bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIGH FASTING BLOOD GLUCOSE LEVEL INCREASE RISK OF HYPERTENSION INCIDENCE INDEPENDENT OF INSULIN RESISTANCE IN JAPANESE: THE SAKU STUDY
Authors: Tatsumi Yukako , Asayama Kei , Morimoto Akiko , Sonoda Nao , Miyamatsu Naomi , Ohno Yuko , Miyamoto Yoshihiro , Izawa Satoshi , Ohkubo Takayoshi 
Published: April 2021

Objective:
Although high fasting blood glucose (FBG) levels is reported to be a risk factor for incidence of hypertension, the predominant confounding effect of insulin resistance may make the current evidence difficult to apply for individuals without insulin resistance. This study aimed to investigate whether high FBG levels increase the risk of incidence of hypertension, regardless of insulin resistance.

Design and method:
This 5-year cohort study included 2210 Japanese aged 30–64 years without hypertension. Participants were stratified by baseline homeostasis model assessment of insulin resistance (HOMA-IR) less than 1.6, 1.7–2.4 and 2.5 or higher. In each HOMA-IR stratum, hazard ratios (HRs) and 95% confidence intervals (CIs) of FBG 7.0 mmol/l or higher for the incidence of hypertension compared with FBG less than 7.0mmol/l were estimated using multivariable-adjusted Cox proportional hazard models. Hypertension was defined as blood pressure 140/90 mmHg or higher or receiving antihypertensive treatment.

Results:
Of 2210 participants, 334 participants showed increased BP levels to 140/90 mmHg or higher, and 212 participants started taking antihypertensive treatment during the median 4.9-year follow-up period (interquartile range: 3.5–5.0 years). After adjustment for age, sex, overweight, dyslipidaemia, smoking status, alcohol consumption, physical activity, family history of hypertension, and systolic BP at baseline, the HRs (95% CIs) of FBG 7.0 mmol/l or higher compared with FBG less than 7.0mmol/l were 1.94 (1.05–3.59), 2.94 (1.36–6.36) and 2.22 (1.03–4.78) in those with HOMA-IR less than 1.6, 1.7–2.4 and 2.5 or higher, respectively.

Conclusions:
FBG 7.0 mmol/l or higher increased future incidence of hypertension compared with FBG less than 7.0 mmol/l in middle-aged Japanese, regardless of insulin resistance defined by HOMA-IR.
HYPOTENSIVE EFFECTIVENESS OF THE INTRARENAL MEDULLARY ENDOTHELIN ETA RECEPTOR BLOCKADE IN THE TWO ANIMAL MODELS OF HYPERTENSION
Authors: Badzynska Bozena , Sadowski Janusz , Vaneckova Ivana , Kompanowska-Jezierska Elzbieta 
Published: April 2021

Objective:
Endothelin-1 (ET-1) is involved in the pathogenesis of arterial hypertension and chronic kidney disease, however, its mechanism of action is unclear. ET-1 is known to act via ETA and ETB receptors; their activation leads, respectively, to constriction or NO-mediated dilation of the systemic and renal vasculature. ET-1 levels are elevated in experimental and in human hypertension. Here we examined the effects of ETA receptor blockade with atrasentan, administered intravenously (i.v.) or directly to the renal medullary interstitium (i.med.) in two models of rat hypertension.

Design and method:
In anaesthetized rats with hypertension induced by uninephrectomy followed by high-salt (4% Na w/w) diet (HS/UNX) and in spontaneously hypertensive rats (SHR) we measured mean arterial pressure (MAP), total renal blood flow (RBF, renal artery probe), renal medullary blood flow (MBF, laser-Doppler flux), and renal medullary nitric oxide (NO) signal. Atrasentan doses were: 0.6 mg/kg/h i.v. or 0.12 mg/kg/h i.med.

Results:
In HS/UNX intravenous atrasentan reduced MAP (142 ± 7 to 117 ± 8 mmHg, p < 0.001) and increased NO signal by 12% (p < 0.05). RBF fell from 25.6 ± 1.7 to 22.3 ± 1.6 ml/min (p < 0.03). Intramedullary atrasentan decreased MAP (127 ± 6 to 115 ± 6, p < 0.04) and increased NO signal by 9.7% (p < 0.03). RBF and MBF did not change significantly. In SHR intravenous atrasentan decreased MAP (171 ± 3 to 152 ± 9 mmHg, p < 0.03) and RBF (6.4 ± 0.5 to 5.0 ± 0.4 ml/min, p < 0.02); NO signal increased by 9.1% (p < 0.01). Intramedullary atrasentan decreased MAP (176 ± 4 to 167 ± 7 mmHg, p < 0.001); NO increased by 10% and MBF by 26% (p < 0.02–0.05). Evidently, in both hypertension models atrasentan always decreased MAP and increased tissue NO.

Conclusions:
To summarise, in both hypertension models blockade of ETA receptors decreased MAP, reflecting systemic vasodilation. The pressure decrease was followed by a decrease in RBF, probably the result of reduced renal perfusion pressure and imperfect autoregulation. Remarkably, MAP decrease was also seen with intramedullary ETA blockade but then without impairment of renal circulation. Of particular interest was a regular increase in tissue NO: we propose that the blockade of ETA unmasked the action of unbound ET-1 via ETB receptors, leading to NO release.
NOX4 PROTECTIVE EFFECT IN ENDOTHELIAL FUNCTION INVOLVES ACTIVATION OF TRANSIENT RECEPTOR POTENTIAL MELASTATIN 2 (TRPM2) CATION CHANNEL
Authors: Alves-Lopes Rheure , Neves Karla , Montezano Augusto , Touyz Rhian 
Published: April 2021

Objective:
Nox4 regulates endothelium-dependent relaxation through production of H2O2, which in turn acts as an EDHF. We demonstrated that TRPM2 is also a target of H2O2 in vascular cells. TRPM2 is a redox-sensitive Ca2+ channel and once activated leads to Ca2 influx. Hypertension-associated endothelial dysfunction involves reduction in eNOS activation and is potentiated in the absence of NOX4. As TRPM2 channel is a H2O2 sensor and regulates Ca2+ entry, we questioned whether impaired vascular relaxation in hypertensive NOX4 KO mice involves the H2O2-TRPM2-Ca2+ axis in endothelial cells.

Design and method:
WT and TTRhRen hypertensive mice were crossed with Nox4 KO mice. Vascular function was measured by wire myograph in resistance arteries. Ca2+ influx was assessed by fluorescence microscopy in aortic endothelial cells. eNOS activation was assessed by immunoblotting.

Results:
Blood pressure was significantly increased in TTRhRen (130.3 ± 7.0 mmHg) and TTRhRen/NOX4 KO mice (141.3 ± 18 mmHg) versus control mice (98.1 ± 8.0 mmHg). TTRhRen mice had reduced endothelium-dependent relaxation (Emax: WT 83.5 ± 4.03 vs TTRhRen 59.1 ± 3.5); an effect worsened by NOX4 KO (37.9 ± 5.4), p<0.05. The TRPM2 activator, ADPR, improved vascular relaxation in TTRhRen/NOX4 KO mice (75.9 ± 7.7); an effect recapitulated by H2O2 (74.2 ± 15.4), p < 0.05. Ang II-induced Ca2+ influx in endothelial cells, important in eNOS activation, was reduced by TRPM2 inhibitors (AUC - Ca2+: 8-br-cADPR 76161 ± 1052.0; Olaparib 74763 ± 843.2 and 2-APB 79625 ± 277.4, p < 0.05) and the NOX1/4 inhibitor GKT137831 (AUC - Ca2+: Ang II 107357 ± 1940.2 vs GKT 60270 ± 255.6, p < 0.05). Ang II-induced activation of eNOS (Ser1177) (%: 72.3 ± 24.7) was blocked by GKT137831, PEG-catalase and the TRPM2 inhibitor 8-br-cADPR (p < 0.05).

Conclusions:
Endothelial dysfunction in TTRhRen mice involves impaired TRPM2 activation. Inhibition/downregulation of Nox4 and reduced bioavailability of H2O2 exacerbates these processes. We identify a novel protective effect of NOX4 in endothelial cells involving H2O2-mediated activation of TRPM2-Ca2+-eNOS signalling.
INFLUENCE OF RENAL FUNCTION ON RETINAL VASCULAR DENSITY ASSESSED BY OCT ANGIOGRAPHY IN HYPERTENSIVE PATIENTS
Authors: Mulè Giuseppe , Vadalà Maria , Guarrasi Giulia , Guarino Laura , Castellucci Massimo , Sorce Alessandra , Dell’Utri Riccardo , Ferotti Alessandra , Cillino Salvatore , Cottone Santina 
Published: April 2021

Objective:
It is well known that the retinal vasculature may be considered as a window through which the body microcirculation can be easily, safely and repeatedly, observed. Alterations of the renal microcirculation have been documented in animal models with hypertensive renal damage and microvasculature changes have been suggested to play a mayor etiological role in a large proportion of subjects with chronic CKD. Angio OCT is a recently developed noninvasive diagnostic imaging technique that employs motion contrast extracted from high-speed OCT images to produce depth-resolved, high-resolution images of retinal and choroidal vasculature without dye injection.

Aim:
Our study was aimed to assess in hypertensive patients the influence of renal function on retinal vascular density assessed by Angio-OCT.

Design and method:
We enrolled 120 consecutive hypertensive subjects (age: 51 ± 13 years; males 68%) attending our Hypertension Centre. All the patients underwent routine biochemical evaluation and angio-OCT. The retinal angiograms obtained allowed to assess vascular density of both superficial (DRS) and deep (DRP) network in the parafoveal area. Only one eye of each subject was randomly selected for analysis. Glomerular filtration rate was estimated by CKD-EPI equation.

Results:
26 subjects showed a GFR value < 60 ml/min/ 1.73 m2. These patients, when compared to those with higher GFR, showed significantly lower values of DRS (36.48 ± 1.23 vs 37.29 ± 0.78 %; p < 0.001) and of DRP (37.69 ± 1.23 vs 38.34 ± 0.97 %; p = 0.005). Moreover, the GFR correlated directly with DRP (r = 0.385; p < 0.001) and with DRS (r = 0.247; p < 0.01). These associations remain statistically significant even after adjustment for age, BP and other confounders in multiple linear regression analyses (respectively, beta = 0.265; p < 0.05 e beta 0.211; p < 0.05).

Conclusions:
Our study, showing a significant association between reduced retinal vascular density and renal function impairment, confirms the close link relating CKD with retinal vascular abnormalities.
DONEPEZIL IMPROVES VASCULAR FUNCTION IN A MOUSE MODEL OF ALZHEIMER'S DISEASE
Authors: Masi Stefano , Antonioli Luca , Duranti Emiliano , Fornai Matteo , Pellegrini Carolina , Baldacci Filippo , Taddei Stefano , Blandizzi Corrado , Virdis Agostino 
Published: April 2021

Objective:
Donepezil represents the most effective drug in the treatment of Alzheimer's Disease (AD). Recent reports suggest that it might have free radical scavenging properties, which could potentially improve the vascular alterations commonly associated with AD and partially account for the cognitive benefits observed during treatment. However, the potential effect of donepezil on vascular function and structure remains largely unexplored.

Objective:
to assess the impact of donepezil on the vascular phenotype of an established model of AD, the SAMP8 (Senescence-Accelerated Mouse-Prone).

Design and method:
3 groups of animals were included: SAMP8 (n = 4), SAMP8 treated with Donepezil for 8 weeks (n = 4) and SAMR1 (Senescence-Accelerated Mouse-Resistant, a mouse model which does not develop the disease, n = 4). Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests, animals were euthanized, their mesenteric arteries were isolated and mounted on a pressurised myograph to assess endothelial function by means of dose-response curves to acetylcholine (Ach) alone or in combination with L-NAME or Vitamin C. Media-to-lumen ratio (M/L ratio) was also measured. In subsequent experiments (n = 4), donepezil was coincubated directly on the arteries isolated from untreated SAMP8 together with Ach.

Results:
Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated the cognitive dysfunction. SAMP8 had higher M/L ratio than SAMR1 and donepezil treated animals (p < 0.001 for both differences, Fig. 1). Endothelial function was impaired in SAMP8 animals compared to SAMR1 (Fig. 1). Addition of Vitamin C improved the vasodilatory response to Ach in SAMP8 (p < 0.001 vs Ach alone). Treatment with donepezil improved endothelial function in SAMP8 animals (p < 0.001 vs untreated SAMP8) and reduced the additional vasodilation induced by Vitamin C (Fig. 1). Acute incubation of mesenteric arteries from SAMP8 animals with donepezil induced a significant improvement of endothelial function from baseline (p < 0.001)and the subsequent addition of Vitamin C did not induce further vasodilation.

Conclusions:
The beneficial effects of donepezil on vascular function and structure might provide a novel mechanism explaining its positive effects on cognitive decline. These effects might be mediated by antioxidant mechanisms.
ALCOHOL – THE MYTH OF CARDIOVASCULAR PROTECTION
Authors: Schutte Rudolph , Wannamethee Goya 
Published: April 2021

Objective:
We investigated three potential errors embedded in epidemiological evidence that could mask the health effects of alcohol, i.e., by using abstainers as reference group, combining alcohol from all drink types, and including protective relationships with ischemic heart disease when assessing overall cardiovascular (CV) risk.

Design and method:
The UK Biobank cohort consists of over 500,000 participants that attended one of 22 assessment centers across the United Kingdom. We calculated baseline alcohol intake as grams per week and followed CV outcomes for a median 6.9 years.

Results:
Never drinkers were at higher risk for all CV events (P < 0.0001), ischemic heart disease (P < 0.0001) and cerebrovascular disease (P < 0.0001). Alcohol from all drink types combined and beer/cider and spirits combined predicted CV events (both P < 0.024) and cerebrovascular events (both P < 0.011). Associations were stronger for beer/cider and spirits for both CV events (hazard ratio, 1.24 vs 1.08, P < 0.0001) and cerebrovascular events (hazard ratio, 1.30 vs 1.15, P < 0.0001). No relationships existed with ischemic heart disease (both P > 0.11). Wine was protective for CV events (P = 0.008) and ischemic heart disease (P < 0.0001), but not cerebrovascular events (P = 0.34). Excluding ischemic heart disease events resulted in the nullification of CV protection from wine (P = 0.95), while alcohol captured from beer/cider and spirits remained predictive (P < 0.0001).

Conclusions:
The use of abstainers as reference group, combining of all drink types including wine when capturing alcohol intake, and embedding the protective relationship between ischemic heart disease and wine in CV risk prediction, masks the health risks associated with alcohol intake and falsely portrays alcohol as protective.
CENTRAL SYSTOLIC BLOOD PRESSURE RELATES INVERSELY TO NITRIC OXIDE SYNTHESIS IN YOUNG BLACK ADULTS: THE AFRICAN-PREDICT STUDY
Authors: Craig Ashleigh , Mels Catharina Mc , Tsikas Dimitrios , Boeger Rainer H. , Schwedhelm Edzard , Schutte Aletta E. , Kruger Ruan 
Published: April 2021

Objective:
Lower nitric oxide bioavailabilty associates with hypertension in diseased and elderly populations. With hypertension known to develop earlier in black populations, we compared both plasma and urinary nitric oxide-related markers and their associations with central systolic blood pressure and arterial stiffness in healthy young black and white adults.

Design and method:
We included healthy black and white men and women (n = 1110; 20–30 years) and measured central systolic blood pressure and pulse wave velocity, along with both plasma and urinary arginine, homoarginine, asymmetric dimethylarginine, symmetric dimethylarginine, as well as urinary ornithine/citrulline, nitrite and nitrate. Additionally, the urinary nitrate-to-nitrite ratio was calculated.

Results:
The black men and women had higher central systolic blood pressure and higher plasma arginine and asymmetric dimethylarginine, but lower urinary nitrate and urinary nitrate-to-nitrite ratio (all p< = 0.003) than their white counterparts. In single and forward stepwise multiple regression analyses, we found an inverse association of central systolic blood pressure (adj. R2 = 0.124; β= –0.134; p = 0.006) and plasma homoarginine in black men. Central systolic blood pressure associated inversely with urinary nitrate-to-nitrite ratio in black women only (adj. R2 = 0.171; β= –0.130; p = 0.029). In the white women, central systolic blood pressure associated positively with urinary asymmetric dimethylarginine (adj. R2 = 0.372; β= 0.162; p = 0.015). Pulse wave velocity associated inversely with plasma asymmetric dimethylarginine (adj. R2 = 0.253; β= –0.163; p = 0.024) in the white women only.

Conclusions:
The lower nitric oxide synthesis and the higher central systolic blood pressure in our black cohort support the notion of a potential increased risk for future large artery stiffness and hypertension development in later life.
IMPLEMENTATION OF THE NOVEL HYPERTENSION-SPECIFIC PATIENT-REPORTED OUTCOME MEASURE IN M-HEALTH. A SINGLE-CENTRE EXPERIENCE
Authors: Ionov Mikhail , Dubinina Elena , Khromov-Borisov Nikita , Tregubenko Ilya , Kurapeev Dmitry , Zvartau Nadezhda , Konradi Alexandra 
Published: April 2021

Objective:
Telehealth techniques are hugely involved in management of hypertension (HTN). Despite much evidence of clinical efficacy, the quality of life (QoL) is still poorly addressed in m-Health studies. Furthermore, generic tools are often used for QoL assessment. The aim was to assess QoL of blood pressure telemonitoring (BPTM) with the brand new HTN-specific patient-reported outcome measure called HYpertension imPact questionnairE (HYPE).

Design and method:
Conceptual model of HYPE was designed and the item pool was created by an expert panel consisting of 4 cardiologists, 2 psychologists. Validation survey was conducted in a 400-cohort of ambulatory patients with HTN Grades 1–3. Exploratory and confirmatory factor analyses (EFA and CFA respectively) were undertaken to confirm validity. Reliability was confirmed with Cronbach's alpha. Free and secure m-Health app was developed for BPTM. 100 patients were enrolled and allocated to BPTM (mean age 48 y.o.) and control (mean age 49 y.o.) in 1:1 ratio. The 6-month program was developed with baseline and end of study clinic visits and HYPE polling.

Results:
There were 5 factors (“symptoms”, “emotions”, “social issues”, “treatment efficacy” and “treatment adherence”) retained with respect to Cattel scree test. Of 80 initial questions only 35 were eligible due to EFA (factor loadings >0.5). CFA indicated SRMR was 0.08, RMSEA was 0.07 (90% CI [0.07–0.08]) and CFI was 0.08. Cronbach's alpha was more 0.80 for each of the factors and 0.89 for the whole scale confirming its reliability. Six-month results reaffirmed the clinical efficacy of BPTM (141,2 ± 10,2 vs 149,5 ± 8,4 mm Hg, p < 0.003). The vast majority of patients in BPTM achieved target office BP instead of control group (50% vs 15%). HYPE score was markedly higher in BPTM group than in controls (+22,4 [+16%] vs +5,6 [4%], p < 0.0001) at the end of the study. Qualitative substudy showed 70% positive patient experience with using BPTM.

Conclusions:
Novel patient-reported outcome measure is a solid tool for assessing different patterns of QoL in patients with HTN. BPTM seems to be effective especially in a patient-centered manner and paves the way for future telehealth studies focusing on quality of life in hypertensive subjects.
RENAL OXIDATIVE STRESS IN A MODEL OF HYPERTENSION INDUCED BY SALINE OVERLOAD: ROLE OF CHLORIDE ANION
Authors: Puyó Ana María , Kouyoumdzian Nicolás Martín , Prince Paula Denise , Robbesaul Gabriel Damián , Kim Gabriel , Pandolfo Marcela , Fernández Belisario Enriqu , Galleano Mónica Liliana , Choi Marcelo Roberto 
Published: April 2021

Objective:
A chronic saline overload in the diet induces a renal inflammatory response and oxidative stress, leading to hypertension development. Our aim was to demonstrate that chloride anion (Cl-), besides sodium cation (Na+), is involved in these inflammatory and oxidative responses. These alterations might be reduced if Cl- is replaced by other anion (like citrate), or if Na+ is replaced by other cations.

Design and method:
Male Wistar rats were divided into four groups (n = 8): control (C); NaCl 8%W/W; high Na+ without Cl- (Na: sodium citrate 11,8%); high Cl- without Na+ (Cl: CaCl2 3,80%; KCl 3,06% and MgCl2 1,30%). After three weeks, systolic blood pressure (SBP) was measured, and rats were housed in metabolic cages in order to collect 24-hour urine to assess renal function. Oxidative stress parameters were determined in renal cortex: TBARS production and antioxidant enzymes activities and expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx).

Results:
In all groups we observed a significant increase of diuresis (∗p < 0,05 versus C) while SBP was increased only in those rats fed with Cl- (mmHg, C:125 ± 9; NaCl:164 ± 8∗; Na:133 ± 4; Cl:152 ± 7∗). These changes were accompanied by an increase in TBARS production in renal cortex (mol TBARS/mg protein) (x1012): C:1,30 ± 0,10; NaCl:1,82 ± 0,18∗; Na:2,01 ± 0,32∗; Cl:1,91 ± 0,34∗. No changes were observed on the activity or expression of SOD and CAT. Despite GPx expression being unaltered, its activity was increased in those groups with Cl- (micromol oxidized glutathione/mg protein.min, C:1,34 ± 0,14; NaCl:2,31 ± 0,37∗; Na:1,30 ± 0,14; Cl:2,77 ± 0,52∗).

Conclusions:
A high salt intake as sodium chloride increased SBP and water, sodium and chloride urinary excretion after 3 weeks of treatment. These changes were associated with an increase in oxidative stress parameters in renal cortex (mainly TBARS production and GPx activity). Only chloride salts could increase diuresis and induce an increase in SBP (compared with C) but reaching lower values than NaCl group. Additionally, chloride salts were able to increase oxidative stress parameters in renal cortex as NaCl group. These findings suggest that chloride component in the diets can be crucial to determine a higher prooxidant state in the kidney, rather than the sodium component in salt diets.
RENAL FUNCTIONAL RESERVE IS RELATED TO THE NON-DIPPING PHENOTYPE AND TO THE EXERCISE HEART RATE RESPONSE IN PATIENTS WITH ESSENTIAL HYPERTESION AND A PRESERVED RENAL FUNCTION
Authors: Damianaki Katerina , Burnier Michel , Tsioufis Constantinos , Dimitriadis Kyriakos , Vlahakos Demetrios , Petras Dimitrios 
Published: April 2021

Objective:
Renal functional reserve (RFR) defined as the difference between stress and resting glomerular filtration rate (GFR) may constitute a diagnostic tool to identify patients at higher risk of developing acute kidney injury or chronic kidney disease. A blunted RFR has been demonstrated in early stages of hypertension and has been attributed to an impaired vascular reactivity due to an overactive sympathetic nervous system. The purpose of this study was to investigate whether RFR correlates with other phenotypes expressing an over-activity of the SNS in patients with essential hypertension and a preserved renal function.

Design and method:
Thirty-six patients with untreated essential hypertension and a GFR >60 ml/min/1.73m2 were enrolled. The following parameters were measured: RFR, a 24 h ambulatory BP profile, a treadmill stress test and an echocardiographic examination. Urine and venous samples were obtained for the determination of clinical parameters and calculation of RFR after an acute oral protein load (1 g/kg).

Results:
Twenty-one patients had a RFR below 30 ml/min/1.73m2 and 15 had a RFR above this cut-off. A non-dipping pattern of 24 h BP was significantly more frequent in patients with low RFR (57.1% vs. 25.0%, p < 0.05 for systolic BP and 52.3% vs 10.0%, p < 0.02 for diastolic BP). Moreover, patients with lower RFR values showed a blunted heart rate response to exercise during treadmill test (r = 0.439, p < 0.05). None of the echocardiographic parameters differed between the two groups of patients.

Conclusions:
In hypertensive patients with a preserved GFR, a reduced RFR is related to non-dipping BP phenotype as well as with an attenuated exercise HR response. An overactivity of the sympathetic nervous may be a common pathway. Since a loss of RFR may represent a risk factor for acute or chronic kidney injury, hypertensive patients with a blunted RFR might need a more careful renal follow-up.