarce, especially among rural population. The study was conducted to evaluate the associations of the midday nap duration with blood pressure and hypertension in Chinese rural population.

Design and method:

From August 2016 to July 2017, a total of 1755 eligible participants were consecutively enrolled in our study in Hunan province, China. Hypertension was defined as systolic blood pressure/diastolic blood pressure > = 140/90mmHg or self-reported hypertension and current use of anti-hypertensive medicines. Participants were categorized into three groups according to midday nap duration, such as no napping (reference), short (<1 h), and long (> = 1 h). Multivariable regression models were applied to assess the potential association.

Results:

Of the 1755 included participants, 908 suffered from hypertension. Participants’ mean age was 55.86 years. 638 (36.35%) were men and 1117 (63.65%) were women. Compared to reference (no napping), fully adjusted odd ratios (ORs) and 95% confidence interval (CI) of hypertension were 0.72 (0.57–0.92) in participants with long midday napping duration (> = 1 h). Linear regression analyses showed that long midday nap duration (b = -2.78, 95% CI: -4.89, -0.67, P = 0.010) were significantly negative association with systolic blood pressure.

Conclusions:

Our findings suggest that long midday nap duration might decrease the risk of hypertension and reduce the levels of systolic blood pressure among rural population. These findings warrant further prospective studies in a larger population.
SOCIOECONOMIC, DEMOGRAPHICS AND HEALTH CHARACTERISTICS OF ADULTS AND ELDERLY WITH SELF-REPORTED HYPERTENSION, UNDER TREATMENT OF ANTIHYPERTENSIVE THERAPY: A POPULATION BASED STUDY
Authors: Da Silva Brunna Raphaelly Amaral , Costa Karen Sarmento
Published: April 2021

Objective:

To describe the socioeconomic, demographics and health characteristics of adults and elderly people who declared a diagnosis of hypertension, with a medical indication to treat that and was in use of antihypertensive drugs at the time of the interview.

Design and method:

Secondary data analysis from the National Survey on Access Use and Promotion of Rational Use of Medicines (PNAUM 2014), the nationwide cross-sectional population-based study, focused on the use of medicines in Brazil with a total of 41,433 interviews. The sample of this study consists of people who self-reported diagnosis of high blood pressure, medical indication to antihypertensive therapy and was in use of those medicines at the time of the interview. The Statistical Analysis System (SAS) version 9.4 was used.

Results:

The sample included 8,177 people with 20 years or more who reported a diagnosis of hypertension, medical indication for treatment with antihypertensive drugs, and were using them at the time of the interview. The use of antihypertensive drugs was distributed in a higher percentage among females, representing 64.4% of the sample, increased simultaneously with increasing age, ranging from 7.9% among individuals aged 20–39 years, to 50.4% among the elderly. Among the Brazilian regions, the use ranged from 4.4% in the North to 53.3% in the Southeast. Considering race/skin color the use of antihypertensives was 48.6% in Whites and 50.3% in Blacks. Individuals who reported being Indigenous and Yellow (Other), represented only 1.2%. People who claimed to have between 1 and 8 years of study and those in economic class C had higher percentages: 43.1% and 55.4% respectively. Describing variables of health conditions, 42% of respondents were overweight, 63.1% were non-smokers and 83% reported never consuming alcohol. Half of the sample reported having two or more chronic disease in addition to hypertension. Furthermore, 27.7% of respondents said they had hypercholesterolemia, 22.7% diabetes and 17.1% another chronic disease.

Conclusions:

The use of antihypertensive drugs occur mostly in Brazil among females, elderly, with 1 to 8 year of study, economic class level C, overweight, with two or more chronic disease in addition to hypertension.
THE IMPACT OF HYPERTENSION STATUS ON SURVIVAL IN THE RUSSIAN FEDERATION
Authors: Vladimir Kutsenko , Balanova Yulia , Imaeva Asiia , Kapustina Anna , Muromtseva Galina , Evstifeeva Svetlana , Karamnova Natalya , Maksimov Sergey , Yarovaya Elena , Shalnova Svetlana
Published: April 2021

Objective:

To evaluate associations between hypertension and mortality among the Russian population.

Design and method:

A cross-sectional study Epidemiology of cardiovascular diseases in the RF (ESSE) was carried out in 14 regions of the Russian Federation (2012–13), response rate>80%. The prospective cohort included randomly selected males (N = 7243) and females (N = 11061) aged 25–64 (11 regions). Standard epidemiology methods and criteria were used. Arterial hypertension (AH) is defined as measured blood pressure (BP) of 140/90 mm Hg or greater and/or treatment with antihypertensive medications. Participants were divided into the four groups by BP levels and hypertension treatment: without hypertension (No AH), treated hypertensives who control their BP level (Controlling), hypertensives never treated (Untreated), and treated but not achieved target BP level (Not controlling). Endpoints were collected once every two years. The mortality follow-up period was 7 years, 397 deaths were observed.

Statistical data was processed using R 3.6.1. We used Kaplan-Meier estimator and log-rank test to investigate the relationship between risk groups and survival. We assessed the same relationship using the age-adjusted Cox proportional hazards model. P < 0.05 was considered as significant.

Results:

During the follow-up period, there were 83 deaths from coronary heart disease, 39 deaths – cerebrovascular accident, 20 deaths – other CVDs, 255 deaths – non-CVD. The impact of hypertension on survival was found among males and among females (p < 0.0001 for both) (fig. 1 A, B). The most significant total mortality risk was noted in the «Not controlling» group (males OR: 1.83, females OR: 1.59) (fig. 1 C, D). Similar results were obtained for CVD mortality (males OR: 2.72, females OR: 3.23, p < 0.005 for both). The survival in groups «Controlling» and «Untreated» did not differ significantly. However, «Controlling» participants were older than «Untreated» participants and had a larger waist size, greater prevalence of hyperlipidemia, and diabetes mellitus.

Conclusions:

The presence of hypertension significantly increases the risk of death. Treated but BP uncontrolled hypertensive subjects had the highest mortality risk. The absence of differences between «Controlling» and «Untreated» participants is due to differences in age and comorbidities.
LONG-TERM EFFECT OF ANTIHYPERTENSIVE AGENTS ON THE NEURAL BAROREFLEX SENSITIVITY-A SUBSTUDY OF THE PARIS PROSPECTIVE STUDY III
Authors: Fortier Catherine , Bruno Rosa Maria , Perier Marie-Cécile , Khettab Hakim , Guibout Catherine , Danchin Nicolas , Jouven Xavier , Empana Jean-Philippe , Boutouyrie Pierre
Published: April 2021

Objective:

The baroreflex is a crucial mechanism regulating moment-to-moment blood pressure (BP) to ensure appropriate flow and pressure to the brain and other organs. All antihypertensive treatments, because of their BP lowering effect, interact with the autonomic nervous system by stimulating the sympathetic response. In addition, specific drugs may further interact with the BRS because of their specific mode of action. Whether antihypertensive agents have remnant effect is still unknown.

Design and method:

In the Paris Prospective Study III, spontaneous baroreflex, carotid stiffness and pharmacological drugs intake were available in 7967 adults (mean age of 60 ± 6 years, 62% men). The neural component of the baroreflex sensitivity (nBRS) was obtained with a cross-spectral analysis of variations in carotid distention rate and R-R intervals. Individuals with a BP lowering medication (BP-treated) were paired to non-BP treated individuals (controls) with similar cardiovascular comorbidities using a propensity score matching procedure (n = 1182 pairs).

Results:

Sympathetic activity was higher in the BP-treated group compared to their matched-controls, as shown by the increased spectral power of distention rate in the low frequency band (log LF distrate: 4.106 ± 0.530 vs 4.055 ± 0.514, p = 0.018). Amongst pharmacological classes of BP lowering agents, only agents acting on the angiotensin system (ACEi-ARB) were associated with nBRS. Compared to their matched controls (n = 331 pairs), ACEi-ARB users had lower nBRS (2.79 ± 0.66 (ln) vs. 2.90 ± 0.62 (ln), p = 0.03). After adjustment for carotid stiffness (stdbeta = 0.25, p < 0.001) and systolic pressure (stdbeta = -0.20, p < 0.001), ACEi-ARB remained significantly associated with nBRS (stdbeta = -0.09, p = 0.025).

Conclusions:

In this community-based population study, antihypertensive treatments induced activation of the autonomic nervous system independently of cardiovascular comorbidities. Taken as a whole, BP treatments did not have any effect on the neural component of the baroreflex loop, with the exception of ACEi-ARB which were negatively associated with nBRS. This effect was independent of BP and stiffness, which may suggest an inhibition of sympathetic activity by ACEi-ARB.
MICRORNA PROFILE IN HUMAN VASCULAR SMOOTH MUSCLE CELLS FROM HYPERTENSIVE SUBJECTS: FOCUS ON OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS
Authors: Wang Yu , Camargo Livia L. , Beatie Wendy , Mcbride Martin , Montezano Augusto C. , Touyz Rhian M.
Published: April 2021

Objective:

miRNAs are important to phenotypic control and function of vascular smooth muscle cells (VSMC). miRNA dysregulation is associated with vascular dysfunction, which involves oxidative and endoplasmic reticulum (ER) stress. We assessed VSMC miRNA profile in human hypertension focusing on oxidative and ER stress pathways.

Design and method:

VSMCs from small arteries from normotensive (NT) and hypertensive (HT) subjects were used. miRNA profiling of 758 miRNAs was performed using TaqMan advanced miRNA assay (TaqMan Low Density Array Human microRNA). Expression of vascular genes and proteins was detected by RT-PCR and immunoblotting respectively. Ingenuity Pathway Analysis (IPA) was used for miRNA target prediction (high predicted results).

Results:

miRNA array identified 25 miRNAs uniquely expressed in HT and 21 miRNAs uniquely expressed in NT (CT < 30). Of the 332 miRNAs present in both HT and NT, 60 miRNAs were significantly upregulated in HT (fold change >1.5), 136 miRNAs were significantly downregulated in HT (fold change >1.5). In HT, mRNA levels of Nox1 (1.71 fold) and protein levels of Nox4 (1.59 fold) and Nox5 (2.04 fold) were increased, p < 0.05. SOD2 (4.43 fold) and GPx1 (1.97 fold) protein expression were upregulated in HT, p < 0.05. PERK (1.57 fold) and elF2a (2.31 fold) protein levels were increased in HT, while ERO1A expression was decreased in HT (2.36 fold), p < 0.05. IPA was performed for the genes differentially expressed in HT compared to NT. After inversely pairing the miRNAs to the changes observed in gene and proteins expression, miR-505–5p (-2.13 fold), miR-324-5p (-1.51 fold), miR-185-5p (-1.742) and miR-491-5p (-1.667), which are predicted to target Nox5, were downregulated. miR-185-5p and miR-491-5p together with, miR-125a-3p (-2.04 fold) and miR-634 (unique in NT, CT = 27.36) were predicted to target GPx1. ER stress was also targeted by downregulated miRNAs in HT, such as miR-200b-3p (-28.57 fold), predicted to target elF2a.

Conclusions:

We identify a cluster of downregulated miRNAs in human hypertension that are linked to pathways that regulate oxidative and ER stress. These findings provide new molecular insights into processes underlying VSMC redox-sensitive dysfunction and may elucidate vascular miRNA signatures in human hypertension.
AFFERENT RENAL NERVE PATHWAYS IN RATS – RESPONSIVENESS TO HIGH SALT INTAKE
Authors: Rodionova Kristina , Ditting Tilmann , Fahrmeier Franziska , Ott Chirstian , Schmieder Roland , Schiffer Mario , Amann Kerstin , Veelken Roland
Published: April 2021

Objective:

Afferent renal nerve pathways are likely involved in the development of salt sensitive hypertension. We recently reported that intrarenal NaCl elicited a long-lasting sympatho-depression via a neuro-humoral TRPV1 dependent and tachykinin mediated renal afferent nerve pathway. We now wanted to test the hypothesis that high sodium intake impairs this afferent sympatho-depressory mechanism.

Design and method:

Respective groups were put on tap water, 0.9 % saline for drinking or chow containing 8% NaCl. Cultured dorsal root ganglion neurons (DRG Th11-L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation during current injection. Rats were equipped with femoral catheters for blood pressure (BP) & heart rate (HR) assessment, drug application, a renal arterial catheter for intrarenal administration (IRA) of NaCl boli (10 % NaCl, 10 microl) or Capsaicin (CAP 10 ∗10-7 M, 10 microl) and a bipolar electrode for renal sympathetic nerve activity (RSNA) recordings; eventually an intravenous (iv) bolus of the NK1-receptor blocker RP67580 (10∗10-3 M, 15 microl) was administered. Results are mean ± SEM.

Results:

In neurons from rats on high salt diet, but not on 0.9 % saline or controls the relation of tonic highly active neurons to less active neurons shifted towards less active units. (62% tonic neurons in the control group and 63% tonic neurons in the saline group vs. 40%∗ tonic neurons in the high salt group, ∗ p < 0.05, z-test, mean +/-SEM). However, cultured renal neurons from rats on 0,9% saline or on high salt diet exhibited increased action potential production upon stimulation (controls 13,3+/11,03 APs/600ms vs. 0.9% saline 19,8+/-2,33∗ APs/600ms vs. high salt diet 22,2+/-4,54 APs/600ms, ∗ p < 0.05, t-test, mean+/-SEM). 10% NaCl boli IRA induced decreases of RSNA from baseline 4.1 ± 0.6 microV∗sec to 2.2 ± 0.8 microV∗sec impaired in rats on 8% NaCl.

Conclusions:

In rats on high salt diet highly active tonic neurons with renal afferents in vitro decreased at the expense of less active phasic neurons in spite of tonic neurons producing more action potentials upon stimulation. The sodium inducible long-lasting sympatho-depression via a neuro-humoral tachykinin mediated afferent renal nerve pathway was eventually impaired.
HIGH-DOSES OF LOSARTAN RATHER ACCELERATE THE SECRETION OF ADRENAL CATECHOLAMINES
Authors: Lim Dong Yoon , Cho Byung Ryul , Koh Young Youp
Published: April 2021

Objective:

Previously, we have found that Losartan (5∼50 microM), an AT1 receptor blocker, dose-dependently inhibits secretion of catecholamines (CA) evoked by cholinergic and angiotensin II (Ang II) receptor stimulation from the perfused rat adrenal medulla. The aim of the present study was to examine the characteristic effects of high-dose losartan on the CA secretion from the isolated perfused rat adrenal gland, and also to establish its mechanism of action.

Design and method:

The adrenal gland was isolated and perfused with Krebs-bicarbonate. CA was measured directly by using the fluorospectrophotometer.

Results:

The perfusion of high-dose losartan (150 ∼ 600 microM) into an adrenal vein for 90 min resulted in great increases in CA secretions evoked by acetylcholine in a dose-dependent fashion. Also, losartan (300 microM) enhanced the CA release evoked by Ang II, high K+ and DMPP (a selective nicotinic receptor agonist), McN-A-343 (a selective muscarinic M1 receptor agonist). Also, in the presence of losartan (300 microM), the CA secretory responses to veratridine (a selective Na+ channel activator), Bay-K-8644 (a Ca2+ channel activator), and cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor) were significantly potentiated, respectively. The facilitatory CA-releasing effect of Ach evoked by high-dose losartan (300 microM) was time-dependently depressed by pretreatment with nifedipine (Ca2+ channel blocker), while not by pretreatment with sodium nitroprusside (an NO donor). High-dose olmesartan (150 ∼ 600 microM), one of ARBs, also potentiated Ach-evoked CA release in time-dependent fashion. However, in the simultaneous presence of losartan (300 microM) and CGP42112 (an AT2 receptor agonist), the facilitatory responses of losartan on the CA secretion evoked by ACh were rather significantly reduced in comparison with that of losartan-treatment alone.

Conclusions:

Conclusively, these results demonstrate that high-dose losartan can potentiate the adrenomedullary CA secretion in a calcium-dependent fashion. It seems that this facilitatory effect of high-dose losartan may be mediated by activation of the Ca2+ influx through L-type Ca2+ channels into adrenomedullary cells without inhibition of NO synthesis, which seems to be relevant to AT2 receptor blockade. It also suggests that high-dose ARBs may be a risk factor in causing hypertensive response.
ALDOSTERONE CONTRIBUTES TO SYSTOLIC BLOOD PRESSURE ELEVATION DURING REST TIME IN MALE MICE INDUCIBLY OVEREXPRESSING HUMAN ENDOTHELIN-1 IN ENDOTHELIUM
Authors: Berillo Olga , Mahjoub Nada , Coelho Suellen C. , Offermanns Stefan , Paradis Pierre , Schiffrin Ernesto L.
Published: April 2021

Objective:

The mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells (ECs) are complex and remain unclear. Transgenic mice with tamoxifen-inducible EC-restricted human ET-1 overexpression (ieET-1) exhibited BP elevation 3 months after induction. ET-1 has been shown to stimulate the release of aldosterone from adrenal cortex (AC). Whether aldosterone plays a role in EC ET-1 overexpression-induced BP elevation and vascular injury is still unknown.

Design and method:

Nine to 12-week-old male ieET-1 mice and control ieCre mice expressing a tamoxifen-inducible Cre recombinase under the control of EC-specific Tie2 promoter were treated with tamoxifen (1 mg/kg/day, SC) for 5 days and studied 3 months later. A set of mice was treated with eplerenone (100 mg/kg/day, PO), a mineralocorticoid receptor antagonist, or the ETA receptor blocker atrasentan (100 mg/kg/day) during the last 2 weeks of the study. BP was measured by telemetry and mesenteric artery function and remodeling by pressurized myography. Plasma aldosterone levels were measured by ELISA. The expression of genes involved in aldosterone biosynthesis was determined by reverse transcription-quantitative PCR in AC. CYP11B2 expression was determined in AC by immunofluorescence.

Results:

Plasma aldosterone levels were increased in ieET-1 vs. ieCre mice (1.21 ± 0.14 vs. 0.70 ± 0.09 ng/mL, P < 0.05), which was reversed by atrasentan. Cyp11b2 (aldosterone synthase), Hsd3b6 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 6) and Cry1 (core-clock component cryptochrome 1) mRNA expression was decreased respectively by 50%, 39% and 31% in AC, and CYP11B2 protein expression was decreased by 51% in adrenal glomerulosa of ieET-1 vs. ieCre mice (P < 0.05). Two week eplerenone treatment reduced systolic BP by 10 mm Hg in ieET-1 mice during rest time (last 3 days, P < 0.05). Eplerenone abrogated the enhanced sensitivity of mesenteric arteries to contraction by norepinephrine in ieET-1 mice (P < 0.05), increased the sensitivity of endothelium-independent relaxation responses to sodium nitroprusside in ieET-1 mice (P < 0.05). Mesenteric artery media/lumen was reduced in eplerenone-treated ieET-1 vs. ieET-1 and ieCre mice (P < 0.05).

Conclusions:

These results demonstrate that aldosterone contributes to human EC ET-1 overexpression-induced BP elevation and vascular remodeling and norepinephrine sensitivity.
THE KALLIKREIN-KININ SYSTEM IS FALLING INTO PIECES: BRADYKININ FRAGMENTS ARE BIOLOGICAL ACTIVE PEPTIDES
Authors: Souza-Silva Igor Maciel , Paula Cristiane , Santos Anderson , Oliveira Vívian , Rocha Isabella , Antunes Maísa , Cordeiro Lídia , Teixeira Vanessa , Scalzo-Júnior Sérgio , Amaral Flávio , Resende Jarbas , Fontes Marco Antônio , Menezes Gustavo , Guatimosim Silvia , Santos Robson , Verano-Braga Thiago
Published: April 2021

Objective:

Bradykinin [BK-(1–9)] is an endogenous peptide involved in many physiological and pathological processes, such as cardiovascular homeostasis and inflammation. The central dogma of the kallikrein-kinin system is that BK-(1–9) fragments are biologically inactive. In this work, we proposed to test whether these fragments were indeed inactive.

Design and method:

Nitric oxide (NO) was quantified in human, mouse and rat cells loaded with DAF-FM after stimulation with BK-(1–9), BK-(1–7), BK-(1–5) and BK-(1–3). We used adult male rat aortic ring preparation to test vascular reactivity mediated by BK-(1–9) fragments. Changes in blood pressure and heart rate was measured in conscious adult male rats by intraarterial catheter method.

Results:

BK-(1–9) induced NO production in all cell types tested by B2 receptor activation. BK-(1–7), BK-(1–5) and BK-(1–3) also induced NO production in all tested cell types but this response was independent of the activation of B1 receptor and/or B2 receptor. BK-(1–7), BK-(1–5) or BK-(1–3) induced only vasorelaxant effect and in a concentration-dependent fashion. Vasorelaxant effects for BK-(1–7), BK-(1–5) or BK-(1–3) were independent of the kinin receptors. BK-(1–9) induced in conscious adult male Wistar rats a dose-dependent hypotension while BK-(1–7), BK-(1–5) and BK-(1–3) induced a dose-independent hypotension. Importantly, these observations diverged from the BK-(1–9) results, highlighting that indeed the BK-(1–9) fragments do not seem to act via the classical kinin receptors.

Conclusions:

In conclusion, BK-(1–7), BK-(1–5) and BK-(1–3) are biologically active components of the kallikrein-kinin system. Importantly, observed pathophysiological outcomes of these peptides are independent of B1R and/or B2R activation.
ASSOCIATION OF AGT GENE M235T AND ACE GENE I/D POLYMORPHISMS WITH HYPERTENSION IN MONGOLIAN POPULATION
Authors: Unurjargal Tsolmon , Byambatsogt Bolortuul , Vanchin Byambasuren , Sodovsuren Naranchimeg , Davaakhuu Gantulga
Published: April 2021

Objective:

In Mongolia, hypertension is major public health problem due to its high prevalence of stroke and mortality rate. The objective of this study was to analyse the relationship between AGT M235T gene variant and ACE I/D gene variant with hypertension in a sample of the Mongolian population of the Ulaanbaatar city.

Design and method:

Design and Method: A case-control study has been performed in 146 subjects including 96 hypertensives and 50 normo-tensive subjects, aged 18–60 years. Hypertension was defined as systolic BP =>130 mm Hg and/or diastolic BP=>80 mm Hg). After isolation DNA from peripheral blood, the following specific primers were used for polymerize chain reaction (PCR). PCR purification kit and QIAquick Gel extraction kit were used to establish nucleic acid sequence.

Results:

The mean age of the participants was 39.6 years and 54.7% were men. The M235T variant of AGT gene was identified in 97.9% of all participants (96.8% of hypertensive patients and 100% of normotensive subjects). According to the genotype results, the frequencies of the AGT TT, MT and MM genotypes were 57.3%, 39.6%, and 3.1% in cases and 64.0%, 36.0% and 0.0% in controls respectively.

The genotypic distribution of the M235T variant of the AGT gene did not differ in hypertensives and normotensives group (p > 0.328). In this study, we did not observe any significant differences in blood pressure levels with regard to ACE gene I/D polymorphism in both hypertensive and normotensive groups (40% vs 38%, p > 0.543).

Conclusions:

Conclusion: This is the first report on the frequency of AGT and ACE gene polymorphisms among Mongolian population. About 97.9% of Mongolians carry the M235T variant of the AGT gene that makes them more prone to hypertension when they eat too much sodium.
IN SILICO DRUG REPOSITIONING OF TOPIRAMATE AS AN ANTIHYPERTENSIVE BY CONVERGING KIDNEY TRANSCRIPTOMIC, EPIGENOMIC AND GENOMIC DATA
Authors: Saluja Sushant , Jiang Xiao , Finan Chris , Chopade Sandeep , Eales James , Xu Xiaoguang , Samani Nilesh , Charchar Fadi , Tomaszewski Maciej
Published: April 2021

Objective:

No new antihypertensive medication has been introduced to clinical practice since 2007. Mendel's second law states that genotype is allocated randomly at conception therefore, short nucleotide variants acting in cis can be utilised to deduce the pharmacological action on the same protein as in an RCT. Here, we investigate new therapeutic opportunities for hypertension through exploiting the druggable genome.

Design and method:

We conducted expression(e), splicing(s) and methylation(m) quantitative trait loci (QTL) analysis on 430 human kidneys from 5 studies [TRANScriptome of renaL humAn TissuE (TRANSLATE) study, Tissue Cancer Genome Atlas (TCGA), moleculAr analysis of human kiDney-Manchester renal tIssue pRojEct (ADMIRE) study, Molecular analysis of mechanisms regulating gene expression in post-ischemic injury to renal allograft (REPAIR) and Renal gEne expreSsion and PredispOsition to cardiovascular and kidNey Disease (RESPOND)]. Through their intersection with blood pressure variants from all previous genome wide association studies (GWAS) we identified genetic variants partnering with protein-coding kidney e-Genes, s-Genes and m-Genes. We then mapped the proteins encoded by these genes onto a set of licensed drugs or compounds with bioactivities against these targets in-silico.

Results:

Altogether, 479 informative genetic variants mapping onto 918 protein coding genes were identified. Of these, 201 (21.9%) genes were druggable. We found 209 unique associations with 44 (21.9%) protein coding genes. Of these, 23 associations acting on 7 drug targets were precisely concordant (captopril associated with ACE gene) and 16 associations (4 targets) had the indication association within the same disease area [for example, ambrisentan (an endothelin receptor antagonist) acting on a BP GWAS gene EDNRA]. 3 (1.3%) drugs were identified as repurposing opportunities for hypertension based on clinical evidence and directionality of effect on gene activity. Of those, topiramate [target for the alpha-subunit of Gamma-Aminobutyric Acid Type A receipt Alpha2 Subunit (GABRA2) gene], was deemed as clinically strongest drug repurposing opportunity for hypertension. The alpha subunit of this receptor is coded by GABRA2 gene, which is a hypertension risk gene identified in our study.

Conclusions:

Integration of pharmacological databases with -omic data of tissue of key relevance to hypertension may uncover novel drug repurposing opportunities.
FUNCTIONAL IN SILICO ANALYSIS OF GENETIC VARIANTS FROM GENOME-WIDE ASSOCIATION STUDIES OF BLOOD PRESSURE AND HYPERTENSION
Authors: Pramanik Sanjeev , Jiang Xiao , Eales James , Xu Xiaoguang , Saluja Sushant , Charchar Fadi , Tomaszewski Maciej
Published: April 2021

Objective:

Hypertension is a complex disease with a strong genetic component. Genome wide association studies (GWAS) have identified hundreds of variants associated with hypertension and its defining traits [systolic blood pressure(SBP), diastolic blood pressure(DBP), pulse pressure(PP)]. Our goal was to catalogue all sentinel variants identified by GWAS of hypertension and investigate their functional effects on transcription/translation in silico.

Design and method:

We compiled a list of all common (minor allele frequency >0.05) sentinel variants associated with SBP, DBP and PP in at least one GWAS at genome-wide level of statistical significance (P < 5x10-8). In silico analyses were conducted to characterise putative biological consequences of these variants at mRNA/protein level. All sentinel variants (and their statistical proxies) were characterised using Ensembl variant effect predictor (VEP) GRCh37 release 90 to identify effects on coding and non-coding exons. Data from the University of California Santa Cruz (UCSC) CpG islands was used to map variants to regulatory regions of open chromatin. Combined Annotation Dependent Depletion (CADD) scores quantified the overall genetic deleteriousness of variants.

Results:

A total of 892 variants were significantly associated with at least one BP-defining trait in GWAS. The effects of each allele copy of these variants on blood pressure ranged from 0.15–1.58mmHg (for SBP) and 0.09–0.81mmHg (for DBP). A total of 599 (67%) variants received at least one functional annotation. Only 92 (10.3%) variants led to missense changes in encoded proteins. A significant number of variants directly mapped to regulatory regions of active chromatin such as active enhancers and transcription start sites [258 (28.9%) and 225 (25.2%), respectively]. Only three variants [rs16859180 in the gene Serine/Threonine Kinase 36(STK36), rs328 in lipoprotein lipase(LPL) and rs11556924 in zinc finger C3HC-type protein 1(ZC3HC1)] had CADD scores >30 (placing them in the top 0.1% of most deleterious variants in the human genome).

Conclusions:

The majority of BP GWAS variants do not alter the amino-acid content of encoded proteins. A significant proportion are located within regions of regulatory importance to transcription, suggesting that many BP GWAS variants operate through quantitative effect on expression of key genes in specific cells and tissues.