bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE ROLE OF ANGIOTENSIN II RECEPTOR BLOCKERS IN THE FUNCTION AND MORPHOLOGY OF PLATELETS IN HYPERTENSIVE PATIENTS
Authors: Konstantinou K. , Tsioufis K. , Kouremeti M. , Mantzouranis M. , Leontsinis I. , Tolis P. , Anastasiou A. , Iliakis P. , Tousoulis D. 
Published: April 2021

Objective:
Activation of platelet angiotensin receptors could potentially contribute to further progression of thrombotic events in hypertension. The aim of our study was to investigate the effect of antihypertensive therapy with ARBs on platelet function and morphology in a population of untreated hypertensive patients.

Design and method:
120 untreated hypertensive patients(mean age 51 years; office blood pressure: 153/87 ± 7.3 mmHg, 55% males; 56% smokers)were divided into groups based on ARBs treatment (group 1) or no (group 2) and were prospectively followed up. Group 1 was further classified into 2 subgroups with subgroup 1 (n = 50) receiving Olmesartan and subgroup 2(n = 50)receiving Candesartan. Platelet function was assessed at baseline and at 40 days by means of a PFA-100 analyzer using epinephrine (EPI) and ADP. Time to aperture occlusion, closure time (CT),was recorded in seconds. Additionally, clotting times, mean platelet volume (MPV), vWf:Ag and fibrinogen levels were assessed.

Results:
At baseline, platelet activity was determined(PFA CTEPI, PFA CTADP)with no statistically significant differences between groups. At reassessment, changes in both CT- PFAEPI and CT-PFAADP were found between groups(group 1: CT-PFAEPI = 138.9 ± 22.3 sec, group 2: CT-PFAEPI = 104.9 ± 22.9 sec, group 1: CT-PFAADP = 85.5 ± 18.6 sec and group 2: CT-PFAADP = 81.5 ± 11.9 sec). However, after checking the significance of these changes (δ)it was found that only CT-PFAEPI change (δ) difference between treatment groups reached statistical significance(group 2 vs subgroup 1: δCT-PFAEPI21.8 [95% CI (2.17 – 41.4)],p = 0,025, group 2 vs subgroup 2: δCT-PFAEPI20.7 [95% CI (1.09 – 40.3)], p = 0.035, subgroup 1 vs subgroup 2: δCT-PFAEPI 1.08[95% CI (-15.3 – 17.4)], p = NS). During follow-up, treatment with ARBs was associated with significant lowering of fibrinogen (from 341.7 ± 62.2 to 316.3 ± 61.8 mg/dl, p < 0.001),MPV levels (from 10.4 ± 0.91 to 8.8 ± 0.9fL, p < 0.001) and vWf:Ag (from 103.2 ± 6.7 to 93.8 ± 7.1)with no corresponding reductions in group 2. After multivariate analysis,CT-PFAEPI changes(δ)were significantly correlated only with ARBs(p < 0.001),irrespectively of specific drug.

Conclusions:
The present study indicates that treatment with ARBs contributes to downregulation of platelet activity in hypertension, suggesting that it could offer additional cardiovascular benefit in hypertensive patients.
DEVELOPING A MOST EQUIVALENT ALDOSTERONE MEASUREMENT TO LC-MS/MS BY A NOVEL HIGH-QUANTITATIVE NONCOMPETITIVE CHEMILUMINESCENCE IMMUNOASSAY
Authors: Satoh Fumitoshi , Ono Yoshikiyo , Tezuka Yuta , Omata Kei , Yamanami Hiroaki , Morimoto Ryo , Ito Sadayoshi 
Published: April 2021

Objective:
Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results even if measured by inaccurate radioimmunoassay, or we must accept high-cost LC/MS, and development of a more rapid and accurate substitute has been long hoped. We have developed a novel, fully-automated, high-quantitative noncompetitive chemiluminescence immunoassay (NC-CLEIA) for detecting aldosterone in serum and plasma, and its performance is evaluated as compared to LC/MS measurement.

Design and method:
Recently a unique anti-metatype antibody, which recognizes the immunocomplex of aldosterone and its monoclonal antibody, was established. Using this antibody for sensing permitted the construction of non-competitive assay for the detection of aldosterone. The reaction protocol of novel aldosterone assay is the following. In the 1st reaction, aldosterone in patient's sample is captured on anti-body coated magnetic particles. Alkaline phosphatase-conjugated anti-metatype antibody is added and incubated as 2nd reaction following a wash. Then substrate solution is added after washing immunocomplex. The resulting reaction signals are proportional to the amount of aldosterone in the sample allowing quantitative determination of in serum or plasma sample. The overall reaction is completed within 30 min.

Results:
Limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ) of our NC-CLEIA aldosterone assay were 0.09 ng/dL, 0.21 ng/dL and 0.57 ng/dL, respectively. NC-CLEIA aldosterone measurements were linearly well correlated with LC/MS aldosterone measurements (N = 130, y = 1.027x - 0.23 ng/dL, Spearman's p = 0.996, p < 0.0001). Bland-Altman plot analysis between NC-CLEIA and LC-MS/MS of aldosterone revealed a bias of 0.40 ng/dL with the limits of agreement of -4.60 and 5.41 ng/dL with 95% confidence interval.

Conclusions:
Our novel NC-CLEIA aldosterone assay was well-correlated and had only a very low bias with LC-MS/MS method and also was able to accurately quantify low level samples even in essential hypertension patients. This assay may be useful for the routine analysis of aldosterone and for the screening and diagnosis of PA from large number of hypertensive patients.
ASSESSMENT OF ANGIOTENSIN RECEPTOR BLOCKERS THERAPY WHEN ASSOCIATED TO MINERALOCORTICOID RECEPTOR ANTAGONISTS OR TO HYDROCHLOROTHIAZIDE ACCORDING CENTRAL HAEMODYNAMIC PARAMETERS
Authors: Paterno Carlos Alberto 
Published: April 2021

Objective:
OBJECTIVE: The goal of antihypertensive therapy is to prevent complications. The harmful effects of aldosterone are innumerable: induced cardiac/renal fibrosis, sodium and water retention, inflammation, oxidative stress, among others, that are involved in arterial/myocardium stiffness, remodelling, heart failure and new onset atrial fibrillation. Thiazide diuretics can activate the neurohormonal system, impair glucose metabolism, increase new-onset diabetes, and are potentially arrhythmogenic. Protective effect of Angiotensin Receptor Blockers (ARBs) on major cardiovascular events might be partly independent of the degree of blood pressure reduction. Mineralocorticoid Receptor Antagonists (MRAs) therapy reduce arterial stiffness, plasma volume, collagen/elastin ratio and vascular/myocardial fibrosis. The objective is to assess the levels reached in central haemodynamic parameters (CHPs) when thiazide is replaced by MRA, and associated with ARBs, during the treatment of hypertensive patients with normal kidney function.

Design and method:
DESIGN AND METHOD: For this cross-sectional retrospective study, data were registered from 70 hypertensive patients, female/male: 39/31 (average age: 66/62), while being treated with hydrochlorothiazide (Hctz) combined to ARBs, and after changing to MRAs+ARBs therapy in the same patients. The average dose of Hctz among female/male were 14/15 mg and the duration of the Hctz+ARB therapy were 35/34 months, while the MRA+ARB therapy were 13/14 months. The CHPs (Central Aortic Pressure, End-Systolic Pressure, Mean Arterial Pressure, Pulse Pressure, Augmentation Pressure, Augmentation Index) were measured by the SphygmoCor System PVX (AtCor-Medical, Australia), according system's standard methods. Also was measured the difference between the normal levels, and the observed values of Augmentation Index (Diff-AIx) according age.

Results:
RESULTS: The results of CHPs, Diff-AIx, systolic and diastolic blood pressure during association of ARBs+MRAs therapy compared to ARBs+Hctz, both genders, showed the lowest values with a highly statistically significant difference, except augmentation pressure and pulse pressure among male. No hyperkalaemia was observed in this sample.

Conclusions:
CONCLUSIONS: These findings suggest that the dual block with MRA+ARB therapy giving better central haemodynamic parameters, reducing the stress to arterial-ventricular coupling, it could be helpful to prevent, in the short- and long-term, the harmful effects of angiotensin-aldosterone system such as the development of heart failure and atrial fibrillation.
A NOVEL PATHWAY FOR ENDOCYTOSIS OF OXIDIZED LDL VIA AN ALLOSTERIC ACTIVATION OF THE ANGIOTENSIN II TYPE 1 RECEPTOR
Authors: Huang Yibin , Yamamoto Koichi , Rakugi Hiromi 
Published: April 2021

Objective:
Arrestin-dependent internalization of a G-protein-coupled receptor (GPCR) can intracellularly transport adjacent molecules. We previously proposed that a pattern recognition receptor (PRR), lectin-like oxidized LDL (oxLDL) receptor (LOX-1) physically interacts with the angiotensin II type 1 receptor (AT1) and the interaction mediates oxLDL-induced allosteric activation of AT1 and endothelial dysfunction. In this study, we analyzed direct downstream signaling pathways of AT1 by oxLDL, and investigated if the oxLDL-LOX-1 complex utilizes AT1-beta arrestin internalization to undergo endocytosis.

Design and method:
We used CHO-cells stably transfected with LOX-1 (CHO-LOX-1), AT1 (CHO-AT1), LOX-1 and AT1 (CHO-LOX-1-AT1), and LOX-1 and mutated AT1 that lacks ability to activate G protein or beta-arrestin pathway (CHO-LOX-1-mAT1). Activation of G(alpha)q and G(alpha)i were quantified by measuring the accumulation of IP1 and the inhibition of forskolin-induced cAMP production, respectively. Endocytosis of the oxLDL-LOX-1 complex through the AT1-beta-arrestin pathway was detected by an AT1-beta-arrestin BRET assay, real-time imaging of the membrane dynamics of LOX-1, and visualization of endocytosis of oxLDL. Endocytosis of oxLDL was assessed by the quantification of fluorescent intensity in cells with treatment and subsequent washout of Dil-labelled oxLDL.

Results:
Using genetically modified CHO cells, we found that oxLDL induced G(alpha)i-dependent inhibition of cAMP production only in the presence of both LOX-1 and AT1 with intact G protein binding. In contrast, oxLDL did not induce the accumulation of IP1, a downstream of G(alpha)q signaling, in CHO cells expressing both AT1 and LOX-1. The BRET signal between AT1-beta-arrestin was exerted by oxLDL only in the presence of LOX-1. Real-time imaging of cellular membrane revealed that oxLDL induced endocytosis of LOX-1 that depends on the intact beta-arrestin pathway of AT1. oxLDL accumulated in CHO cells expressing both LOX-1 and AT1 more prominently than those expressing LOX-1 or AT1 alone. This enhanced accumulation depended on the beta-arrestin-binding potency of AT1, and was abolished by dominant-negative or pharmacological inhibition of beta-arrestin. Accumulation of oxLDL was similarly attenuated by knockdown of AT1, beta-arrestin or LOX-1 in human vascular endothelial cells.

Conclusions:
oxLDL triggers selective G protein activation and beta-arrestin-dependent internalization of AT1 whereby the oxLDL-LOX-1 complex undergo endocytosis.
INFLUENCE OF ANTIHYPERTENSIVE TREATMENT ON RAAS PEPTIDES IN NEWLY DIAGNOSED HYPERTENSIVE PATIENTS
Authors: Vischer Annina , Kuster Gabriela , Twerenbold Raphael , Pfister Otmar , Zhou Qian , Villiger Andrea , Poglitsch Marko , Krähenbühl Stephan , Mayr Michael , Osswald Stefan , Haschke Manuel , Burkard Thilo 
Published: April 2021

Objective:
Recently, the influence of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) gained increasing attention, especially since concerns were raised regarding a potential influence of RAAS inhibitors on Corona Virus Disease 2019 (COVID-19). Our objective was to study the effect of recently initiated antihypertensive drugs on Angiotensin (Ang) II (1–8) and Ang (1–7) as markers of the pro-inflammatory ACE/Ang II/Ang Type 1 receptor (AT1R) axis and the counteractive ACE2/Ang (1–7)/Mas R axis in patients with newly diagnosed hypertension.

Design and method:
Randomized, open-label trial investigating RAAS peptide profiles after initiation of antihypertensive treatment with either perindopril, olmesartan, amlodipine, or hydrochlorothiazide. Ang II and Ang (1–7) concentrations were measured at 8am and 12am at day of treatment initiation and after four weeks of treatment.

Results:
80 patients were randomized in a 1:1:1:1 fashion. Between the four substances, we found significant differences for the concentrations of Ang II (p < 0.0005 for 8 and 12am) and Ang (1–7) (p = 0.019 for 8am and <0.0005 for 12am) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005) and amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001) (Figure panel A). Ang (1–7) was increased by perindopril and olmesartan (p = 0.008 and 0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317 and 0.109) (Figure panel B).

Conclusions:
Initiation of antihypertensive therapy causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptide shifts upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.
RESISTANT HYPERTENSION ON TREATMENT (RESHYPOT) TRIAL: SEQUENTIAL NEPHRON BLOCKADE COMPARED TO DUAL BLOCKADE OF THE RENIN- ANGIOTENSIN-ALDOSTERONE SYSTEM PLUS BISOPROLOL
Authors: Yugar-Toledo Juan Carlos , Cestari Elizabeth do Espirito Santo , Souza Maira Regina de , Rubio Tatiane de Azevedo , Mello Priscilla Galisteu de , Gonzales Elizangela Gianini , Uyemura Jéssia Rodrigues , Martin Luciana Nesves Cosenso , Tacito Lúcia Helena Buonalumi , J Heitor Moreno , Cunha Pedro , Vilela-Martin José Fernendo 
Published: April 2021

Objective:
Resistant hypertension (RHTN) is a clinical entity, difficult to manage. To identify the contribution of the volume as well as the renin activity from the maintenance of blood pressure levels could individualize the treatment.

Objectives
: To demonstrate the efficacy of therapy of sequential nephron blocking (SNB) in relation to the double blockade of the renin-angiotensin system associated with beta-blockers (DBRAS) in patients with RHTN with > 85%-adherence rate after 20 weeks of treatment.

Design and method:
A prospective study was conducted, open, randomized, parallel comparison between two regimens for RHT: SNB versus DBRAS. SNB consists in a progressive increase of sodium depletion with thiazide, followed by a blockade of mineralocorticoid receptor, followed by progressive doses of loop diuretics and finally blocking sodium channels. DBRAS consists in reinforcing the effect of angiotensin receptor blocker (ARB) with an angiotensin converting enzyme inhibitors (ACEI), followed by betablockers to decrease the renin secretion. Seventy-two patients were randomized (35 to SNB 13 M/22F and 37 to RASDB 14 M/23F) coming from the tertiary outpatient clinic (HB-FAMERP). We used the criteria of the Brazilian VII Guidelines for Hypertension and V Guidelines for ABPM and HBPM. The BP was monitored with the SpaceLabs 90207.

Results:
Baseline clinical characteristics and laboratory parameters of the 72 RHTM randomized to SNB (n = 35) or DBRAS (n = 37) were similar across both study groups. At the end of the study, a significant reduction of the office pressure was observed (SBP and DBP) in both post-intervention groups (SNB group: initial SBP: 174.5 ± 21.08; final SBP: 127.0 ± 14.74; Initial DBP: 105.3 ± 15.5, final DBP: 78.11 ± 9.28 (p < 0.0001), RAASDB group: initial SBP: 178.4 ± 21.08, final SBP: 134.4 ± 23.25, initial DBP: 102.7 ± 11.07, final DBP: 77.33 ± 13.75 (p < 0.0001). No discontinuation due drug-related adverse events in both study groups.

Conclusions:
SNB and DBRAS associated with the beta-blocker in RHTN patients with full adherence to the treatment showed excellent therapeutic efficacy. However, the SNB group disclosed a greater absolute reduction of central blood pressure values.
LONG-TERM EFFICACY AND SAFETY OF SPIRONOLACTONE IN THE TREATMENT OF RESISTANT ARTERIAL HYPERTENSION
Authors: Vaclavik Jan , Jelinek Libor , Jarkovsky Jiri , Benesova Klara , Ramik Zdenek , Kamasova Monika , Kocianova Eva , Vykoupil Karel 
Published: April 2021

Objective:
Spironolactone is recommended as a fourth line antihypertensive drug by current hypertension guidelines. However, data about its long-term efficacy and safety is limited.

Design and method:
We prospectively followed 274 patients with resistant arterial hypertension who started treatment with spironolactone between September 2007 and December 2016. Change of office and ambulatory blood pressure (BP) between baseline and the last clinical examination was recorded, as well as the duration of spironolactone use, its dose, changes of other antihypertensive medications, laboratory parameters and the incidence of adverse events.

Results:
Patients were followed for an average of 35 (± 29) months, the mean daily dose of spironolactone was 27.5 mg. Mean office BP decreased during follow-up from 149/87 mmHg to 136/80 mmHg by a mean 13/7 mmHg (P < 0.001 for both). Mean 24-hour, day-time and night-time ambulatory BP decreased by 12/6 mmHg, 11/6 mmHg and 14/9 mmHg respectively (P < 0.001 for all). Adverse effects occurred in 72 patients (26.3%) and in 61 (22.2%) lead to discontinuation of spironolactone. Adverse events occurred more frequently in patients using angiotensin receptor blockers (hazard ratio – HR 1.65, P = 0.040), in the elderly (HR 1.38, P = 0.007) and patients with higher baseline serum creatinine (HR 1.12, P = 0.035).

Conclusions:
Our data confirm good long-term antihypertensive efficacy of spironolactone in patients who tolerate it. However, in more than a quarter of patients the use of spironolactone leads to side effects, which usually necessitate its discontinuation.
ASSOCIATION OF HEMODYNAMIC AND NON-HEMODYNAMIC FACTORS WITH DIASTOLIC DYSFUNCTION IN PATIENTS WITH RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS
Authors: Manukyan Musheg , Falkovskaya Alla , Mordovin Victor , Zyubanova Irina , Pekarski Stanislav , Lichikaki Valeriya , Ryabova Tamara , Gusakova Anna 
Published: April 2021

Objective:
To identify factors associated with the development of diastolic dysfunction in diabetic patients with resistant hypertension (RHTN).

Design and method:
The study included 36 patients with RHTN and type 2 diabetes mellitus (DM) (mean age 61,4 ± 6,4 years, 14 men, mean 24-hour (24 h) blood pressure (BP) (systolic/diastolic) 158,6 ± 15,2/79,8 ± 12,7mmHg, mean HbA1c 7,2 ± 1,2%). Office BP, and 24 h ambulatory BP measurements (ABPM), renal Doppler ultrasound, tissue doppler echocardiography, lab tests (24 h urine volume, the plasma levels of metalloproteinases-9 (MMP-9)) were performed in all patients.

Results:
Average E/e‘ significantly correlated with the duration of diabetes (p = 0.005, R = 0.46), the level of daytime (p = 0.003, R = 0.48), nighttime (p = 0.007, R = 0.44 and average daily (p = 0.037, R = 0.35) pulse BP; the level of MMP- 9 (p = 0.016, R = 0.47), with renal resistive indices (RI) in the main renal arteries: right-sided R = 0.37, p = 0.034, left-sided R = 0.38, p = 0.029; in the segmental arteries - on the right R = 0.41, p = 0.020 and R = 0.35, p = 0.048 on the left. In a multiple regression analysis, average E / e ’ significantly correlated with nighttime pulse BP (b ∗ = 0.42; SE (b) = 0.041; p = 0.004), MMP -9 (b ∗ = - 0.47; SE (b) = 0.001; p = 0.002), 24 h urine volume (b ∗ = - 0.47; SE (b) = 0.001; p = 0.001). Final model R = 0.81, R2 = 0.65, adjusted R2 = 0.61, estimate standard error = 2.56, p = 0.00004. Residuals did not differ from the normal distribution (p = 0.09)

Conclusions:
Diastolic dysfunction in diabetic patients with RHTN depends from complex of hemodynamic and non-hemodynamic factors, including duration of DM, value both of pulse BP, MMP and 24 h urine volume, as well of renal resistive indexes.
HIGH RENAL RESISTANCE INDICES AND HIGH PULSE PRESSURE MAY LIMIT NEPHROPROTECTIVE EFFICACY OF RENAL DENERVATION IN PATIENTS WITH RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS
Authors: Falkovskaya Alla , Mordovin V. , Pekarskiy S. , Manukyan M. , Zyubanova I. , Lichikaki V. , Ryabova T. , Baev A. , Shelemehov A. , Vtorushina A. , Moiseeva A. , Caraus A. 
Published: April 2021

Objective:
The combination of diabetes mellitus (DM) and resistant hypertension (RHTN) is associated with an increased risk of development and progression of chronic kidney disease (CKD). It has been shown that renal denervation have nephroprotective efficacy by slowing the decline in renal function in some patients. The aim of the study was to identify factors limiting the nephroprotective effect of renal denervation in patients with RHTN and DM.

Design and method:
Twenty seven patients with RHTN and type 2 DM were included in single-arm prospective interventional study (protocol number NCT01499810 on ClinicalTrial.gov) (mean age 61.6 ± 7.3 years, mean office (systolic/diastolic) blood pressure (BP) 171.8 ± 21.9/87.7 ± 17.7mmHg, mean eGFR 72.1 ± 19.9 ml/min/1.73 m2, HbA1c 6.3 ± 1.1%, 7 patients (26%) with stage 3 CKD, 8 men). All patients were underwent to ambulatory 24-hour BP, renal Doppler ultrasound and assessment of eGFR (CKD-EPI formula) at baseline and 3 years follow-up. The patients were advised not to change their medication regimen during the study. Nineteen patients completed 3 years of follow-up. The renal outcomes were 1) a decrease in eGFR =  > 30% from baseline; 2) decrease in eGFR > 5 ml/min/1.73 m2/year; 3) their combination.

Results:
There was a significant decrease in mean 24-hour BP (SBP/DBP) (-14.3 ± 20.6 / -7.7 ± 10.6 mmHg, P = 0.02 /0.04). Six patients (32%) had renal outcomes at 3 years follow-up (5 pts (26%) with both outcomes, 5 patients (26%) had a decrease in eGFR = > 30% from baseline and 5 patients had a decrease in eGFR > 5 mL/min/1.73 m2/year). At baseline, patients with renal outcomes compared with patients without them had higher values of both 24-hour pulse BP (90.3 ± 7.1 vs 73.1 ± 12.5 mmHg, p = 0.007) and its variability (15.6 ± 2.6 versus 11.7 ± 3.0 mmHg, p = 0.01), as well as a higher mean value of renal resistive indices (RI) (RI in the trunk 0.79 ± 0.04 vs0.71 ± 0.06, p = 0.007; RI in segmental arteries 0.75 ± 0.08 vs 0.66 ± 0.08, p = 0.04).

Conclusions:
Our data indicate that a high value of pulse blood pressure and its variability, as well as high indices of renal resistance, can limit the nephroprotective efficacy of renal denervation, possibly due to chronic intrarenal barotrauma and irreversible changes in the kidneys.