bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
GENETIC SUSCEPTIBILITY TO EARLY ONSET OF TRANSFORMING GROWTH FACTOR-BETA DRIVEN CARDIAC REMODELING IN MICE IS ASSOCIATED WITH EGR1 AND STAT3
Authors: Kökény Gábor , Fazekas Krisztina , Popovics Helga , Mózes Miklós 
Published: April 2021

Objective:
We have previously described that the severity of TGF-b induced cardiac remodeling was associated with genetic background differences in alb/TGF-b1 transgenic mice (with elevated plasma TGF-b1 levels) on B6 vs CBAxB6 strains. Early growth response factor-1 (EGR1) has been associated with kidney fibrosis, and we recently demonstrated non-canonical TGF-b induced STAT3 activation in vascular smooth muscle cells, but their role in cardiac fibrosis or hypertrophy was not yet elucidated. The present study investigated whether genetic susceptibility to TGF-b induced early cardiac remodeling is associated with transcription factors EGR1 and STAT3.

Design and method:
As the albumin promoter driven TGF-b1 transgene is expressed after birth only in males reaching early high plasma TGF-b1 levels, we investigated 14-day old male transgenic and wild type control mice. Blood pressure of TGF-b1 transgenic (B6-TGFb and CBAxB6-TGFb) mice, and wild type (B6 and CBAxB6) controls (n = 6–9/group) was assessed, then cardiac samples were harvested and analyzed for mRNA and protein expression. Data are presented as mean ± SD and evaluated using Kruskal-Wallis test with Dunn's post-hoc test.

Results:
Blood pressure was elevated in both transgenic strains as compared to controls (MAP mmHg, B6: 46 ± 3; CBAxB6: 48 ± 4; B6-TGFb:54 ± 9; CBAxB6-TGFb:68 ± 7, p < 0.01). Compared to B6-TGFb and wild type, CBAxB6-TGFb hearts showed 20-fold elevation in BNP mRNA relative expression (B6: 1.5 ± 0.9; CBAxB6: 2.3 ± 0.9; B6-TGFb:1.5 ± 1.0; CBAxB6-TGFb:23.5 ± 13,3 p < 0.001) associated with increased Collagen-I (B6: 1.3 ± 0.2; CBAxB6: 1.2 ± 0.1; B6-TGFb:1.2 ± 0.2; CBAxB6-TGFb:1.9 ± 0.6, p < 0.05) and EGR1 (B6: 0.9 ± 0.2; CBAxB6: 0.8 ± 0.3; B6-TGFb:0.9 ± 0.6; CBAxB6-TGFb:1.8 ± 0.5, p < 0.01) as well as STAT3 mRNA overexpression (B6: 0.8 ± 0.1; CBAxB6: 1.2 ± 0.2; B6-TGFb:1.1 ± 0.1; CBAxB6-TGFb:1.7 ± 0.6, p < 0.01) and STAT3 phosphorylation. Early cardiac remodeling was further associated with 12-fold and 2-fold overexpression of TIMP-1 (B6: 1.0 ± 0.4; CBAxB6: 0.8 ± 0.4; B6-TGFb:0.7 ± 0.3; CBAxB6-TGFb:12.2 ± 9.0, p < 0.01) and TIMP-2 (B6: 1.1 ± 0.1; CBAxB6: 1.2 ± 0.2; B6-TGFb:1.3 ± 0.4; CBAxB6-TGFb:2.1 ± 1.1, p < 0.05), respectively. Significant EGR1 immunoreactivity was detected only in cardiomyocytes of CBAxB6-TGFb hearts.

Conclusions:
We conclude that EGR1 and STAT3 might strongly contribute to the initiation and early progression of cardiac remodeling driven by high circulating TGF-b levels. We postulate that EGR1 and STAT3 could be potential targets to inhibit early cardiac remodeling.
POLYGENIC RISK SCORES PREDICT HYPERTENSION ONSET AND CARDIOVASCULAR RISK
Authors: Vaura Felix , Kauko Anni , Suvila Karri , Havulinna Aki , Mars Nina , Salomaa Veikko , Cheng Susan , Niiranen Teemu 
Published: April 2021

Abstract

Objective:
We aimed to quantify the predictive ability of polygenic risk scores in hypertension and demonstrate that they improve a gold standard clinical risk score of hypertension in the general population.

Design and method:
Our study sample comprised N = 218,792 FinnGen Study participants with lifetime follow-up (mean age 58 years, 56% women). We used recently developed Bayesian methodology and publicly available genome-wide association data to compute polygenic risk scores (PRS) for systolic (SBP) and diastolic blood pressure (DBP). Next, in a well-phenotyped subset of 22,624 FINRISK study participants, we calculated the 4-year clinical risk of hypertension and 10-year clinical risk of cardiovascular disease (CVD) using gold standard risk scores. Using time-to-event analysis, we then assessed (1) the association of blood pressure PRSs with hypertension, age of hypertension onset, and CVD in all FinnGen participants, and (2) the incremental improvement in model discrimination when combining blood pressure PRSs with the 4-year and 10-year clinical risk predictions of hypertension and CVD in the FINRISK cohorts.

Results:
Compared to having an average PRS, elevated PRS was associated with up to 2.3-fold risk of hypertension and an 11-year earlier disease onset (Figure). In subgroup analyses, the risk was only 1.6-fold for late-onset hypertension (age > = 55 years), whereas it was 2.8-fold for early-onset hypertension (age < 55 years). Elevated SBP PRS was also associated with up to 1.3-fold risk of CVD and a 4-year earlier disease onset. SBP and DBP PRSs improved clinical risk prediction for hypertension, increasing the C-statistic by 0.7% (0.3–1.1; P = 0.0017) and generating a category-free Net Reclassification Improvement of 9.3% (1.9–16.8; P = 0.014). Inclusion of blood pressure PRSs did not improve the clinical CVD risk score.

Conclusions:
We demonstrated that genetic information improves clinical risk prediction of hypertension. Blood pressure PRSs could be used together with traditional risk factors to improve prediction of hypertension and particularly early-onset hypertension, which confers substantially increased CVD risk. When used independently, PRSs offer a simple and increasingly affordable way to measure genetic predisposition to hypertension at any point in life. Individuals with elevated blood pressure PRSs could benefit from genetic counseling and intensive early intervention.
THE CAUSAL EFFECT OF ADIPOSITY MEASURES ON BLOOD PRESSURE TRAITS IN TWO URBAN SWEDISH COHORTS: A MENDELIAN RANDOMIZATION STUDY
Authors: Giontella Alice , A. Luca Lotta , D. John Overton , Melander Olle , Gill Depender , Fava Cristiano 
Published: April 2021

Abstract

Objective:
Different adiposity traits may be causally related to hypertension in different ways. By using genetic variants as randomly allocated proxies for studying the effect of modifying adiposity traits, the Mendelian randomization approach can be used to investigate this.

Design and method:
In this study, we used four different genetic risk scores (GRSs: GRS-BMI565, GRS-WHR324, GRS-VAT208, GRS-BF81) including hundreds of single nucleotide polymorphisms (SNPs) associated with Body Mass Index (BMI), Waist to Hip Ratio (WHR), Visceral Adipose Tissue (VAT), and Body Fat (BF), respectively, using risk alleles and weight from largest available GWAS meta-analyses. These were applied as instrumental variables (IVs) in Mendelian Randomization analyses. Two Swedish urban-based cohort studies, the Malmö Diet and Cancer (MDC) and the Malmö Preventive Projects (MPP; subjects evaluated both at baseline and after an average follow-up of 23 ± 4.7 years), were used to obtain genetic association estimates with blood pressure (BP).

Results:
In both the MPP and MDC, with the exception of that for BF, all the GRSs were significantly associated with systolic BP and diastolic BP, but with different magnitude.: In particular, each standard deviation (SD) increase in the GRS-WHR324 doubled the likelihood of hypertension prevalence at MDC or MPP baseline exam. However, only the GRS-BMI565 was significantly associated to BP and with hypertension incidence during 23.6 ± 4.3 years of follow-up in MPP.

Conclusions:
In conclusion, we have confirmed a causal link between genetically mediated adiposity, especially WHR and BMI, and BP-related traits including hypertension prevalence and, for the first time to our knowledge, hypertension incidence. The differences in magnitude between these associations might suggest different mechanisms by which different adiposity traits mediate their effect on BP/hypertension and consequently may indicate that tailored interventions are needed to reduce cardiovascular risk.
PREVALENCE AND ASSOCIATED FACTORS OF HYPERTENSION AMONG RETIRED INDIAN ARMY IN POKHARA METROPOLITAN
Authors: Sapkota Abhishek , Neupane Dinesh , Adhikari Tara Ballav , Shrestha Aamod Dhoj , Shrestha Naveen 
Published: April 2021

Objective:
To assess the prevalence and associated factors with hypertension among the retired Indian army living in a semi-urban area of Pokhara metropolitan.

Design and method:
The cross-sectional study was conducted among retired Indian army living in a semi-urban area of Pokhara metropolitan. Data on blood pressure (BP), anthropometric measurements, smoking, alcohol intake, physical activity, obesity and dietary factors were collected by face-to-face interview using WHO STEPwise approach to non-communicable disease risk factor surveillance (STEPS) questionnaire translated in Nepali language.

Results:
Among the 317 retired Indian army interviewed, the prevalence of hypertension was 68.1%. Mean blood pressure systolic was 144.48 mmHg, and diastolic was 89.3 mmHg. Prevalence of smoking any tobacco products was 12.9%, and consumption of alcohol products was 86.1%. One fourth (25.9%) of the respondents had a family history of hypertension. Over one half (51.4%) were classified as overweight (BMI), and 6.6% had central obesity. Respondents with age group (55–64) years were found more than three times (OR: 3.21, 95% CI: 1.91–8.68) likely to have hypertension. Alcohol consumers were 1.8 times more likely to have hypertension than non-consumers. Respondents with a family history of hypertension were found 2.57 folds to have hypertension.

Conclusions:
Hypertension among retired Indian army is comparatively much higher than the general population in the study area. The finding of the study calls for an immediate primary care to the high-risk occupation groups targeting prevention, screening and control measures for blood pressure and associated risk factors.
HYPERTENSIVE EMERGENCIES AND URGENCIES IN EMERGENCY DEPARTMENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Astarita Anna , Covella Michele , Vallelonga Fabrizio , Cesareo Marco , Totaro Silvia , Ventre Luca , Apra’ Franco , Veglio Franco , Milan Alberto 
Published: April 2021

Objective:
The prevalence of hypertensive emergencies (HEs) and urgencies (HUs) and of acute hypertension-mediated organ damage (aHMOD) in emergency departments (EDs) is unknown. Moreover, the predictive value of symptoms, blood pressure (BP) levels and cardiovascular risk factors to suspect the presence of aHMOD is still unclear. The aim of this study was to investigate the prevalence of HEs and HUs in EDs and of the relative frequency of subtypes of aHMOD, as well as to assess the clinical variables associated with aHMOD.

Design and method:
We conducted a systematic literature search on Pubmed, OVID and Web of Science from their inception to August 22, 2019. Two independent investigators extracted study-level data for a random-effects meta-analysis.

Results:
Eight studies were analysed, including 1970 HEs and 4983 HUs. The prevalence of HEs and HUs was 0.3% and 0.9%, respectively (O.R.for HUs vs HEs:2.5 (1.4–4.3)). Pulmonary oedema/heart failure was the most frequent subtype of aHMOD (32%), followed by ischemic stroke (29%), acute coronary syndrome (18%), haemorragic stroke (11%), acute aortic syndrome (2%) and hypertensive encephalopathy (2%). No clinically meaningful difference was found for BP levels at presentations. HU patients were younger than HE patients by 5.4 years and more often complained of non-specific symptoms and/or headache, while specific symptoms were more frequent among HE patients.

Conclusions:
HEs and HUs are a frequent cause of access to EDs, with HUs being significantly more common. BP levels alone do not reliably predict the presence of aHMOD, which should be suspected according to the presenting signs and symptoms.
HOSPITAL-BASED INTERVENTION TO ENHANCE HYPERTENSION DIAGNOSIS IN HOSPITAL K, THAILAND, 2017–2019: A PRE-POST PILOT INTERVENTION STUDY
Authors: Yueayai Khaneungnij , Moran Andrew , Pratipanwat Piyanut , Chaisongkram Siwaboon , Anosri Ladda , Thitichai Phanthanee 
Published: April 2021

Objective:
In Thailand 5.9 million individuals ?15 years old have undiagnosed hypertension. The intervention to reduce undiagnosed hypertension was piloted and aimed to compare pre? and post?intervention hypertension diagnosis rate and follow?up rate. A hospital?based pre? and post?intervention study was piloted in a general hospital in Thailand. The intervention included an electronic pop?up alert when raised blood pressure was observed and a follow?up protocol. The follow?up protocol entered patient information in a follow?up book that scheduled an appointment to recheck blood pressure. Statistical analyses compared the rate of hypertension diagnosis and follow?up between the pre? and post?intervention periods, adjusted for differences in baseline characteristics. A post?intervention, self?report survey among nurses and nurse?aids explored perceptions about raised blood pressure management and solicited suggestions to improve the intervention. 574 raised blood pressure patients visited the hospital in the pre?intervention period; 27.4% returned for follow??up; and hypertension diagnosis rate was 1.4%. Among 686 post?intervention raised blood pressure patients, overall hypertension diagnosis rate improved to 6.1%. In per?protocol patients, 81.9% were booked to follow?up, hypertension diagnosis rate was 18.6%, and the adjusted odds ratio of hypertension diagnosis was 4.5 times higher compared with the pre?intervention period. By self?report, 20% of health workers had no time to provide the follow?up book due to work overload, yet >57% reported that information technology improved detection of raised blood pressure and improved follow?up. The interventions significantly increased the hypertension diagnosis rate and follow?up among raised blood pressure patients in a single hospital but may benefit from incorporating an information technology?assisted follow?up protocol
KNOWLEDGE ABOUT ARTERIAL HYPERTENSION IN GENERAL POPULATION: RESULTS OF A COMMUNITY PHARMACY SCREENING PROGRAM
Authors: Fanelli Elvira , Ravetto Lorenzo Enri , Fasano Chiara , Di Monaco Silvia , Pappaccogli Marco , Irene Pignata , Elisabetta Eula , Guglielmo Masera , Franco Rabbia , Brusa Paola , Veglio Franco 
Published: April 2021

Objective:
Hypertension is a cardiovascular and cerebrovascular risk factor. Prevention of hypertension mediated organ damage is a main health problem. Guidelines underlines the importance of screening and educational programs in general population and the role of non-medical sanitary subjects, particularly pharmacists. This study evaluated knowledge about hypertension in a population afferent to community pharmacies of Piedmont and Ligury.

Design and method:
A questionnaire about knowledge of hypertension has been collected from 2731 community pharmacy costumers, participating to an arterial hypertension screening program. It included three sections about prevalence of hypertension, hypertension-mediated organ damage and preventive lifestyle behaviour. Blood pressure was measured with an Omron HEM 1040-E device. Further information about home blood pressure levels, cardiovascular, metabolic and cerebrovascular comorbidity were collected.

Results:
57,5% of subjects were female and mean age was 58,3 ± 15,9 ys. 47% subjects declared a hypertensive status, 41% normotensive one and 12% didn’t know their pressure status. Mean systolic blood pressure was 130 ± 18 mmHg and diastolic blood pressure 79 ± 10 mmHg. 69% of hypertensive subjects was not controlled at pharmacy evaluation, on the base of guidelines office target values. 10% of subjects self-declared normotensive and 35% who didn’t know their blood pressure status had a blood pressure >= 140/90 mmHg. In the questionnaire only 15% of subjects knew hypertension prevalence; 23% had a poor knowledge about lifestyle prevention interventions and 36% have poor knowledge about hypertension mediated organ damage. The proportion of people with poor knowledge was particularly higher in people who didn’t know their pressure status (low level consciousness about lifestyle and consequences in 30% and 48% of subjects respectively). Subjects with a low global knowledge about hypertension had significantly higher blood pressure levels compared to those with a good consciousness.

Conclusions:
Many people have poor knowledge of hypertension as risk factor; this is the base of poor blood pressure control and non-adherence. Community pharmacies may represent an important resource for education and prevention among general population, including people not seeking medical care.
RELATIONSHIP BETWEEN 24-HOURS URINARY SODIUM EXCRETION AND ARTERIAL STIFFNESS IN CONTROLLED HYPERTENSIVE AND RESISTANT HYPERTENSIVE INDIVIDUALS
Authors: Zanatta João Marcos De M. , Ricardi Fábio Dos S. , Uyemura Jéssica R.R. , Cosenso-Martin Luciana N. , Yugar-Toledo Juan C. , Vilela-Martin José F. 
Published: April 2021

Objective:
To compare the influence of dietary sodium intake through 24-hours urinary sodium excretion (Na + Ur24 h) on arterial stiffness markers in controlled and resistant hypertensive individuals.

Design and method:
126 patients were randomized in an observational and cross-sectional study, divided into two groups: 63 in the controlled hypertension group (CHTN) and 63 in the resistant hypertension group (RHTN). All were submitted to clinical evaluation, laboratory tests, Na + Ur24 h and non-invasive central hemodynamic evaluation by the SphygmoCor® and Mobil-O-Graph® system to determine arterial stiffness parameters.

Results:
Clinical characteristics and laboratory tests were similar in both groups. There was no statistical significance between CHTN and RHTN for Na + Ur24 h values (186.60 ± 92.15 vs.179.76 ± 66.91 mEq/L, respectively). The carotid-femoral pulse wave velocity (cfPWVc) showed no statistically significant difference between CHTN and RHTN (10.52 ± 2.47 m/s vs. 10.21 ± 2.27 m/s, respectively). Central hemodynamic parameters were statistically different between the groups assessed by 24-hour ambulatory blood pressure monitoring (ABPM - Mobil-O-Graph®). RHTN group had higher cardiac output during sleep and greater vascular resistance during wakefulness and 24 hours than CHTN group (p < 0.05) in ABPM.

Conclusions:
Na + Ur24 h excretion is similar between groups, but there is better adherence to dietary sodium intake restriction in the resistant hypertension group. Physiological hemodynamic parameters are altered in the RHTN group, such as cardiac output and peripheral vascular resistance, a fact that evidences their participation in the pathophysiological process of resistant hypertension.