bluuebunny/crossref_metadata_2025_split huggingface dataset:
METABOLIC EFFECT OF A MINERALOCORTICOID RECEPTOR ANTAGONIST IN A NEW MODEL OF DIABETIC NEPHROPATHY
Authors: Palacios Roberto , Bonnard Benjamin , Lima-Posada Ixchel , Genty Marie , Jaisser Frederic 
Published: April 2021

Objective:
Diabetic nephropathy (DN) is the most prevalent form of chronic kidney disease (CKD) and is associated with cardiovascular diseases. Several studies reported beneficial effects of mineralocorticoid receptor (MR) antagonists in DN, indicating the importance of aldosterone/MR axis in this pathology
We investigated the metabolic alterations associated to a new model of DN and explored the effect of the MR antagonist canrenoate and conditional MR knock-down

Design and method:
One month after CKD induction by 5/6 nephrectomy, mice were split in 4 groups: SHAM, CKD, CKD with 60% fat diet (CKD-HFD) and CKD-HFD treated with 30 mg/kg/day canrenoate (CKD-HFD-CAN). Another series was split in 2 groups CKD-HFD Ctrl and CKD-HFD-AdipoMRKO (in which the MR gene is deleted in adipocytes only). Glycated hemoglobin (HbA1c) was measured and glucose tolerance test (ipGTT) and insulin tolerance test (ipITT) were performed between 5 and 7 weeks after the starting of the diet/treatment. The whole body fat content was determined by MRI (Brucker). The comparisons were performed by one-way ANOVA and two-way ANOVA for the insulin and glucose tolerance tests. Results were considered significant with p < 0.05.

Results:
The body weight, the fat content, the epididymal visceral adipose tissue (EVAT) size and HbAc1 were significantly higher in the CKD-HFD group vs SHAM or CKD, an effect prevented by the treatment with canrenoate. The glucose tolerance and the response to insulin were impaired in CKD-HFD vs SHAM or CKD, an effect ameliorated by canrenoate (Table). The impact on body weight, fat content and EVAT size was similar in CKD-HFD-adipoMRKO mice when compared to CKD-HFD Ctrl mice, however the improvement of the glucose tolerance was milder (Table).

Conclusions:
MR antagonism improves metabolic alterations associated to DN, partially due to its effect on adipose tissue, which could be translated in a better prognosis of the disease
HYPERTENSION AND RENIN-ANGIOTENSIN SYSTEM BLOCKERS ARE NOT ASSOCIATED WITH EXPRESSION OF ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) IN THE KIDNEY
Authors: Jiang Xiao , Eales James , Scannali David , Nazgiewicz Alicja , Prestes Priscilla , Maier Michelle , Denniff Matthew , Xu Xiaoguang , Saluja Sushant , Wystrychowski Wojciech , Zywiec Joanna , Zukowska-Szczechowska Ewa , Burrell Louise M. , Greenstein Adam , Bogdanski Pawel , Keavney Bernard , Morris Adrew P. , Heagerty Anthony , Samani Nilesh J. , Guzik Tomasz J. , Charchar Fadi J. , Tomaszewski Maciej 
Published: April 2021

Objective:
Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) – the cause of COVID-19 disease. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported.

Design and method:
We examined how hypertension, its major metabolic co-phenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model.

Results:
Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis.

Conclusions:
Our results indicate that neither hypertension nor antihypertensive treatment are likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
RENIN-ANGIOTENSIN SYSTEM INHIBITORS AND COVID-19: A SYSTEMATIC REVIEW AND META-ANALYSIS EVIDENCE FOR SIGNIFICANT GEOGRAPHICAL DISPARITIES
Authors: Patoulias Dimitrios , Katsimardo Alexandra , Stavropoulo Konstantinos , Imprialos Konstantinos , Kalogirou Maria -Styliani , Doumas Michael 
Published: April 2021

Objective:
While the COVID-19 pandemic is constantly evolving, it remains unclear whether the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) affects the clinical course of SARS-CoV-2 infection.

Design and method:
For this meta-analysis, PubMed, CENTRAL, and grey literature were searched from their inception to 19 May 2020 for randomized, controlled trials or observational studies that evaluate the association between the use of either ACE inhibitors or ARBs and the risk for major clinical endpoints (infection, hospitalization, admission to ICU, death) in adult patients during the COVID-19 pandemic. In addition, a subgroup geographical analysis of outcomes was performed. Studies including less than 100 subjects were excluded from our analysis.

Results:
In total, 25 observational studies were included. ACE inhibitors and ARBs were not associated with increased odds for SARS-CoV-2 infection, admission to hospital, severe or critical illness, admission to ICU, and SARS-CoV-2-related death. In Asian countries, the use of ACE inhibitors/ARBs decreased the odds for severe or critical illness and death (OR = 0.37, 95% CI 0.16–0.89, I2 = 83%, and OR = 0.62, 95% CI 0.39–0.99, I2 = 0%, respectively), whereas they increased the odds for ICU admission in North America and death in Europe (OR = 1.75, 95% CI 1.37–2.23, I2 = 0%, and OR = 1.68, 95% CI 1.05–2.70, I2 = 82%, respectively). ACE inhibitors might be marginally protective regarding SARS-CoV-2-related death compared with ARBs (OR = 0.86, 95% CI 0.74–1.00, I2 = 0%).

Conclusions:
Randomized controlled trials are needed to confirm the aforementioned associations between ACE inhibitors, ARBs, and SARS-CoV-2.
ANGIOTENSIN II-INDUCED ER STRESS RESPONSE CONTRIBUTES TO PROFIBROTIC VSMC PHENOTYPE AND SUBSEQUENT HYPERTENSIVE ARTERIAL STIFFNESS
Authors: Cicalese Stephanie , Cooper Hannah , Preston Kyle , Kawai Tatsuo , Scalia Rosario , Eguchi Satoru 
Published: April 2021

Objective:
The renin-angiotensin-aldosterone system is known to play a pivotal role in human hypertension, and specifically angiotensin II (Ang II) is believed to mediate arterial stiffness through maladaptive responses from vascular smooth muscle cells (VSMCs). The objective of this study was to elucidate Ang II activation of the endoplasmic reticulum unfolded protein response (ER UPR) in VSMCs, how this contributes to hypertrophic and fibrotic responses, and how inhibition of ER UPR may mitigate increased aortic pulse propagation velocity (PPV, a surrogate measurement for aortic stiffness).

Design and method:
ApoE-/- mice were infused with 1 ug/kg/min angiotensin II for 14 days with or without 1 mg/mL 4-PBA For in vitro studies, rat VSMCs were explanted and used from P4-P8. 4-PBA 30 min pretreatment at 1 mM before Ang II 48 hr stimulation or adeno GRP78 infection used to assess chaperoning effect on sirius red collagen assay, THP-1 adhesion, and protein aggregate accumulation.

Results:
Chronic 14 day infusion of Ang II in apoE-/- mice leads to increased PPV from 0.06 m/s to 0.12 m/s, whereas supplementing drinking water with 1 mg/mL chemical ER chaperone 4-PBA mitigates this induction (PPV = 0.055 m/s), P = 0.039. Fibrosis of the heart, kidney and aorta were reduced with 4-PBA treatment as well. ER stress markers pIRE1a and XBP1S were activated in the thoracic aorta by Ang II infusion and inhibited by 4-PBA. Preamyloid oligomer accumulation induced by Ang II in the aorta was also reduced by 4-PBA. Rat VSMCs stimulated with Ang II were stained with aggregate dye Proteostat, which was increased with 48 hour Ang II treatment, and inhibited with 4-PBA pretreatment (P < 0.05). To evaluate VSMC stiffness promoting phenotype, collagen production and immune cell adhesion were assessed by Sirius Red assay and THP-1 adhesion, respectively. Both inductions by Ang II were decreased by 4-PBA. Overexpression of GRP78 significantly mitigated aggregate formation (P < 0.05) and immune cell infiltration (P < 0.05).

Conclusions:
Ang II induced pulse pressure and vascular amyloid deposition is decreased by chaperoning nascent protein folding. Targeting GRP78 to reduce ER UPR activation and subsequent disturbances in proteostasis may be a therapeutic strategy for aortic stiffness.
BLOOD PRESSURE PREVALENCE WITH STRATIFICATION AND ASSOCIATIONS: A COMMUNITY-BASED STUDY FROM LONGITUDINAL COHORT HOUSEHOLD SURVEY 2019
Authors: Chakaraborty Nilanjana , Chakraborty Kaushik , Mitra Ramendra Nath , Saha Angana , Chatterjee Papri , Manna Subhankar , Mitra Dipra 
Published: April 2021

Objective:
For decades morbidity and mortality due to hypertension remains the major contributor of NCD burden worldwide. Objective is to assess the prevalence of a community cohort's Blood Pressure of all categories: measured hypertension (mHTN), self-reported doctor diagnosed hypertension (DDH), undiagnosed hypertension (UDH), also blood pressure stratification followed as per Joint National Committee-8 guideline. Associations with socio-demographic variables also reported. Aim being to use the study data with collated same cohort's past relevant information as primary tool to formulate burden minimisation intervention protocol of the ongoing population health Study.

Design and method:
Barrackpore Population Health Study, an urban household-based community cohort of 3030 households commenced in 2001. Third household survey enrolled 6632 participants (Male2576; Female 4056). Beside pre-tested structured questionnaire, real time anthropometric measurements for BMI assessment and Blood Pressure measurement termed as ‘Measured Hypertension (mHTN)’ also performed in the survey. All measurements were carried out at participants’ residence on a working day during working hours according to standard protocol.

Results:
Among total participants of mHTN (N6632) 31.48% were normotensive, 39.02% were prehypertensive, 20.73% were HTNstg1, 8.76% were HTNstg2. Prevalence of DDH (n = 1563) was 23.57%. Among DDH, prevalence of normotensive 12.35%, well controlled; prehypertensive 37.17%, moderately controlled; HTNstg1 33.21% and HTNstg2 17.27%, both uncontrolled. Undiagnosed HTN (n = 3174) 47.86%. of total population. Among UDH, prehypertensive 63.23%, moderately controlled; HTNstg1 26.97% and HTNstg2 9.79% not controlled. Increasing age was a higher odds of DDH [OR = 1.08, CI: 1.07,1.10; p < .0001]. Smokers were 27% [OR = 0.73, CI: 0.60, 0.89; P = 0.0019] and alcohol drinkers 47% [OR = 0.53, CI: 0.40, 0.71; p < .0001]. Compare to non-snorers, always snorers were two times [OR = 2.27, CI: 1.93,2.54; p < .0001] and diabetics were four times [OR = 4.885, CI: 4.20, 5.68; p < .0001] likely to be higher in DDH population.

Conclusions:
Almost half of the hypertensives remain undiagnosed. Among the diagnosed population, significant majority were not controlled. Association of age, alcohol consumption, smoking, snoring, diabetes and above normal BMI were confirmed. Monitoring of the efficacy of the burden reduction intervention program of the established longitudinal study cohort should be considered.
ASSOCIATION OF CHILDHOOD PHYSICAL EXAMINATION AND LABORATORY PARAMETERS WITH HIGH BLOOD PRESSURE IN JAPANESE YOUNG ADULTS
Authors: Azegami Tatsuhiko , Uchida Keiko , Arima Fujiyo , Sato Yasunori , Awazu Midori , Inokuchi Mikako , Takeda Ayano , Itoh Hiroshi , Tokumura Mitsuaki , Mori Masaaki 
Published: April 2021

Objective:
We aimed to identify childhood risk factors for high blood pressure (BP) in young adults.

Design and method:
Childhood data were obtained from medical checkups of Japanese male and female junior high school students aged 12-13 years during the period from 2008 to 2009. Childhood variables were sex, body weight, body mass index (BMI), systolic BP, complete blood count, uric acid, total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. The 1129 participants were followed up for average 8.6 years with a range of 6.0 to 9.0 years. High BP was defined as elevated BP and hypertension of ACC/AHA BP category (systolic BP 120 mmHg or more and/or diastolic BP 80 mmHg or more).

Results:
At the follow-up, the prevalence of high BP was 42.2% in male young adults and 7.7% in female young adults. The mean systolic/diastolic BP was 117.8 [SD, 10.1] / 63.6 [SD, 6.1] mmHg in men and 105.2 [SD, 9.6] / 59.6 [SD, 5.5] mmHg in women. Univariable logistic regression analysis showed that systolic BP (odds ratio 1.56), body weight (1.50), uric acid (1.38), and red blood cell (1.31) at childhood baseline were significantly associated with high BP in male young adult, whereas variables associated with high BP were not found in female young adults because few women developed high BP. A logistic regression analysis with the stepwise method indicated that the regression model including systolic BP, body weight, WBC, platelet count, and uric acid had a high prediction power for high BP in male young adults (Area under curve 0.660, p < 0.001).

Conclusions:
These results suggest that childhood medical checkup information including BP, anthropometric data, and laboratory parameter can contribute to the prediction of future high BP in young adults.
PHYSICIAN- AND PATIENT REPORTED ADHERENCE TO ANTIHYPERTENSIVE DRUGS VERIFIED BY SERUM DRUG CONCENTRATION
Authors: Bergland Ola Undrum , Søraas Camilla Lund , Halvorsen Lene Vernås , Rognstad Stine , Hjørnholm Ulla , Kjær Vibeke , Opdal Mimi Stokke , Rostrup Morten , Larstorp Anne Cecilie , Høieggen Aud , Fadl Elmula Fadl Elmula M. 
Published: April 2021

Objective:
Non-adherence to drugs remains a challenge in hypertension treatment. Indirect assessments such as questionnaires and physician guessing have been the mainstay of such evaluation. Existing adherence questionnaires suffer from lack of both consensus and validation against objective methods. Recently, direct measurement of antihypertensive drugs in serum has become available. We aimed to compare both physician- and patient-reported adherence to antihypertensive treatment with serum drug concentration measurements.

Design and method:
We extracted data from 161 consecutive patients in an ongoing, national multicenter study, who were examined at a hypertension clinic. Patients were aged 18 years or older and used 2 or more antihypertensive drugs. All completed a medical history assessment, laboratory analyses and office- and ambulatory blood pressure (BP) measurements. Additionally, they filled out a five-item questionnaire designed to uncover both non-intended and intended non-adherence to antihypertensive drugs. Each item was scored 1–4, with the lowest obtainable total score of 5 indicating perfect adherence, and 20 points indicating absolute non-adherence. Investigators guessed patient adherence status prior to measuring BP and the results of serum drug concentrations became available. Adherence was objectively confirmed by serum drug concentration measurement using liquid chromatography tandem mass spectrometry, of which the patient was not informed. Patients were defined as non-adherent if serum concentration of at least one drug was below a pre-specified level.

Results:
We identified 149 (92%) adherent- and 12 (8%) non-adherent patients. Descriptives and results are listed in Table 1. Non-adherent patients were significantly younger and had lower diastolic BP and daytime ambulatory heart rate. Mean total adherence scores obtained from the questionnaire did not differ between groups (5.9 ± 1.7 vs. 5.9 ± 1.0, p = 0.84). Among the non-adherent patients, 33% had daytime ambulatory BP < 135 mmHg, and 58% stated that they never forgot to take their prescribed antihypertensive drugs compared to 44% in the adherent group. Only 17% were correctly classified as non-adherent by investigators, while 8% of adherent patients were erroneously classified as non-adherent.

Conclusions:
Our results suggest that indirect methods of assessing antihypertensive drug adherence are inadequate when compared to direct serum drug concentration measurements.
TWO-DRUG FIXED-DOSE COMBINATION AS INITIAL ANTIHYPERTENSIVE TREATMENT STRATEGY CONFERS HIGHER MEDICATION ADHERENCE COMPARED TO MONOTHERAPY
Authors: Rea Federico , Savaré Laura , Corrao Giovanni , Mancia Giuseppe 
Published: April 2021

Objective:
The recent European guidelines recommend to start treatment with two drugs in a single tablet in most hypertensive patients to improve on the low adherence to the treatment regimen that characterizes the hypertensive population. Evidence that this is the case is limited, however. Aim of our study was to compare adherence to antihypertensive drug therapy between newly treated patients who were prescribed initial monotherapy or a fixed-dose combination of two drugs.

Design and method:
The target population consisted of Lombardy residents (Italy), aged 40–80 years, who were beneficiaries of the National Health Service. 63,448 patients, newly treated with antihypertensive drugs during 2016, were followed for 1 year after the first prescription. Adherence to drug therapy was measured according to the “proportion of days covered” (PDC) criterion, i.e. the ratio between the number of days in which the drug was available from prescription and the days of follow-up. Patients who had a PDC greater than 75% were defined as adherent to drug therapy. Log-binomial regression models were fitted to estimate the risk (HR) or propensity to treatment adherence in relation to the initial therapeutic strategy. Adjustment was made for baseline demographic and clinical covariates.

Results:
47% of patients showed high adherence to treatment during the first year of drug therapy. Compared to patients under initial monotherapy, those who were initially treated with a fixed dose combination had a higher propensity to adhere to antihypertensive treatment (HR 1.19, 95%CI 1.17–1.22, p < 0.0001). This was the case in all strata, i.e. both genders, an age below or above 65 years, different clinical statuses, and no or previous cardiovascular event. It was also the case across the different initial fixed-dose-combinations, most of which promoted better adherence than the corresponding monotherapies.

Conclusions:
In a real-life setting, patients who were initially prescribed a fixed-dose combination of two antihypertensive drugs exhibited more frequently a good adherence to antihypertensive treatment than those starting with a single drug. This provides strong support to the initial fixed-dose-combination strategy as a means to improve adherence and favour blood pressure control.
ASSOCIATIONS OF RENALASE WITH BLOOD PRESSURE AND THE RISK OF HYPERTENSION IN CHINESE ADULTS
Authors: Wang Yang , Gao Ke , Chen Chen , Yan Yu , Yuan Yue , Wang Ke-Ke , Hu Jia-Wen , Chu Chao , Ma Qiong , Fu Bo-Wen , Liao Yue-Yuan , Li Min , Sun Yue , He Ming-Jun , Mu Jian-Jun 
Published: April 2021

Objective:
Renalase, a novel secretory flavoprotein with amine oxidase activity, is secreted into the blood by the kidneys and is hypothesized to participate in catecholamine metabolism. The aim of the study was to investigate the associations of renalase with blood pressure (BP) and the risk of hypertension from three perspectives of genetic variations, serum and kidney levels in humans.

Design and method:
1. A total of 515 Chinese participants from 124 families were eligible for this study. We followed up this cohort in 2009, 2012 and 2018, respectively. 10 SNPs in renalase gene were genotyped to examine the associations with longitudinal BP changes and incident hypertension during 14 years of follow-up.
2. 2342 participants from the Hanzhong Adolescent Hypertension Study cohort who were followed up in 2017 were included. Cross-sectional analysis was used to examine the relationships between serum renalase and the risk of hypertension.
3. 204 patients undergoing renal biopsy were recruited from our hospital. Expression of renalase in renal biopsy specimens were measured by immunohistochemistry (IHC).

Results:
1. During 14 years of follow-up, 160 (53.9%) participants developed hypertension. renalase SNPs rs10887800, rs796945, rs1935582, rs2296545 and rs2576178 were significantly associated with 14-year change in DBP while SNP rs7922058 was associated with longitudinal SBP change. In addition, SNPs rs796945, rs1935582 and rs2576178 were significantly associated with hypertension incidence over 14 years. Gene-based analysis found that renalase was significantly associated with hypertension incidence over 14-year follow-up.
2. Hypertensive subjects have higher levels of serum renalase than in the normotensive subjects. Serum renalase showed a linear association with increased BP (24.8, 25.6, 27.1, and 27.7 ug/mL for subjects with normotension, prehypertension, stage 1 and stage 2 hypertension). In addition, serum renalase [1.018 (1.006–1.030)] was significantly associated with the risk of hypertension in 2392 Chinese subjects.
3. The levels of SBP and DBP were positively correlated with the level of renalase in renal tubular epithelial cells (RTEC). The RTEC renalase expression was decreased in hypertensive patients compared to non-hypertensive patients.

Conclusions:
These findings indicate that renalase may play an important role in BP progression and development of hypertension.