bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE ROLE OF GUT METABOLITE-SENSING RECEPTORS GPR41 AND GPR43 IN CARDIOVASCULAR DISEASE
Authors: Muralitharan Rikeish R. , Nakai Michael , Paterson Madeleine , Jama Hamdi , Mackay Charles R. , Marques Francine Z. 
Published: April 2021

Objective:
Fibre intake is associated with lower incidence of hypertension and cardiovascular mortality. Prebiotic fibre, such as resistant starches and soluble fibre, are fermented by commensal gut microbiota to short-chain fatty acids (SCFAs), which have a protective role in cardiovascular disease. We, and now others, have shown that supplementation of SCFA such as acetate, propionate and butyrate can reduce blood pressure (BP) and their complications. The main receptors for SCFAs, the G-coupled protein receptors GPR41 and GPR43, have redundant functions, but their contribution to cardiovascular health and disease is uncertain. Therefore, we aimed to characterize their contribution to the cardiovascular phenotype using a unique mouse model where both receptors are absent, the GPR41/43 knockout (KO)

Design and method:
We studied female (n = 12) and male (n = 15) double GPPR41/43 KO mice compared to wild-type (WT) C57BL/6 mice (n = 4–8) at 10 weeks of age. We performed BP measurements using tail cuff, sodium and water loading, real-time PCR, flow-cytometry of immune cells, and histology of the heart, kidney and gut

Results:
GPR41/43 KO male and female mice did not have significant difference in BP compared to WT mice (P = 0.387–0.676), but female GPR41/43 KO had significantly smaller kidneys (adjusted to tibia length) compared to WT female (P = 0.006). Upon saline challenge, both male and female GPR41/43 KO mice excreted more urine (P = 0.01 male, P = 0.116 female), but not sodium (P = 0.461 male, P = 0.141 female), compared to WT mice over a 5 hour period. GPR41/43 KO had lower levels of pro-renin receptor (Atp6ap2) mRNA (P = 0.012 male, P = 0.057 female) but higher levels of renal collagen genes mRNA (Col3a1 P = 0.055 male, Col1a1 P = 0.023 female), indicative of fibrosis.

Conclusions:
GPR41/43 KO mice expressed lower pro-renin receptor mRNA but higher levels of fibrosis markers. GPR41/43 KO mice excreted more urine than WT mice and did not have higher BP. Moreover, female GPR41/43 KO mice had significantly smaller kidneys, proposing a role for these receptors in renal development. Together, these findings suggest that the gut metabolite-sensing receptors GPR41/43 are likely to contribute to cardiovascular regulation via a role in water absorption and excretion, as well as in fibrosis
MIR-338-3P DOWN-REGULATION IN SMALL ARTERIES OF HYPERTENSIVE PATIENTS WITH CHRONIC KIDNEY DISEASE MAY ACT VIA UP-REGULATION OF ALKALINE CERAMIDASE 2 AND GLUTATHIONE PEROXIDASE 3
Authors: Paradis Pierre , Mahjoub Nada , Huo Ku-Geng , Berillo Olga , Richer Chantal , Fraulob-Aquino Julio C. , Briet Marie , Boutouyrie Pierre , Lipman Mark L. , Sinnett Daniel , Schiffrin Ernesto L 
Published: April 2021

Objective:
Hypertension (HTN) is associated with vascular damage characterized by vascular remodeling and stiffening and endothelial dysfunction, which is a cause of end-organ damage such as chronic kidney disease (CKD). microRNAs are small non-coding RNA that regulate gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation or translational repression. Their participation in mechanisms leading to vascular injury remains unclear. We aimed to identify differentially expressed (DE) microRNAs in small arteries of human subjects with HTN associated or not with CKD to gain insight into pathophysiological molecular mechanisms in these conditions.

Design and method:
Normotensive subjects and patients with HTN associated or not with CKD grades 3-4 were studied (n = 15-16). Blood pressure was determined by automated office measurement (AOBP). Small arteries were isolated from subcutaneous gluteal biopsies and RNA extracted for small and total RNA sequencing using Illumina HiSeq-2500. Differentially expressed (DE) genes were identified with a P < 0.05. The selected DE miRNAs were confirmed by reverse transcription-quantitative PCR (RT-qPCR). Putative microRNA targets were validated using gain- and loss-of-function in human aortic vascular cells by RT-qPCR and luciferase reporter assay.

Results:
Small RNA sequencing identified DE microRNAs uniquely associated with HTN (3 up and 6 down), CKD (42 up and 39 down) or both groups (2 up). One of 14 tested DE microRNAs was validated. RT-qPCR showed that miR-338-3p was decreased by 59% in CKD (P < 0.05). miR-338-3p and three of its predicted targets were highly expressed in human aortic endothelial cells (HAECs). Two of them, alkaline ceramidase 2 (ACER2) and glutathione peroxidase 3 (GPX3), were up-regulated by 48% and 90% in human aortic endothelial cells (HAECs) transfected with anti-miR-338-3p, respectively (P < 0.05). miR-338-3p mimic co-transfection in HAECs decreased respectively by 13% and 24% luciferase activity of reporter vectors containing the conserved wild-type but not mutated ACER2 or GPX3 3’ untranslated transcribed region miR-338-3p-5p binding sites (P < 0.05).

Conclusions:
miR-338-3p down-regulation in small arteries may act via mRNA up-regulation of alkaline ceramidase 2 and glutathione peroxidase 3 to play a role in vascular injury in hypertensive patients with chronic kidney disease.
INTERCONNECTION BETWEEN TUBULAR RENAL DYSFUNCTION AND GENES POLYMORPHISM IN PATIENTS WITH ARTERIAL HYPERTENSION
Authors: Koziolova Natalya , Chernyavina Anna 
Published: April 2021

Objective:
Objective: to assess the relationship between NGAL concentration as an indicator of tubular disorders, and genetic markers of cardiovascular risk in hypertensive patients.

Design and method:
Materials and methods: 89 patients of working age with hypertension (mean age 48.32 ± 8.71) were examined, who were divided into 2 groups depending on serum NGAL. Group 1 - 20 patients with NGAL levels above reference values, Group 2 - 69 patients with NGAL levels in the range of normal values. For all patients, to evaluate tubular renal function, the concentration of NGAL in serum was determined by ELISA. All patients were examined for genotypes of AGT Thr174Met, GNB3 C825T, MTHFR C677T, MTRR Ile22Met, ApoE Cys130Arg, PRARA rs4253778.

Results:
Results: patients in the groups did not significantly differ in age, gender, risk factors, concomitant diseases and therapy, blood pressure and lipid profile. In group 1, the occurrence of AGT, MTHFR, and PRARA gene polymorphism was significantly higher in heterozygous form than in group 2 (p = 0.002, p < 0.001, and p = 0.037, respectively). Patients in the groups did not significantly differ in occurrence of GNB3, MTRR, and ApoE gene polymorphism. Correlation analysis showed a direct relationship between the concentration of NGAL in the blood and the presence of AGT gene polymorphism (r = 0.38; p < 0.05), GNB3 (r = 0.33; p < 0.05), MTHFR (r = 0.35; p < 0.05). The association of NGAL with the polymorphism of the GNB3, MTRR, and ApoE genes was not statistically significant.

Conclusions:
Conclusions: in patients of working age with hypertension, tubular dysfunction, assessed by the concentration of NGAL in the blood, is associated with the presence of AGT, MTHFR, PRARA gene polymorphism in a heterozygous form.
RARE LOSS-OF-FUNCTION MUTATIONS OF PTGIR IDENTIFIED IN FIBROMUSCULAR DYSPLASIA AND SPONTANEOUS CORONARY ARTERY DISSECTION
Authors: Georges Adrien , Albuisson Juliette , Berrandou Takiy , Dupré Délia , Lorthioir Aurélien , Amar Laurence , Januszewicz Andrzej , Motreff Pascal , Adlam David , Azizi Michel , Gornik Heather , Ganesh Santhi , Kovacic Jason , Jeunemaitre Xavier , Bouatia-Naji Nabila 
Published: April 2021

Objective:
Fibromuscular Dysplasia (FMD) and Spontaneous Coronary Artery Dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.

Design and method:
We analyzed 29 exomes that included familial and sporadic FMD. Follow-up was conducted by targeted or Sanger sequencing (1,071 FMD and 365 SCAD patients) or lookups in exome (264 FMD) or genome sequences (488 SCAD), all independent and unrelated. We used TRAPD burden test to test for enrichment in patients compared to gnomAD controls. The biological effects of variants on receptor signaling and protein expression were characterized using transient overexpression in human cells.

Results:
We identified one rare loss-of-function variant (LoF) (MAFgnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor (hIP) gene (PTGIR), a key player in vascular remodeling. Follow-up in >1,300 FMD patients revealed four additional LoF allele carriers and a putative enrichment in FMD (PTRAPD = 8 × 10-4), in addition to several rare missense variants. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P) to severely impair hIP function in vitro. Genetic analyses of PTGIR in SCAD revealed one patient who carries Q163X, one with L67P and one carrying a rare splicing mutation (c.768+1C>G), but not a significant enrichment (PTRAPD = 0.12) in SCAD.

Conclusions:
Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection.
DIFFERENTIALLY EXPRESSED MICRORNAS AND THEIR TARGETS WERE IDENTIFIED IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH HYPERTENSION ASSOCIATED OR NOT WITH TARGET ORGAN DAMAGE
Authors: Berillo Olga , Huo Ku-Geng , Fraulob-Aquino Julio C. , Richer Chantal , Briet Marie , Boutouyrie Pierre , Lipman Mark L. , Sinnett Daniel , Paradis Pierre , Schiffrin Ernesto L. 
Published: April 2021

Objective:
Hypertension is associated with subclinical target organ damage including cardiac, vascular and kidney injury. The immune system plays a role in HTN and target organ damage in animal models. Activation of T cells has been reported among peripheral blood mononuclear cells (PBMCs) of patients with HTN. MicroRNAs are crucial post-transcriptional regulators of immune cells. Whether microRNAs play a role in the activation of immune cells in HTN complicated by target organ damage in humans remains unknown. We aimed to address this question by identifying differentially expressed (DE) microRNAs and their mRNA and non-coding RNA (ncRNA) targets in PBMCs of patients with HTN complicated or not with target organ damage. mRNA targets of DE microRNAs were predicted with TargetScan using the inversely related DE mRNAs as a filter to improve prediction efficiency.

Design and method:
Normotensive (NTN), hypertensive patients (HTN) and patients with HTN associated with at least 2 other features of the metabolic syndrome (MetS) or with chronic kidney disease (CKD) grades 3-4 were studied (n = 15-16 in each group). PBMCs were isolated from blood, RNA extracted for RNA sequencing (RNA-seq) using Illumina HiSeq-2500 and data were analyzed using a systems biology approach. DE genes microRNAs and mRNAs were identified with fold change (FC) >1.5 and P < 0.005. DE miRNAs with FC >2 and RNA-seq count number (CM) >500, and with predicted targets with CM >300 were validated by reverse transcription-quantitative PCR (RT-qPCR).

Results:
DE microRNAs, mRNAs and other ncRNAs were identified by RNA-seq in HTN (22, 19 and 0), MetS (57, 401 and 11) and CKD (6, 26 and 2) compared to NTN. TargetScan predicted that 7 microRNAs target 3 mRNAs in NTN, 57 microRNAs target 55 mRNAs in MetS and 3 microRNA target 2 mRNAs in CKD. Three of 14 selected miRNAs were validated by RT-qPCR: miR-409-5p (46% down, P < 0.05) and miR-411-5p (60% down, P < 0.001) and novel miR-pl-86 (2-fold up, P < 0.05) in MetS vs NTN.

Conclusions:
RNA-seq and RT-qPCR validation showed that DE miR-409-5p, miR-411-5p and the novel miR-pl-86 may play a role in HTN associated with MetS.
EFFECT OF A COMMON UMOD VARIANT ON RENAL FUNCTION, BLOOD PRESSURE, AND FITNESS IN A COMMUNITY-BASED COHORT OF ELDERLY SUBJECTS
Authors: Algharably Engi Abdel Hady , Fuentes Linda Elizabeth Villagomez , Toepfer Sarah , König Maximilian , Demuth Ilja , Bertram Lars , Kreutz Reinhold , Bolbrinker Juliane 
Published: April 2021

Objective:
Uromodulin is encoded by UMOD and common genetic variants in UMOD have been associated with renal function, blood pressure (BP), and hypertension. Observational studies indicated that elevated BP during middle age might be associated with dementia and impaired cognitive function in later life. The aim of this study was to investigate the association of UMOD rs4293393-A>G with renal function, BP, and fitness outcomes in older participants of the Berlin Aging Study II (BASE-II).

Design and method:
Data for 1556 participants (median age 68 years, range 60–84, 51.2% females) in BASE-II were analyzed. BP measurements were determined by standardized automated measurements, estimated glomerular filtration rate (eGFR) by the CKD Epidemiology Collaboration equation, and genotypes by Affymetrix SNP Array 6.0. Genotype-phenotype association analysis was performed by analysis of covariance and logistic regression models

Results:
The number of subjects with rs4293393-genotype AA, AG, and GG were 1038 (66.7 %), 416 (29.6 %) and 57 (3.7%), respectively. Carriers of the G-allele exhibited significantly lower serum creatinine levels compared to non-carriers (AA, 0.91 mg/dl, CI: 0.90 – 0.92 vs. AG, 0.88 mg/dl, CI: 0.87–0.90 vs. GG, 0.88 mg / dl, CI: 0.84–0.93; P = 0.010). G-allele carriers had significantly higher eGFR values (AA, 76.4 ml/min pro 1.73 m2, CI: 75.7–77.2 vs. AG, 78.4 ml/min pro 1.73 m2, CI: 77.3–79.5 vs. GG, 78.5 ml/min pro 1.73 m2, CI: 75.4–81.7; p = 0.010) and a lower risk of chronic kidney disease (OR: 0.651 [95% CI: 0.43–0.98], P = 0.038). UMOD genotypes were not associated with BP, diagnosis of hypertension or with parameters of cognitive function and physical performance

Conclusions:
These findings corroborate previous findings on the role of UMOD for renal function in the elderly. However, our data reveal no association between UMOD variants and BP or parameters of fitness in a cohort of elderly subjects in a community-based cohort in Germany.
PARTIAL EPITHELIAL-TO-MESENCHYMAL TRANSITION AND T CELL-MEDIATED INFLAMMATION IN BENIGN NEPHROSCLEROSIS AND DIABETIC NEPHROPATHY
Authors: Nordbø Ole Petter , Landolt Lea , Eikrem Øystein , Scherer Andreas , Leh Sabine , Palmer Jessica Furriol , Apeland Terje , Marti Hans-Peter 
Published: April 2021

Abstract

Objective:
We wanted to investigate to which degree patients with benign nephrosclerosis (BN) or type 2 diabetic nephropathy (T2DN) present inflammation and/or partial epithelial-to-mesenchymal transition (EMT) in renal formalin-fixed and paraffin-embedded (FFPE) biopsies.

Design and method:
The following FFPE kidney biopsies from adult patients (n = 6 biopsies per group) were analysed: BN, T2DN and normal-appearing renal biopsy tissue (Ctrl). Messenger RNA was purified from whole tissue sections (10 mm) and subjected to RNA sequencing. Immunohistochemistry (IHC) was performed on 3-mm FFPE sections.

Results:
Dimention reduction with principal component analysis showed a distinct separation between diseased and Ctrl tissues. Further, the BN expression profile overlapped significantly with T2DN.
More detailed analysis of gene expression profiles revealed the activation of T-helper type 1 (TH1) and CD8 cytotoxic T-cell (CTL) signatures and the upregulation of the complement system in both diseases. IHC validated CD8 and CD4 cells as well as complement component 3 and the terminal complement complex C5b-9. We show upregulation of EMT- related genes and validated increased abundance of AXL and Vimentin by IHC.

Conclusions:
BN and T2DN tissues show a phenotype related to TH1, CD8 CTL inflammation and the complement system. Further, processes related to EMT were upregulated in both diseases.
LOWERING CUTOFF FOR HYPERTENSION IS RAISING THREE TIMES HEALTH EXPENDITURE IN INDIA
Authors: Maheshwari Anuj , Verma Narsingh , Gupta Arvind , Gupta Vitull Kumar , Patni Bijay , Gupta Balkishan , Saboo Banshi , Kaur Amrit , Srivastava Saurabh , Kumar B. Rajendra , Agarwal Vivek , Gupta Amit , Jain Payal , Singh Smriti , Chaowdhary Sandeep , Chandra Kp , Rangwala Joozer , Kumar Santosh , Kumar Ch Vasanth , Muthusamy Vv 
Published: April 2021

Objective:
Recently American College of Cardiology (ACC)/AHA high blood pressure guideline drops both the systolic and diastolic blood pressure levels by 10 mm Hg leading the rise of overall crude prevalence of hypertension among U.S. adults from 31.9% to 45.6%. Surely these recommendations suggesting target 130/80 based on almost 50% reduction in CV events and mortality but at the same time clubbed with a rise of hypotension and acute renal failure apart from possible increase in adverse events of hypertension medications.

Design and method:
Keeping aim to study the impact of reducing cut off for hypertension in developing country like India we screened apparently healthy 129710 individuals, who never checked their blood pressure before, picked at various public places after their due consent to reveal data without disclosing their identity for blood pressure measurement in seated position after five minutes rest with three readings and taken the average of last two readings. Their demographic and details of habit also recorded.

Results:
There has been a tremendous rise in prevalence from 16.49% to 44.71% while dropping the cut off from 140/90 to 130/80. Interestingly in younger population less than 30 years of age prevalence of hypertension has been 7.7% with classical cut off 140/90 but rising more than four times 33.11% when cut off drops to 130/80. In elderly population above 60 years, a considerable rise of more than double from 28.8% to 59.6% noted.

Conclusions:
For developing world it is not only a huge rise in health expenditure but also in a country like India where 72% population is less than 40 years of age, it imparts an impression of being sick in a larger part. With this new cut off every third youngster can be labelled hypertensive. As sympathetic overdrive plays a major role in young population with hypertension, it is necessary to find an appropriate cut off for them which can not be similar to elderly. Early use of anti-hypertensive drugs not only opens door to various side effects but also paves way for lightheaded, fatigue, weakness while endeavoring lower targets.
HYPERTENSION AWARENESS, TREATMENT AND CONTROL AMONG MINORITY ETHNIC POPULATIONS IN EUROPE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Linden Eva Van Der , Couwenhoven Brandon , Daams Joost , Born Bert-Jan Van Den , Agyemang Charles 
Published: April 2021

Objective:
Ethnic minority populations in Europe are disproportionally affected by hypertension-related complications. Early detection, adequate treatment and control of hypertension can help to prevent these complications. We conducted a systematic review and meta-analysis to quantify levels of hypertension awareness, treatment and control among minority ethnic populations residing in Europe compared to the host European population.

Design and method:
MEDLINE, EMBASE and Web of Science were systematically searched for population-based studies reporting levels of hypertension awareness, treatment or control in minority ethnic populations in Europe. Using Review Manager, pooled odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated, stratified by ethnic group.

Results:
3532 records were screened of which sixteen were included in the analysis, comparing data of 26,800 subjects from five minority ethnic groups with 57,000 subjects from the European host population. African origin populations were more likely to be aware (OR 1.26, 95% CI 1.02–1.56) and treated (OR 1.49, 1.18–1.88) for hypertension, but less likely to have their blood pressure (BP) controlled (OR 0.56, 0.40–0.78), compared to the European host population. Compared to the host population, South Asian (SA) origin populations were more likely to be aware (OR 1.15, 1.02–1.30) of their hypertension status, but there were no differences in treatment and control rates. In Turkish and Moroccan origin populations, hypertension awareness rates were lower (Turkish OR 0.81, 0.65–1.00; Moroccan OR 0.46, 0.62–1.00), as were treatment levels in Moroccan population (OR 0.77, 0.60–0.97), and a trend towards lower BP control rates compared to the European populations. Hypertension awareness and control rates did not differ between Chinese origin populations and the European host population (no data on treatment available).

Conclusions:
Levels of hypertension awareness, treatment and control differ between ethnic groups in Europe. Effort should be made to improve hypertension control in African origin populations and awareness, treatment and control in Turkish and Moroccan populations, aiming to reduce ethnic inequalities in hypertension-related complications.
A PREDICTIVE TOOL FOR FORECASTING ANTI-HYPERTENSION MEDICATION REQUIREMENTS IN LOW- AND MIDDLE-INCOME COUNTRIES
Authors: Sahoo Swagata Kumar , Pathni Anupam K. , Kaur Prabhdeep , Kunwar Abhishek , Sharma Bhawna , Farrell Margaret L. , Moran Andrew E. , Komrska Jan , Frieden Thomas R. 
Published: April 2021

Objective:
To develop a mathematical tool for estimating medication requirement that would improve the uninterrupted supply of medications for large-scale hypertension control programs in low- and middle-income countries.

Design and method:
In a steady state, annual drug procurement forecasts can simply replicate the previous year's consumption. For a new or rapidly growing hypertension control program, however, forecasting drug requirement requires consideration of not only patients currently on medication, but also rates of new patient registration and drop-out.
To forecast antihypertensive drug requirements, a simple mathematical tool was developed based on the morbidity method, requiring minimal inputs and assumptions. The tool hinges on use of a standard step-wise treatment protocol which uses specific medications and doses and considers hypertension prevalence, number of existing patients, expected new monthly enrollments, proportion of patients with controlled blood pressure at each protocol step, and expected loss-to-follow up over time. Outputs include forecasted quantities of specific medications for any specific time period and associated budgets. The tool provides flexibility for correction of projected requirements based on programmatic data, thus making the estimation more accurate.

Results:
The tool was implemented in an Indian hypertension control program starting with a priori assumptions and refined iteratively as program data became available. It was customised for use in specific Indian states based on their treatment protocol, population size and primary health care coverage. The monthly drug requirement projected by the tool helped to quantify drug volumes for periodic procurement, and to overcome shortages observed in some areas in first year of the program. More than 10 states in India have adopted this tool for procurement and budget planning.

Conclusions:
This simple, pragmatic antihypertension drug forecasting tool can help ensure prudent resource allocation in hypertension control programs and facilitate reliable delivery of medications for patients in low- and middle-income countries. This tool can also quantify the financial implications of alternative treatment protocols, inform protocol design, and be adapted to other chronic disease control programs.