bluuebunny/crossref_metadata_2025_split huggingface dataset:
GENES ASSOCIATED WITH BLOOD PRESSURE TRAITS SHOW CELL TYPE-SPECIFIC EXPRESSION AND CONTROL MULTIPLE CAUSAL LINKS TO BLOOD PRESSURE REGULATION IN THE HUMAN KIDNEY
Authors: Eales James , Jiang Xiao , Xu Xiaoguang , Saluja Sushant , Cano-Gamez Eddie , Pramanik Sanjeev , Bogdanski Pawel , Wystrychowski Wojciech , Zywiec Joanna , Zukowska-Szczechowska Ewa , Woolf Adrian , Maffia Pasquale , Guzik Tomasz , Samani Nilesh , Charchar Fadi , Tomaszewski Maciej 
Published: April 2021

Objective:
Hypertension affects 35% of the global adult population. It is a major risk factor for stroke, heart failure and coronary artery disease and is the leading preventable risk factor for premature death globally. Here we describe our approach to determine the causal pathways between genetic variants and blood pressure through the expression of kidney genes.

Design and method:
We used a catalogue of all known blood pressure associated genetic variants, gene expression profiles from 430 human kidney tissue samples and a single-cell gene expression data set to identify causal relationships with blood pressure using a colocalisation analysis and an ensemble of Mendelian randomisation methods.

Results:
By combining genome-wide genotypes and gene expression profiles from RNA-sequencing in an expression quantitative trait loci (eQTL) analysis we identify 418 genes where expression is modified by genetic variants previously associated with blood pressure traits. To investigate how these genes are expressed in the kidney we used gene expression profiles from 41,778 human renal cells and identified 390 (93%) of these genes to be expressed in these cells with 69 (18%) showing expression specific to individual renal cell types. There was a statistically significant enrichment for expression of blood pressure associated genes in juxtaglomerular cells and cells from the collecting tubule. We identified 111 genes where the eQTL and blood pressure association colocalised and then applied an ensemble of Mendelian randomisation (MR) methods to determine which genes also have a causal effect on blood pressure in the kidney. Our MR analysis identified 53 (13%) genes where expression is causally linked to blood pressure, these included: guanylate cyclase 1 (GUCY1A3), the main receptor for nitric oxide and the target of riociguat and nuclear receptor coactivator 7 (NCOA7) which regulates vacuolar proton pumping ATPase (V-ATPase) activity in the intercalated cells of the collecting duct.

Conclusions:
We have identified 53 kidney genes where expression is causally linked to blood pressure. This not only highlights the importance of the kidney in blood pressure regulation, but also identifies putative targets for drug development or repurposing.
LEFT VENTRICULAR MASS AND URINARY METABOLOMICS IN YOUNG BLACK AND WHITE ADULTS: THE AFRICAN-PREDICT STUDY
Authors: De Beer Dalene , Mels Catharina Mc , Schutte Aletta E. , Louw Roan , Delles Christian , Kruger Ruan 
Published: April 2021

Objective:
Increased left ventricular mass is an independent predictor for cardiovascular events, and shown to be higher in black than white populations. To gain a better understanding of early factors contributing to increased left ventricular mass in young black adults, we investigated metabolomic profiles and identified metabolites associated with left ventricular mass index in healthy black and white adults aged 20–30 years.

Design and method:
We included normotensive black (N = 80) and white (N = 80) participants from the African-PREDICT study, with data on urinary metabolomics and echocardiography. Urinary metabolites were measured using nuclear magnetic resonance spectroscopy, liquid chromatography tandem mass spectrometry and gas chromatography time-of-flight mass spectrometry. Univariate statistical analyses, including independent t-test (adjusted for multiple comparisons), effect size (d > = 0.3) and single regression analyses were used to identify metabolites.

Results:
When comparing the black and white groups, the black group had lower body weight (p < 0.001) and protein intake (p = 0.014). Central systolic blood pressure was higher in the black group compared to the white group (p > 0.005), whereas left ventricular mass index was similar between the groups (p = 0.97). Three from a total of 192 metabolites were identified to be more abundant (p < 0.046) and inversely associated with left ventricular mass index in the black group only: hydroxyproline (beta = –0.24; p = 0.020), glycine (beta = –0.23; p = 0.025) and trimethylamine (beta = –0.22; p = 0.026).

Conclusions:
Higher urinary levels of hydroxyproline, glycine and trimethylamine were inversely associated with left ventricular mass index in the black adults only. Hydroxyproline and glycine are important in maintaining healthy collagen turnover and stability in the heart. Our results may reflect an increase in collagen biosynthesis and collagen deposition in the left ventricle due to higher central systolic blood pressure in the black population.
PROXIMAL TUBULE-SPECIFIC DELETION OF AT1A RECEPTORS ATTENUATES CIRCULATING AND INTRATUBULAR ANGIOTENSIN II-INDUCED HYPERTENSION IN MICE
Authors: Li Xiao , Leite Ana Paulo , Zheng Xiaowen , Zhao Chunling , Zhang Liang , Chen Xu , Zhou Xinchun , Zhuo Jia 
Published: April 2021

Objective:
The present study used a novel mouse model with proximal tubule-specific knockout of AT1a receptors in the kidney, PT-Agtr1a-/-, to test the hypothesis that intratubular angiotensin II (Ang II) and AT1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II-induced hypertension.

Design and method:
To test our hypothesis, eight groups (n = 7–15 per group) of adult male wild-type, global Agtr1a-/-, and PT-Agtr1a-/-, and PT-Nhe3-/- mice were infused with Ang II (1.5 mg/kg/day, i.p.), or overexpressed an intracellular Ang II fusion protein (Ad-sglt2-ECFP/Ang II) in the proximal tubules of the kidney for 2 weeks. Basal blood pressure and the pressor responses, glomerular filtration rate (GFR) and 24 h urinary natriuretic response, and the pressure-natriuresis response were determined.

Results:
Basal telemetry blood pressure were ∼15 ± 3 mmHg lower in PT-Agtr1a-/- than wild-type mice and ∼13 ± 3 mmHg higher than Agtr1a-/- mice (P < 0.01). Basal glomerular filtration was ∼23.9% higher (P < 0.01), whereas fractional proximal tubule Na+ reabsorption was lower in PT-Agtr1a-/- mice (P < 0.01). Deletion of AT1a receptors in the proximal tubules augmented the pressure-natriuresis response (P < 0.01), and natriuretic responses to salt loading or Ang III infusion (P < 0.01). Ang II induced hypertension in wild-type, PT-Agtr1a-/- and PT-Nhe3-/- mice, but the pressor response was ∼16 ± 2 mmHg lower in PT-Agtr1a-/- and PT-Nhe3-/-mice (P < 0.01). Deletion of AT1a receptors or NHE3 in the proximal tubules attenuated ∼50% of Ang II-induced hypertension in wild-type mice (P < 0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT-Agtr1a-/- mice (P < 0.01).

Conclusions:
Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT1 (AT1a)/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II-induced hypertension.
BLOOD PRESSURE-LOWERING, ANTIHYPERTENSIVE TREATMENT AND INCIDENT DIABETES
Authors: Nazarzadeh Milad , Bidel Zeinab , Canoy Dexter , Copland Emma , Wamil Malgorzata , Byrne Karl Smith , Sundström Johan , Teo Koon , Davis Barry R. , Chalmers John , Pepine Carl J. , Dehghan Abbas , Bennet Derrick A. , Smith George Davey , Rahimi Kazem 
Published: April 2021

Objective:
To investigate the effect of blood pressure lowering and specific antihypertensives on the risk of new-onset type 2 diabetes, leveraging the strengths of both genetic data and individual-level data from randomised trials of blood pressure-lowering treatments.

Design and method:
We pooled individual-level data of 145,939 participants from nineteen randomised clinical trials. We used stratified Cox proportional hazard models, with fixed treatment effects, and participants as the unit of analysis. Analyses were complemented with Mendelian randomisation studies using naturally randomised genetic variants associated with systolic blood pressure and genetic variants encoding the therapeutic targets of each drug class.

Results:
After a median of 4.4 years follow-up, 9,883 participants were diagnosed with new-onset diabetes in clinical trials. Blood pressure-lowering treatment was found to reduce the risk of diabetes by 11% (hazard ratio [HR] per 5-mm Hg reduction in systolic blood pressure 0.89 [95% confidence interval [CI] 0.84 to 0.95]). Similarly, in the Mendelian randomisation study, each 5-mm Hg genetically-influenced lower systolic blood pressure was associated with an 11% lower risk of diabetes (odds ratio [OR] 0.88 [95% CI 0.84 to 0.92]). Evidence from genetic data and trials were also consistent in that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduced the risk of diabetes, and beta-blockers increased this risk. There was no evidence of an effect for calcium channel blockers and findings for thiazide diuretics were inconsistent; while genetic analysis showed a reduction in risk, the mostly indirect estimation from network analysis of trials suggested an increased risk compared with placebo.

Conclusions:
We found consistent evidence supporting that lowering blood pressure reduces the risk of new-onset diabetes. However, this protective effect was not uniform among different antihypertensive classes. Whereas ACEIs and ARBs reduced the risk of new-onset diabetes, the converse was observed with beta-blockers and possibly with thiazide diuretics. In determining which class of drug to use to manage elevated blood pressure, consideration of diabetes risk may help inform clinical decision-making.
ANATOMY OF RENAL DENERVATION DURABILITY
Authors: Sharp Andrew , Tunev Stefan , Schlaich Markus , Lee David , Finn Aloke , Melder Robert , Trudel Julie , Kandzari David 
Published: April 2021

Objective:
Safety and efficacy of catheter-based renal denervation (RDN) have been demonstrated in previous randomized, sham-controlled trials. Ongoing registries also suggest long-term durability of the RDN procedure. However, the exact mechanisms for RDN durability have not been previously elucidated. This report aimed to characterize the pathophysiological processes post radiofrequency (RF) RDN that translate into procedural durability utilizing animal models.

Design and method:
Animal studies were conducted in accordance with published guidelines. RDN was performed using the Symplicity RDN system (Medtronic, Santa Rosa, CA, USA) and the multielectrode RF Symplicity Spyral catheter in 164 healthy swine. Serial histological tissue samples were obtained 7, 28, 60, and 180 days post-procedure and followed by immunohistochemical and histopathologic analysis of RF-treated regions, sympathetic nerves and renal cortical axons.

Results:
At 7 days post-RDN, inflammation and swelling predominated the nerve lesions at the treatment site. A progressive nerve deterioration accompanied by Schwann cell reaction occurred over time leading to terminal atrophy and fibrosis at 180 days post-RDN. Nerve atrophy also became present distal to the treatment site. Although new Schwann cells appeared post-RDN, they failed to form the characteristic nerve fascicles and bundles which would reconstitute normal nerve morphology and support functional axons. Quantitative comparison of nerve necrosis and nerve atrophy indicated that proximal nerve necrosis peaks in the treated segments of the vessel, whereas nerve atrophy and low-grade nerve inflammation originates at the region of peak necrosis and extends distally beyond the RDN lesion. Thus, despite anatomic Schwann cell regeneration, the functional axonal nerve component did not recover.

Conclusions:
Histological analyses of porcine tissues demonstrated that terminal atrophy and fibrosis of the renal nerves developed within 180 days post-RF RDN procedure. Although new Schwan cell formation occurred, it did not reconstitute native nerve morphology suggesting functional nerve recovery is unlikely.
CARDIOVASCULAR OUTCOMES AND ALL-CAUSE MORTALITY ASSOCIATED WITH APPARENT TREATMENT-RESISTANT HYPERTENSION APPLYING THE 2017 ACC/AHA GUIDELINE
Authors: Jaejin An , Sim John , Lui Ran , Zhou Hui , Calhoun David , Wei Rong , Luong Tiffany , Reynolds Kristi 
Published: April 2021

Objective:
The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline lowered BP treatment goals from < 140/90 mmHg to < 130/80 mmHg for most adults with hypertension. We investigated cardiovascular (CV) outcomes and all-cause mortality associated with apparent treatment-resistant hypertension (aTRH) according to the 2017 ACC/AHA guideline.

Design and method:
We included adults aged > = 18 years identified from the 2014–2015 hypertension registry in a large US integrated healthcare system. aTRH was defined as either BP above goal while taking > = 3 classes of antihypertensive medication or taking > = 4 classes regardless of BP level. We identified individuals with non-aTRH, newly classified aTRH according to 2017 ACC/AHA, controlled and uncontrolled aTRH, and refractory hypertension (RH) (BP above goal with > = 5 classes). Individuals were followed from their first date meeting the aTRH criteria (aTRH group) or first date of entering the registry (non-aTRH group) until disenrollment from the health plan, the study end date (6/30/2019), or the outcomes of interest [composite CV events (myocardial infarction, stroke, and congestive heart failure), and death]. Multivariable Cox proportional hazards models were used to compare outcomes.

Results:
We included 450,181 individuals with treated hypertension [mean age 65 years, 46% White, 27% Hispanic, 14% Black, and 12% Asian], and 21% were considered as aTRH [5% newly classified aTRH, 3% controlled aTRH, 12% uncontrolled aTRH, and 1% RH]. The crude composite CV event rate was highest among patients with RH [RH = 39.9, controlled aTRH = 32.2, uncontrolled aTRH = 24.4, newly classified aTRH = 12.2, non-aTRH = 9.3 events per 1,000 person-years]. A higher risk of CV events was associated with aTRH compared with non-aTRH [Adjusted hazard ratios (HR) (95% CI) = 1.64 (1.60, 1.69)]. Newly classified aTRH was associated with higher CV events and all-cause mortality compared with non-aTRH [HR = 1.43 (1.35, 1.52) for CV events, 1.15 (1.09, 1.20) for all-cause mortality].

Conclusions:
Newly classified aTRH, per the 2017 ACC/AHA BP guideline, was associated with a higher risk of CV events compared with non-aTRH, which supports more stringent BP goals for individuals taking 3 or more classes of antihypertensive medication.
THE ASSOCIATION OF TESTOSTERONE IN UMBILICAL CORD BLOOD AND SYSTOLIC BLOOD PRESSURE IN OFFSPRING IN YOUNG ADULTHOOD
Authors: Beilin Lawrence , Le-Ha Chi , Mori Trevor , Hickey Martha , Keelan Jeffrey , Burrows Sally 
Published: April 2021

Objective:
Animal studies have shown intrauterine androgen exposure leads to offspring adult cardiovascular dysfunction, including hypertension. In humans, androgens in umbilical cord blood at birth reflect the androgen environment in pregnancy.
In a population-based sample studied from in utero, we aimed to explore the association between prenatal testosterone exposure and BP in young adulthood.

Design and method:
In the Raine Study cohort, data was available on umbilical cord blood androgens and on BP, anthropometric and socio-behavioural information in 387 participants at 20 years and 319 at 27 years. Total testosterone was measured using liquid chromatography-tandem mass spectrometry; free testosterone, by empirical method (Sartorius et al.); and sex hormone binding globulin, by ELISA. Bioavailable testosterone (BioT; nmol L) was calculated employing the formula: BioT = free testosterone + albumin-bound testosterone. We employed hierarchical linear mixed effects regression, with maximum likelihood estimation, to assess the association of BioT with blood pressure at 20 and 27 years adjusting for potential confounders.

Results:
Umbilical cord BioT levels were significantly higher in males than in females (0.14 [95%CI 0.13; 0.16] vs 0.08 [95%CI 0.07; 0.09] nM/L; p < 0.001). Mean systolic BP were 122.9 (95%CI 121.3; 124.6) and 110.5 (95%CI 109.1; 111.9) mmHg at 20 years, and 122.4 (95%CI 120.7; 124.1) and 111.2 (95%CI 109.8; 112.7) mmHg at 27 years, in males and females, respectively. Longitudinal regression models showed higher BioT levels were positively associated with systolic BP (coefficient: 16.1 [95% CI: 1.8; 30.4]; p = 0.027) at both 20 and 27 years, after adjusting for BMI, sex and hormone contraceptive use. This translates to a 1 mmHg increase in systolic BP for a 1 standard deviation increase in BioT. There was no difference in this association between sexes.

Conclusions:
To our knowledge, this is the first population-based study that shows testosterone in umbilical cord blood at birth is significantly associated with systolic BP in young adulthood. Our data support previous findings in animal studies of a causal relationship. The data suggest that higher testosterone levels in utero may increase the risk of hypertension later in life.
LOW-DOSE FOLIC ACID PROTECTS AGAINST ADVERSE CARDIAC REMODELING IN SPONTANEOUSLY HYPERTENSIVE RATS WITH HYPERHOMOCYSTEINEMIA
Authors: Xu Rui , Cao Ping 
Published: April 2021

Objective:
The interaction between hypertension and hyperhomocysteinemia (Hhcy) leads to adverse myocardial and coronary vascular remodeling in the hypertensive heart, resulting in impaired diastolic function. Folic acid (FA) is a free radical scavenger with antioxidant properties that effectively reduces homocysteine (Hcy) levels. The aim of this study was to evaluate whether lowering plasma homocysteine (Hcy) with different dose of folic acid (FA) could against Hhcy-induced myocardial injury in spontaneously hypertensive rats (SHRs) and its possible mechanisms.

Design and method:
Thirty-two adult male SHRs were randomly divided into four groups (n = 8/group), namely control group, Hhcy intervention group, Hhcy + Low-dose FA treatment group (0.4 mg/Kg·d), Hhcy + High-dose FA treatment group (4 mg/Kg·d), and then three Hhcy groups were subcutaneously injected 2% DL- homocysteine 5 ml/Kg. FA intervention started after 4 weeks’ Hcy injection. The total duration of the trial was 16 weeks. Cardiac echocardiography was performed at the last week. The Systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma Hcy, serum malondialdehyde (MDA), superoxide dismutase (SOD) were measured, and Masson's trichrome stain to enable evaluation of collagen deposition under a microscope. Furthermore, the levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) protein were detected by extraction of nuclear protein from cardiac tissue.

Results:
Intragastric administration of FA significantly reduced plasma Hcy levels. Serum SOD was significantly increased and serum MDA were also significantly attenuated by FA. Low-dose folic acid is more effective than high-dose folic acid in relieving Hhcy-induced anomalies in the heart of SHRs, such as the decline in cardiac diastolic function, perivascular collagen accumulation, and arteriolar wall thickening. FA increased the expression of Nrf2 and HO-1, and exhibited a protective effect against Hhcy-induced oxidative stress (OS), and there were no significant difference between high-dose and low-dose FA groups.

Conclusions:
Low-dose FA treatment can better protect against Hhcy-induced myocardial injury in SHRs, which may be due to its inhibition of OS and upregulation of Nrf2/HO-1 pathway.
CONTROL OF ANTIHYPERTENSIVE EFFECT MEDIATED BY SMALL INTERFERING RNA TARGETING ANGIOTENSINOGEN
Authors: Uijl Estrellita , Colafella Katrina M. Mirabito , Ren Liwei , Hoorn Ewout J. , Zlatev Ivan , Kim Jae B. , Huang Stephen , Melton Lauren , Foster Don , Danser A.H. Jan , Van Veghel Richard , Garrelds Ingrid M. 
Published: April 2021

Objective:
A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and durable antihypertensive effect, lasting weeks to months in preclinical models. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion and reverse RNAi-mediated blood pressure lowering.

Design and method:
Spontaneously hypertensive rats on a low-salt diet (<0.03% NaCl) were treated for 4 weeks with siRNA (10 mg/kg fortnightly; s.c.), supplemented with fludrocortisone (6 mg/kg/day; s.c.), midodrine (4 mg/kg/day; s.c.) or a high-salt diet (4% NaCl) during the final 2 weeks (n = 6–7 per group). Before and after 2 weeks of siRNA, blood pressure responses to intravenous bolus injections of angiotensin II (0.05; 0.5 and 5 mg/kg) and noradrenalin (0.1; 1.0 and 10 mg/kg) were recorded via radiotelemetry in anaesthetised rats.

Results:
Baseline mean arterial pressure (MAP; 136 ± 3 mmHg) was lowered by 19 ± 1 mmHg by AGT siRNA in combination with a low-salt diet. Acute pressor responses to angiotensin II and noradrenalin were identical before and after siRNA. Fludrocortisone restored MAP to baseline levels (137 ± 3 mmHg), as did replacing the low-salt diet with a high-salt diet (139 ± 4 mmHg). Midodrine had no effect. Under low salt conditions, siRNA virtually abolished plasma AGT by 99.2 ± 0.1% to 6 ± 1 nM, and increased active plasma renin concentrations. AGT was not altered by midodrine, only marginally raised by high sodium intake, but increased to 20 ± 5% of pre-siRNA treatment levels by fludrocortisone, paralleled by near-elimination of plasma renin levels by 98 ± 1% to 2.1 ± 0.9 ng angiotensin I/mL/h.

Conclusions:
The efficacy of angiotensin II and noradrenaline to raise blood pressure is not affected by RNAi-mediated AGT suppression. Increased sodium intake or fludrocortisone may represent chronic, less invasive alternatives for controlling blood pressure during AGT depletion, of which the latter seems to be facilitated by amplification of AGT production.