bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANTIHYPERTENSIVE EFFECTS AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH MODERATE KIDNEY DYSFUNCTION
Authors: Ito Sadayoshi , Itoh Hiroshi , Rakugi Hiromi , Okuda Yasuyuki , Iijima Setsuko 
Published: April 2021

Objective:
Mineralocorticoid receptor blockers (MRB) adding to renin–angiotensin system (RAS) inhibitors should be an effective treatment option for the strict blood pressure (BP) control of the hypertensive patients with moderate kidney dysfunction. Esaxerenone is a novel, first non-steroidal MRB with a dose-dependent antihypertensive effect and renal protective potential. We investigated the efficacy and safety of esaxerenone in Japanese hypertensive patients with moderate kidney dysfunction.

Design and method:
Two multicenter, open-label, non-randomized, dose-escalation studies were conducted to assess the efficacy and safety of esaxerenone monotherapy and add-on therapy to RAS inhibitor. Esaxerenone therapy started from 1.25 mg/day, titrated to 5 mg/day and continued until 12 weeks. Primary endpoint was change from baseline in sitting BP. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also evaluated.

Results:
Of 91 patients, 33 received monotherapy and 58 received add-on therapy; mean baseline estimated glomerular filtration rates were 52 and 51 mL/min/1.73m2, respectively. The esaxerenone dose was increased to 2.5 mg/day and above in 100% (n = 33) and 93% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. After the initiation of treatment, significant reduction in sitting SBP/DBP at the end of treatment was observed in both studies (monotherapy: 19/9 mmHg; add-on therapy: 18/8 mmHg; both P < 0.001); 64% and 48% of patients achieved target blood pressure (<140/90 mmHg). The antihypertensive effects were consistent across patient subgroups by age, BMI, and eGFR. The UACR decreased significantly from baseline to Week 12: by 26% in the monotherapy study (P < 0.01) and 29% in the add-on therapy study (P < 0.001). An increased serum K+ level of 5.5 mEq/L and above occurred in 7 patients (12%) receiving add-on therapy, but in none receiving monotherapy. All increases in serum K+ were transient and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment due to kidney function decline.

Conclusions:
Esaxerenone demonstrated sufficient antihypertensive effects and was well tolerated in hypertensive patients with moderate kidney dysfunction, both as monotherapy and add-on therapy to a RAS inhibitor.
AGE-SPECIFIC ACUTE CHANGES IN CAROTID-FEMORAL PULSE WAVE VELOCITY DURING HEAD-UP TILTING
Authors: Pucci Giacomo , Avolio Alberto , Spronk Bart , Tap Lisanne , Vaudo Gaetano , Anastasio Fabio , Van De Meiracker Anton , Mattace-Raso Francesco 
Published: April 2021

Objective:
Hydrostatic blood pressure (BP) gradient following changes in body posture may generate concomitant, age-dependent, increases in aortic stiffness. We analyzed the relationship between BP gradient, measured during head-up body tilting, and related changes in carotid-femoral pulse wave velocity (cf-PWV) at different age ranges, with the aim to separate the BP-dependent and BP-independent components of cf-PWV.

Design and method:
cf-PWV and other hemodynamic parameters were measured in 30 healthy individuals during head-up tilting at 0°, 30° and 60°. BP was taken at the upper arm, constantly kept at heart level. Aortic BP was reconstructed from radial tonometry (SphygmoCor). Stiffness index β0 was estimated at 0° (Spronck et al, J Hypertens 2017;35:98–104). We assumed that: from MRI studies (Sugawara et al, Am J Hypertens. 2016;29:1237–1244), the effective cf-PWV travel distance (ETD, 80% of straight carotid-to-femoral distance) begins at heart level; the change in DBP along the aorta is predictable from the hydrostatic pressure gradient (0.73 mmHg/cm, Gavish et al, J Hypertens. 2011;29:2099–2104); cf-PWV and hydrostatic pressure relate linearly, hence predicted cf-PWV can be calculated as the average of aortic (using β0 and aortic DBP) and femoral (using β0 and femoral DBP, corresponding to aortic DBP + (ETD x sin(α)∗0.73)) PWVs.

Results:
cf-PWV and peripheral SBP increases during head-up body tilting were different between age groups, being more pronounced in the “old” (>45 years) vs “young” group (both p for interaction <0.05), whereas both central and peripheral DBP changes were not influenced by age (Figure, panel left). Central SBP was not affected by tilt angles. When cf-PWV gradient measured by applanation tonometry (observed), was compared with that predicted from estimated DBP gradient (predicted), the difference in observed-vs-predicted PWV gradient increased non-linearly as a function of age (R2 for quadratic trend=0.38, p < 0.01, p vs linear=0.04, Figure panel right).

Conclusions:
Under a hydrostatic pressor gradient, the pulse wave travelling along the aorta undergoes positive acceleration which, for any given pressor change, increases non-linearly as a function of age. The evaluation of aortic pulse wave acceleration induced by pressor gradient may be of clinical relevance as a marker of vascular ageing.
A HIGH ALDOSTERONE TO RENIN RATIO MEDIATES MICROVASCULAR AND MACROVASCULAR DAMAGE IN NEWLY-DIAGNOSED, TREATMENT-NAÏVE ESSENTIAL HYPERTENSION
Authors: Mahmud Azra , Barhoumi Tlili , Aklabi Ali A. , Feely(Late) John , Silke Bernard 
Published: April 2021

Objective:
The role of aldosterone in hypertension was generally considered in the context of primary hyperaldosteronism, an uncommon condition (less than 2% in the hypertensive population). However, based on an increased ambulant aldosterone-to-renin ratio (ARR), a marker of inappropriate aldosterone activity, the prevalence of primary hyperaldosteronism in the hypertensive population may be as high as 10% to 15%. There is increasing evidence to suggest a BP-independent effect of aldosterone on left ventricular structure, increased collagen deposition with fibrosis, diastolic dysfunction and arterial stiffness. We hypothesized that aldosterone and renin will be associated with microvascular and macrovascular alterations in never treated essential hypertension.

Design and method:
We prospectively studied newly diagnosed, untreated essential hypertensive and normotensive subjects (n = 1482, 47% females, mean age 51 ± 0.77, SEM). Pulse wave velocity (PWV), augmentation index (AIx), aortic systolic BP and pulse pressure amplification were measured with applanation tonometry(SphygmoCor). Albumin-creatinine ratio, urine sodium and potassium concentrations were determined from spot urine samples. Laboratory tests included serum creatinine and clearance, plasma renin activity, serum aldosterone, and high-sensitivity C-reactive protein(hs-CRP). Aldosterone to renin ratio(ARR) was divided into tertiles. Results were analysed using JMP Pro(Version 13, SAS for Windows). The patients gave informed consent and the study had Institutional ethics committee permission.

Results:
The top ARR tertile was associated with the highest levels of brachial BP, aortic systolic BP, AIx, pulse pressure amplification and PWV(P < 0.001 for all). Stepwise regression analysis showed that the positive association between PWV and increasing ARR tertiles remained significant after adjustment for BP, age and other potential confounders(R2 = 0.39, p < 0.05). The top ARR tertile was also associated with high potassium and low sodium urinary excretion, high ACR, low creatinine clearance and high hs-CRP (All p < 0.01).

Conclusions:
In untreated hypertensive subjects with mild to moderate hypertension, there are significant interactions between ARR and indices of microvascular and macrovascular damage. Our findings indicate that aldosterone and renin adversely modulate microvascular and macrovascular function very early in the evolution of hypertension. While aldosterone antagonism is recommended currently for treatment-resistant hypertension, our findings suggest that it should be initiated early in hypertension.
KEEP THE FIRST READING: AN ARGUMENT FOR THE IMPORTANCE OF THE FIRST OFFICE BLOOD PRESSURE READING IN CHILDREN
Authors: Myette Robert , Feber Janusz 
Published: April 2021

Objective:
Lately, clinicians are using oscillometric devices with repeated blood pressure (BP) measurements (on the same occasion) to diagnose hypertension in children. It is unclear which of these measurements, or which combination of measurements, is the most predictive of ambulatory hypertension. Our objective was to determine which measurements of office BP correlate best with the 24-hour automated BP (ABPM).

Design and method:
We consecutively enrolled all pediatric patients, aged 1–18 years, who underwent ABPM in the last 3 years at The Children's Hospital of Eastern Ontario; all patients also had 3 consecutive oscillometric office blood pressure readings at the same time. We compared the first, second, and third and the average of all three measurements as well as the average of the last 2 readings with daytime BP from ABPM. All BP readings were converted to Z-scores based on published, normative paediatric data for office and ABPM.

Results:
Two-hundred and forty-five children (male=133) were included in the study. The median [IQR] of first, second and third systolic BP Z-scores (SBPz) were 2.29[1.44,3.21], 1.91[1.13,2.72] and 1.65[0.82, 2.47], respectively, and all were significantly different from one another (p < 0.001). The largest difference/effect size was noted between the first and third measurement of SBPz (Cohen-d 0.51). Similar differences were observed in diastolic blood pressure Z-scores (DBPz), with medians [IQR] of 0.97[0.00, 1.87], 0.77[-0.19, 1.75] and 0.55[-0.37, 1.54] respectively (p < 0.001, Cohen-d between first and third reading 0.32). On multivariate analysis, the only significant predictor of systolic daytime BP was the first office systolic BP reading (p = 0.001, relative importance 43%). Similarly, the only significant predictor of diastolic daytime BP was the first office diastolic BP reading (p < 0.001, relative importance 43%). The first office SBPz and DBPz were also the best predictors of daytime systolic (ABPM SBPz > 1.65) and diastolic (ABPM DBPz > 1.65) hypertension on ROC with area under the curve (AUC) analysis (SBPz AUC = 0.69, DBPz AUC = 0.81).

Conclusions:
We observed significant differences between first, second and third office BP measurements. The first office systolic and diastolic BP readings appear to be the best predictors of ABPM daytime systolic and diastolic BP.
HYPERTENSION PHENOTYPES IN YOUNG INDIVIDUALS DEFINED BY OFFICE, AMBULATORY AND HOME BLOOD PRESSURE MEASUREMENT: PREVALENCE AND ASSOCIATION WITH TARGET ORGAN DAMAGE
Authors: Zeniodi Maria Elena , Ntineri Angeliki , Kollias Anastasios , Servos George , Moyssakis Ioannis , Destounis Antonios , Vazeou Andriani , Stergiou George 
Published: April 2021

Objective:
To assess the prevalence of hypertension phenotypes in young individuals defined by combined use of office (OBP), ambulatory (ABP), and home blood pressure (HBP) measurements and their association with target organ damage.

Design and method:
Subjects referred for suspected hypertension and healthy volunteers aged 6-25 years were evaluated with OBP (2–3 visits), 7-day HBP and 24 h ABP monitoring and classified as normotensives (NT), white-coat (WC), masked (MH) and sustained hypertensives (SH). Organ damage was assessed by echocardiographic left ventricular mass index (LVMI), carotid ultrasonography (intima-media thickness [IMT]) and pulse wave velocity (PWV; piezo-electronic principle).

Results:
233 individuals were included (mean age 14.1 ± 4.0 years, 72% males, BMI 23.8 ± 4.6 kg/m2, 31.8% children, 53.2% adolescents, 15% young adults) of whom 189 had LVMI, 123 IMT and 73 PWV measurements. NT/WC/MH/SH were diagnosed in 60.5/14.2/9.9/15.5% of the participants with HBP and 57.9/14.2/12.4/15.5% with ABP (84.9% agreement, kappa 0.74). HBP and ABP gave comparable stratification for preclinical target organ damage according to BP phenotypes, with SH having higher LVMI and PWV than NT (P < 0.01) and a similar trend for IMT (P = 0.07) (Figure).

Conclusions:
HBP and ABP identified similar proportions of BP phenotypes among young individuals. More importantly, SH identified by both methods was associated with more severe organ damage than NT.
GLUCO- AND MINERALOCORTICOIDS SYNERGISTICALLY DOWNREGULATE BKCA CHANNEL TRANSCRIPTION IN VASCULAR SMOOTH MUSCLE CELLS BUT DO NOT AFFECT THE EPOXYEICOSATRIENOIC ACID PATHWAY
Authors: Schneider Holger , Fruehbuss Laura , Sun Jing , Meng Yao , Marques Jair Gonzales , Koletzko Berthold , Schnitzler Michael Mederos Y. , Gudermann Thomas , Beuschlein Felix , Williams Tracy Ann , Reincke Martin 
Published: April 2021

Objective:
A major driver of cardiovascular morbidity and mortality in primary aldosteronism (PA) is endothelial dysfunction. Endothelial dysfunction in PA is well established, but the precise mechanism underlying this phenomenon is incompletely investigated. Specifically, the cytochrome P450 monoxygenase (CYP)-dependent epoxyeicosatrienoic (EET) acid pathway has not been studied comprehensively. Promiscuity of mineralocorticoid receptors due to activation by glucocorticoids further complicates understanding of mechanisms.

Design and method:
Primary human coronary artery smooth muscle and endothelial cells were challenged with aldosterone concentrations typically found in primary aldosteronism (1 nM) in a background of physiological cortisol levels (140 nM). In both cell types, we analysed expression levels of transcripts which are vital for the generation and inactivation of EETs as well as their proposed mode of action. Smooth muscle cell responses to EETs were assessed by calcium imaging with Fura2. Release of EETs by aldosterone and cortisol-treated endothelial cells were measured by high-pressure liquid chromatography followed by tandem mass spectrometry.

Results:
Glucocorticoids and mineralocorticoids synergistically reduced BKCa potassium channel transcription in smooth muscle cells. Antagonist studies demonstrated that this effect was predominantly related to glucocorticoid receptor stimulation. The aldosterone-mediated decrease in BKCa mRNA levels was not reflected at the protein level. In line with preserved BKCa protein expression, aldosterone treatment did not affect the calcium response of smooth muscle cells to 14,15 EET stimulation. Endothelial cells challenged with aldosterone showed unchanged mRNA levels of the CYP monoxygenases and epoxide hydrolases, which are relevant for the synthesis and degradation of EETs, respectively. Mass spectrometry of supernatants from acetylcholine-stimulated endothelial cells did not reveal significant differences in concentrations of any of the 4 EET regioisomeres or their respective degradation products (dihydroxyeicosatrienoic acids).

Conclusions:
In endothelial dysfunction related to mineralocorticoid excess, targeting the EET pathway may be a promising therapeutic approach because all constituents of EET signalling appear to be expressed and functionally intact. Soluble epoxide hydrolase inhibition may thus represent a feasible specific therapy of endothelial dysfunction in PA. The effects of glucocorticoids on BKCa channel expression warrant further investigation under conditions such as glucocorticoid co-secretion in PA and Cushing syndrome.
DISTRIBUTION OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BIOMARKERS IN TREATED HYPERTENSIVE INDIVIDUALS FROM THE GENERAL POPULATION: THE CHRIS STUDY
Authors: Foco Luisa , Poglitsch Marko , Gögele Martin , Pramstaller Peter Paul , Pattaro Cristian 
Published: April 2021

Objective:
Renin-Angiotensin-Aldosterone System (RAAS) is a critical target in hypertension management. However, direct quantification of angiotensin I (AngI) and II (AngII) is challenging due to compound instability, and was never attempted in large population-based cohorts before. Recently, a novel high throughput approach for molecular profiling of the circulating RAAS became available. We aimed at assessing AngI, AngII and aldosterone's distributions in individuals under anti-hypertensive drugs (AHDs) in a real-world setting.

Design and method:
We selected 500 participants under AHDs and 300 controls from the Cooperative Health Research in South Tyrol (CHRIS) study, a population-based study from an Alpine rural environment, defining age- and sex-matched groups (N = 100 each). Five groups included individuals under AHDs: (i) plain AngI-converting enzyme inhibitor (ACEi); (ii) ACEi+diuretic; (iii) plain AngII type 1 receptor blocker (ARB); (iv) ARB+diuretic; and (v) plain beta-blocker. Three were control groups: (vi) hypertensive without medication (vii) under non-AHDs, (viii) normotensive. Using RAAS Triple-A testing, a novel liquid chromatography combined with tandem mass spectrometry analysis, we simultaneously quantified aldosterone and equilibrium AngI and AngII, and used them to estimate markers of plasma renin activity (PRA-S pmol/L), ace-activity (ACE-S, [pmol/L]/[pmol/L]) and adrenal function (AA2-Ratio, [pmol/L]/[pmol/L]).

Results:
An evaluation of the first 240 analysed samples revealed specific molecular effects of AHDs, proving the performance of the approach. ACEi and ARB result in compensatory renin up-regulation: PRA-S median (interquartile range) was 54.6 (29.6–86.6) in the pooled controls, 77.4 (49.7–186.4) in ACEi, and 154.6 (55.2–600.4) in ARB (Kruskal-Wallis test p = 0.0001). Using ACEi was associated with suppression of ACE-S, whose median was 5.0 (4.2–6.4) in the pooled controls and 0.3 (0.1–0.6) in ACEi (p < 0.0001). Using ARBs resulted in AA2-Ratio suppression, with a median of 2.3 (1.4–3.9) and 0.7 (0.2–1.7) in the no-medication and ARB groups (p = 0.0001). Combining ACEi or ARB with diuretics was associated with further increase of PRA-S. Data did not support the hypothesis of different aldosterone levels (median = 101.7 pmol/L pooled sample) across groups (p = 0.179).

Conclusions:
Results point to a potential application of angiotensin-based biomarkers in class-specific drug monitoring, and will be further evaluated in the context of personalized treatment and therapeutic biomarkers.
ANGIOTENSIN AT2 RECEPTORS IN THE NUCLEUS OF THE SOLITARY TRACT REDUCE BLOOD PRESSURE VIA INHIBITION OF GABA SIGNALING
Authors: Mohammed Mazher , Sumners Colin , Johnson Dominique , Scott Karen , Krause Eric , De Kloet Annette , Elsaafien Khalid 
Published: April 2021

Objective:
Sustained CNS administration of angiotensin AT2 receptor (AT2R) agonists lowers blood pressure (BP) in normal and hypertensive rodents, but the location(s) and mechanism(s) of action are unknown. One locus may be the intermediate solitary tract nucleus (intNTS), which contains a high density of AT2R located on GABA neurons, and it is well-known that increased GABA signaling in the intNTS contributes to increased BP and hypertension. Our studies have revealed that reductions in BP (∼8 mmHg) induced by 2-week intracerebroventricular (icv) infusion of the AT2R agonist C21 (7.5 ng/kg/h) in normotensive mice is associated with significant decreases in gene expression of GABA synthetic enzymes (GAD-1 & GAD-2) in the intNTS. From this, we developed the hypothesis that the depressor action of C21 is mediated through AT2R located on intNTS GABA neurons and a reduction of GABA signaling.

Design and method:
To test this, we engineered a novel mouse line that has Cre-recombinase expression directed to the AT2R gene (AT2R-Cre), and demonstrated that Cre recombinase activity mirrors AT2R mRNA expression within the NTS. Next, we used the Cre-LoxP system and virally (AAV)-mediated gene transfer to direct expression of the light-sensitive excitatory opsin channelrhodopsin-2 (ChR2) and/or eYFP specifically to neurons in the NTS that synthesize AT2R. Using these mice, we performed cardiovascular recordings during optogenetic manipulations (blue light) that selectively excite AT2R-expressing neurons in the intNTS.

Results:
These studies revealed that: (i) Optogenetic stimulation of the AT2R intNTS neurons expressing ChR2 in isoflurane anesthetized mice elicited significant increases in BP compared with control mice that express only eYFP; (ii) The AT2R-containing neurons that were activated by blue light stimulation are GABAergic, as indicated by increased expression and co-localization of c-Fos mRNA with GAD-1 mRNA and eYFP; (iii) Chronic icv infusion of C21 as above significantly blunted the light-induced increases in BP, an effect that was present across all patterns of optical stimulation.

Conclusions:
Collectively, these data indicate that AT2R-mediated decreases in BP involve a blunting of GABA signaling in the intNTS, and suggest that neurons expressing AT2R at this site may be an access point for cardiovascular control.
PREVALENCE AND PREDICTORS OF HYPOTENSION IN NURSING HOME RESIDENTS UNDERGOING AMBULATORY BLOOD PRESSURE MONITORING
Authors: Rivasi Giulia , Tortu’ Virginia , D’Andria Maria Flora , Turrin Giada , Giuliani Evelina , Ceolin Ludovica , Rafanelli Martina , Mossello Enrico , Ungar Andrea 
Published: April 2021

Objective:
In nursing home (NH) residents, hypotension may predispose to adverse events including falls, fractures and mortality. Yet, evidence on hypotension detected by ambulatory blood pressure monitoring (ABPM) is scarce in this setting. This study aimed to determine the prevalence and the clinical predictors of ambulatory hypotension in NH residents and to analyze its related ABPM profile.

Design and method:
We retrospectively analysed data from a sample of 100 NH residents undergoing a comprehensive geriatric assessment and ABPM. Ambulatory hypotension was defined as a systolic blood pressure (SBP) drop of 20 mmHg or greater between two consecutive measurements to a minimum SBP < 100 mmHg. Participants with nocturnal hypotension were excluded from the analysis. Predictors of ambulatory hypotension were investigated using multivariate logistic regression adjusted for comorbidities, functional status and hypotensive medications.

Results:
Among 91 residents (mean age 83, 56% female), 50 showed ambulatory hypotension. They had a higher prevalence of heart failure (p = 0.02) and atrial fibrillation (p = 0.007) and more commonly received digoxin (p = 0.001) and benzodiazepines (p = 0.015). At ABPM they had lower 24 h, daytime and nighttime SBP (p < 0.001) and more frequently showed a white coat effect (p < 0.001) and a reverse-dipping profile (p = 0.013). At multivariate analysis, benzodiazepines (OR 4.040), digoxin (OR 19.987) and creatinine  < 1 mg/dl (OR 3.939) were independently associated with ambulatory hypotension.

Conclusions:
Hypotension is common in NH residents undergoing ABPM and more frequently occurs in subjects with lower ambulatory SBP, a reverse dipping profile and a white coat effect. Benzodiazepines, digoxin and low creatinine are predictors of ambulatory hypotension in NH residents.