bluuebunny/crossref_metadata_2025_split huggingface dataset:
SYSTOLIC BLOOD PRESSURE AT BIRTH: THE IMPACT OF MOTHEŔS OBESITY
Authors: Alvarez Julio , Torro Maria Isabel , Redon Pau , Aguilar Francisco , Redon Josep , Lurbe Empar 
Published: April 2021

Objective:
Rates of overweight and obesity are high in the obstetric population, and this is of particular importance because being overweight prior to pregnancy increases, among others, the risk for infants being large for gestational age. The impact of motheŕs weight condition on BP at birth has not been previously analyzed.

Design and method:
Three hundred and twenty one newborns (160 females) born at term (gestational age > 36 weeks) after uncomplicated pregnancies and in the absence of perinatal illness were included. Subjects were divided according to size at birth in small, appropriate, and large for gestational age. Anthropometric parameters were obtained at birth and BP was measured on the second day of life. Motheŕs characteristics were obtained.

Results:
Among mother's characteristics were: age (mean age 32.0 ± 4.6 years), smoking habits (no smokers 70.7%, heavy smokers 4.6%) weight gain during pregnancy (mean 12.8 ± 5.9 kg) and normal weight, overweight and obese (32.4%, 28%, 39.6% respectively). Subjects according to size at birth were small, appropriate, and large for gestational age, 6.9%, 74.5% and 18.6%, respectively. Motheŕs weight was positively related with birth weight (r = 0.212, p < 0.001), length (r = 0.132, p = 0.03) and head circumference (r = 0.194, p = 0.01). Likewise, a positive relationship between SBP and birth weight (r = 0.43, p < 0.001), and SBP with motheŕs weight (r 0.22, <0.001), were observed. When gestational age, sex, length, head circumference and motheŕs characteristics were considered, birth weight was the main and positive determinant of SBP at birth. In addition, motheŕs weight condition assessed by BMI (kg/m2) was also an independent determinant. The concurrent influence of both birth weight and motherś BMI is shown in the table.

Conclusions:
Systolic BP at birth depends of birth weight and motheŕs weight categories. The increment on the prevalence of obesity before pregnancy may contribute to future BP elevation in the offspring.
METHODS TO RECTIFY DISCREPANCIES WITH ADULT BLOOD PRESSURE GUIDELINES
Authors: Larkins Nicholas , Mori Trevor , Choong Cathy , Schlaich Markus , Beilin Laurence 
Published: April 2021

Objective:
The American Academy of Pediatrics (AAP) guidelines for screening and managing high blood pressure (BP) for children and adolescents are commonly used for Australian children. These were updated in 2017 to remain consistent with recommendations for adults in the United States (hypertension defined as >=130/80mmHg), which differ from guidelines for Australian adults (>=140/90mmHg). We sought to investigate the applicability of the AAP guidelines to define BP thresholds for Australian children.

Design and method:
The West Australian Pregnancy Cohort (Raine) Study has followed since birth a cohort of 2868 children born between 1989–1991. BP was measured at 3/5/8/10/14/17 years, in the seated position after 5 minutes rest, using an oscillometric sphygmomanometer (Dinamap™). Three readings were taken every 2 minutes until the 10-year visit, and subsequently 6 readings every 2 minutes, with the first measurement discarded and mean of following results calculated to give the BP value. Centile curves were constructed by the LMS method, adjusted for height and stratified by sex, and then compared to the published AAP centile curves. In this analysis we focus on systolic BP (SBP).

Results:
2202 participants were included, contributing 7850 observations (1127 males, 51.2%). The 95th SBP centile according to the fitted curves for a child on the 50th height centile are displayed in Fig. 1, along with equivalent AAP curves. The fitted were higher than the AAP curves for both sexes in early and mid-childhood, before converging in adolescence for females but not males in whom the fitted curve approached 140mmHg at 18 years. Comparing absolute BP thresholds, 13.5% of children had an SBP >=130mmHg between 14 and 18 years of age, but only 3.0% had an SBP >=140mmHg.

Conclusions:
Using data from Australian children and adolescents to define the threshold for hypertension led to curves more congruous with current Australian adult hypertension guidelines. Sex stratification better represents physiologic changes in BP, but again leads to inconsistencies between paediatric and adult guidelines. A better method would be to develop net-benefit or risk-based guidelines based on future clinical events or phenotypes, which we aim to do in future work.
TRENDS IN OFFICE AND AMBULATORY BP ACROSS PEDIATRIC AGE
Authors: Lurbe Empar , Alvarez Julio , Torro Maria Isabel , Redon Josep , Aguilar Francisco , Redon Pau 
Published: April 2021

Objective:
ABPM is gaining ground in the assessment of BP in children and adolescents, becoming an aid for diagnosis and management of HTN. The 24-hours ABPM values obtained have generally been higher than those of their office BP counterparts, however the differences across the pediatric age have not been analyzed. The objective of the present study was to assess trends in office and 24-hours in children and adolescents.

Design and method:
Two thousand two hundred and sixty-four BP assessments (office and 24h-ABPM) were performed in 778 Caucasians youth of both sexes (387 females), of European origin, from 5 to 18 years of age (mean age 10.9 3.3 years) in the absence of antihypertensive treatment. Office BP was measured in the non-dominant arm and the three measurements were averaged for analysis. The same day, 24h-ABPM was performed and the averages of the valid readings for 24 h, daytime and nighttime, respectively, were calculated. Differences in trends of office and 24-hours ABPM, according to age and sex were analyzed using the slope of the regression lines.

Results:
Total ABPM measurements were 72+/- 14. Overall 24-hour SBP was higher than the office counterparts, however the magnitude of the differences changes according to age and sex (figure). In girls, the gap between office SBP and 24-hour SBP slightly reduces over the years, in contrast in boys the gap disappears at 15 years and thereafter. The slope of the regression lines was not significant in girls (ß 0.736 0.078 vs 1.199 0.284) while achieving statistically significance in boys (ß 0.395 0.0022 vs 0.759 0.062).

Conclusions:
Differences in trends between office and ABPM are observed across age in both sexes. The reasons that fully explain this, need to be clarified. Disparities in trends may impact on the diagnosis of white-coat and masked HTN.
ACE2 AND ANGIOTENSIN-(1-7) AND ALDOSTERONE BIOSYNTHESIS IN HUMAN ADRENOCORTICAL TISSUES
Authors: Caroccia Brasilina , Vanderriele Paul -Emmanuel , Seccia Teresa Maria , Piazza Maria , Lenzini Livia , Prisco Selene , Torressan Francesca , Domening Oliver , Poglitsch Marko , Iacobone Maurizio , Rossi Gian Paolo 
Published: April 2021

Objective:
The angiotensin converting enzyme 2 (ACE2) and its product angiotensin-(1–7) (Ang-(1–7)) were suggested to play cardiovascular protective effects via angiotensin type 2 (AT2R), MasR and alamandine receptors. Whether this involves blunting of aldosterone biosynthesis in humans remains unknown.

Design and method:
We quantified ACE2 mRNA in human aldosterone-producing adenoma (APA) and APA-adjacent tissue obtained ex vivo from primary aldosteronism (PA) patients with real-time and ddPCR. We also investigated the effects of Ang-(1–7) and diminazene aceturate (DIZE), a putative ACE2 activator, on aldosterone synthase (CYP11B2) and 11b-hydroxylase (CYP11B1) as proxy for aldosterone and cortisol secretion, respectively, in the absence and presence of the AT1R antagonist irbesartan, or the MasR antagonist A779.

Results:
We detected ACE2 mRNA at higher amounts in APA-adjacent tissue than in APA. Functional in vitro studies with LC-MS showed active conversion of Ang II into Ang 1–7, albeit at low level, through ACE-2-independent mechanisms. At [10–8 M] Ang-(1–7) did not affect CYP11B1 and CYP11B2 gene transcripts, while at high concentration [10–6 M] it increased both mRNAs (p < 0.001 vs vehicle) through an AT1-R-mediated mechanism as these stimulatory effects were abolished by irbesartan. To investigate if Ang-(1–7) could blunt aldosterone production when CYP11B2 is upregulated, we exposed H295 cells to [10–8 M] Ang II and found that Ang-(1–7) did not blunt Ang II-induced expression of CYP11B1 and CYP11B2 mRNA. Moreover, we discovered that [10–7 M] DIZE increased ACE2 mRNA by 1.5 fold from baseline (p = 0.01) but left CYP11B1 or CYP11B2 mRNA levels unaffected. DIZE did not blunt the AT1R mediated stimulatory effect of [10–6 M] Ang-(1–7) on CYP11B1 and CYP11B2 mRNA.

Conclusions:
Thus, although Ang-(1–7) can be locally generated at low levels and MasR and ACE2 mRNAs are detectable in APA and APA-adjacent tissue, neither Ang-(1–7) nor DIZE were able to blunt Ang II-mediated aldosterone synthase expression. Collectively these results suggest that the ACE2/Ang-(1–7)/MasR axis is unlikely to counteract aldosterone biosynthesis under conditions of enhanced aldosterone secretion as PA and heart failure.
EFFECTS OF THE MTORC1 INHIBITOR EVEROLIMUS ON HEMODYNAMIC CHARACTERISTICS OF PATIENTS WITH PRIMARY ALDOSTERONISM
Authors: Burkard Thilo , Trinh Beckey 
Published: April 2021

Objective:
We recently showed that treatment with the mTORC1 inhibitor everolimus lowers home measured blood pressure (BP) and improves renin suppression in subjects with primary aldosteronism (PA). Aldosterone levels were markedly reduced in a subset of subjects. The aim of this study was to perform an explorative, secondary analysis of hemodynamic parameters acquired during this trial.

Design and method:
Design and Methods:
This is an explorative, secondary analysis of an open-label proof-of-concept trial. Fourteen adult patients with PA diagnosed according to the current guidelines of the American Endocrine Society were recruited between June 2017 and June 2018 at our institution. Subjects were treated with everolimus 0.75 mg orally twice daily for 2 weeks. Peripheral and central BP, heart rate, pulse wave velocity, cardiac index, inotropic state index, left stroke work index, stroke systemic vascular resistance and system-integrated hemodynamic maps were measured at baseline, after the treatment and after a 2-week washout. Hemodynamic profiles were generated by thoracic electrical bioimpedance method using the HOTMAN® System. Central BP and pulse wave velocity (PWA) where estimated using Mobil-O-Graph PWA.

Results:
Full hemodynamic data with good recording quality were available for 7 patients, central BP and PWV data for 10 patients, respectively. After treatment with everolimus, we found a significant decrease in peripheral (median 94 mmHg [IQR 85–104] to 88 mmHg [IQR 78–96], p = 0.049, N = 10) and central diastolic blood pressure (median 95 mmHg [IQR 87–106] to 89 mmHg [IQR 82–97], p = 0.037, N = 10), a trend towards decreased peripheral (median 149 mmHg [IQR 130–165] to 144 [IQR 124–149], p = 0.073, N = 10) and central systolic blood pressure (median 138 mmHg [IQR 121–157] to 137 mmHg [IQR 117–141], p = 0.166, N = 10) and significantly reduced hypervolemia (p = 0.008, N = 7). Other hemodynamic parameters of the system-integrated hemodynamic maps remained unchanged (Figure).

Conclusions:
Everolimus decreases central and peripheral diastolic blood pressure in subjects with primary aldosteronism which is possibly mediated by a decrease in preload and primary aldosteronism-induced hypervolemia.
PREVALENCE OF PRIMARY ALDOSTERONISM AND HYPOKALEMIA IN 5,100 PATIENTS REFERRED TO A TERTIARY HYPERTENSION UNIT
Authors: Burrello Jacopo , Monticone Silvia , Losano Isabel , Cavaglia’ Giovanni , Buffolo Fabrizio , Tetti Martina , Covella Michele , Rabbia Franco , Veglio Franco , Pasini Barbara , Williams Tracy Ann , Mulatero Paolo 
Published: April 2021

Objective:
Primary aldosteronism (PA) was considered a rare disorder almost always associated with hypokalemia. After the introduction of aldosterone-to-renin ratio, the widespread screening of hypertensive patients unveiled a higher prevalence of normokalemic PA, which now represents the prevailing phenotype. Many studies have described the prevalence of hypokalemia in patients with PA, conversely the prevalence of PA in patients with hypokalemia is unknown. In this retrospective observational study, we define the prevalence of hypokalemia in referred patients with hypertension and the prevalence of PA in patients with hypokalemia and hypertension.

Design and method:
For each patient, medical records were reviewed by three independent reviewers, who were blinded to patients’ identification and diagnosis. Hypokalemia was defined for potassium levels lower than 3.7 mmol/L. PA was diagnosed according to the Endocrine Society guideline. Multivariate logistic regression analysis was used to assess the association of hypokalemia and PA with cardiovascular risk indicators.

Results:
Hypokalemia was present in 15.8% of 5,100 patients with hypertension whereas 76.9% of these patients were normokalemic. PA prevalence in this cohort was significantly higher than in a cohort of 1,672 unselected patients with hypertension in primary care from the PATO study (7.8% vs. 5.9%, P = 0.011). The prevalence of PA in patients with hypokalemia was 28.1% and increased with decreasing serum potassium concentrations up to 88.5% of patients with spontaneous hypokalemia and serum potassium concentrations below 2.5 mmol/L. A multivariate regression analysis demonstrated the association of hypokalemia with the occurrence of cardiovascular events independent of PA diagnosis. An association of PA with the occurrence of cardiovascular events and target organ damage independent of hypokalemia was also demonstrated.

Conclusions:
Our results confirm that PA is a frequent cause of secondary hypertension in patients with hypokalemia and the presence of hypertension and spontaneous hypokalemia are strong indications for a diagnosis of PA. Finally, we show that PA and hypokalemia are associated with an increased risk of cardiovascular events.
THE 2020 ITALIAN SOCIETY OF HYPERTENSION (SIIA) PRACTICAL GUIDELINES FOR THE MANAGEMENT OF PRIMARY ALDOSTERONISM
Authors: Rossi Gian Paolo , Bisogni Valeria , Cesari Maurizio , Maiolino Giuseppe , Seccia Teresa M. 
Published: April 2021

Objective:
Considering the amount of novel knowledge generated in the last five years, a team of experienced hypertensiologists was assembled to furnish updated clinical practice guidelines for the management of primary aldosteronism (PA).

Design and method:
They were asked to undertake a systematic review of the literature in international databases by using the PICO strategy, to identify the most relevant studies and to grade their quality. Predefined quality criteria were in compliance with STARD (Standards for Reporting of Diagnostic Accuracy) recommendations. Each section of the guidelines was then jointly prepared by at least two coauthors, who provided, whenever possible, a Class of Recommendation and Level of Evidence, following the American Heart Association (AHA) methodology. The resulting guidelines underwent two rounds of revision, followed by review by an External Committee, two face-to-face meetings with all coauthors to clarify standing queries, a joint presentation on occasion of the 36th SIIA Conference to gather further feedbacks by the all Society members and, on these bases, a further conclusive peer review.

Results:
As a potentially curable cause of hypertension, PA should always be suspected in hypertensive patients and identified in a cost-effective manner by physicians dealing with these patients. Screening for PA is particularly beneficial when hypertension is severe and/or resistant to treatment, because target treatment and/or surgery allows to control BP, to withdraw or markedly reduce the number and dosage of antihypertensive medications, and to prevent or regress organ damage and associated comorbidities. Subtyping should be performed at third level referral centers that are proficient in performing and interpreting AVS. Adrenalectomy usually cure hyperaldosteronism and hypokalemia when a unilateral cause of PA is discovered; BP can also be normalized or considerably reduced in a substantial proportion of patients. Even when subtyping is unfeasible/failed, identification of PA allows undertaking a target treatment, which will provide better control of high BP.

Conclusions:
The proposed guidelines, offering substantial updated information, could simplify the diagnosis of PA and assist practicing physicians in the optimization of treatment and follow-up of patients with one of the most common curable causes of arterial hypertension.
DOCA-SALT DIMINISHES BRAIN RAS ACTIVITY IN PARALLEL WITH PLASMA AND RENAL RAS ACTIVITY – NO EVIDENCE FOR SELECTIVE BRAIN RAS ACTIVATION
Authors: Uijl Estrellita , Ren Liwei , Colafella Katrina M. Mirabito , Poglitsch Marko , Domenig Oliver , Zlatev Ivan , Kim Jae B. , Huang Stephen , Melton Lauren , Foster Don , Danser A.H. Jan 
Published: April 2021

Objective:
Deoxycorticosterone acetate (DOCA)-salt is suggested to promote hypertension by selectively upregulating the brain renin-angiotensin system (RAS), while suppressing the circulating RAS. Yet, we previously observed parallel downregulation of plasma and brain renin in mice. Here, we quantified angiotensinogen (AGT) and angiotensin (Ang) in rat brainstems.

Design and method:
For 7 weeks, rats received DOCA (200 mg; 60-day release pellet) and saline as drinking water. The contribution of AGT (liver vs. kidney/brain), Ang II type 1 receptors (AT1R) and blood pressure to tissue Ang content was determined by treatment with vehicle, liver-targeted AGT siRNA (30 mg/kg fortnightly; s.c.), valsartan (31 mg/kg/day; s.c.) or spironolactone (80 mg/kg/day; s.c.) during the final 3 weeks (n = 7–8/group). Plasma renin and AGT were quantified by enzyme-kinetic assay, tissue AGT by western blotting, and Ang I and II by LC-MS/MS.

Results:
Plasma renin, AGT, Ang I and II in rats not exposed to DOCA-salt were 20 ± 4 ng Ang I/mL/h, 730 ± 37 nM, 140 ± 24 pM and 108 ± 24 pM. AGT was present in liver, kidney and brainstem. Kidney Ang I and II were 540 ± 135 and 510 ± 97 fmol/g, while brainstem Ang I and II were undetectable in all and 30% of the rats, respectively (LLOQ <6 fmol/g). DOCA-salt increased blood pressure by 19 ± 1 mmHg and lowered plasma and renal Ang I and II by ∼90%, while brainstem Ang II became undetectable in 70% of the rats. AGT siRNA lowered plasma AGT by 97 ± 0.3%, with similar reductions in the liver and kidney, while brain AGT was unaltered. Whereas spironolactone normalized blood pressure, it increased plasma renin, and plasma, renal and brain Ang I and II. siRNA and valsartan tended to further lower renal Ang, without affecting blood pressure, plasma renin or plasma and brain Ang I and II.

Conclusions:
DOCA-salt suppresses plasma, renal and brain Ang II in parallel. Renal Ang II depends on hepatic AGT and AT1R-mediated internalization. Brain AGT is liver-independent, but unaltered by DOCA-salt, thus not permitting selective brain RAS upregulation. The RAS upregulation during spironolactone, combined with its antihypertensive effect, argues against the (brain) RAS as a major blood pressure determinant in this model.
ESTABLISHMENT OF A NEW SPECIFIC HIGH SENSITIVITY MEASUREMENT SYSTEM FOR SOLUBLE ANGIOTENSIN IV RECEPTOR
Authors: Konoshita Tadashi , Azuma Shinichiro , Sugiyama Mitsutoshi , Furutani Machi , Kaeriyama Saori , Saito Rie , Sato Satsuki , Imagawa Michiko , Zenimaru Yasuo , Suzuki Jinya , Fujii Miki , Makino Yasukazu 
Published: April 2021

Objective:
The renin angiotensin system plays a pivotal role in the development of cardiovascular and renal conditions. We had identified angiotensin IV receptor (AT4) as a hypertension/diabetes-specific gene through systemic transcriptome analysis followed by ontology based hierarchical clustering. Previously we have established a measurement system for soluble AT4 (sAT4) by polyclonal antibodies with 1 μg/ml sensitivity. Actual measurements for clinical subjects suggest the sAT4 measurement system would be useful for assessment of the pathophysiology of hypertension/obesity. Thus, we tried to establish a new specific high sensitivity measurement system for sAT4 with monoclonal antibodies.

Design and method:
As the antigen, we prepared a recombinant protein of AT4. Mice were immunized with the protein then spleen and lymph nodes were applied to make hybridomas with X63. We have screened the clones and selected candidate clones. Then we tested the best combination of the antibodies for the sandwich ELISA system and then optimized the reaction conditions. With this system, as a pilot study, we measured plasma concentrations of 114 subjects with life style related diseases and investigated relationships of sAT4 with various clinical and biochemical parameters by ANOVA.

Results:
Based on the standard curve for serial-step dilutions against reference molecules, the new measurement system for sAT4 showed 20 pg/ml sensitivity, 3–8 % intra-assay CV and about 10 % inter-assay CV without cross reactivities against 3 standard substrates. Actual measurements on clinical subjects revealed that the sAT4 values tended to be lower on hypertensive cases, obesity cases and dyslipidemic cases and that the sAT4 values were significantly low on CKD cases.

Conclusions:
Thus, we could establish a new specific high sensitivity measurement system for sAT4. The AT4 was originally identified from GLUT4 vesicles and thought to be involved in insulin sensitivity. It is also known to degrade angiotensin III to IV. Besides these findings, our data suggest the possibility that AT4 is involved in the pathophysiology of hypertension/obesity in a high sensitivity level for the first time. As perspectives we will assess the distribution of the concentrations and will measure the adequate numbers based on statistical power.