bluuebunny/crossref_metadata_2025_split huggingface dataset:
S-07-6: NEUTROPHIL EXTRACELLULAR TRAPS AS MEDIATORS OF ENDOTHELIAL DAMAGE IN HYPERTENSION AND DIABETES
Authors: Landry Chloe , Xiao Fengxia , Thibodeau Jean Francois , Holterman Chet E , Xhu Lihua , Gutsol Alex , Kennedy Christopher RJ , Burger Dylan 
Published: January 2023

Objective:
Endothelial dysfunction (ED) plays a key role in the pathogenesis of hypertension and diabetes, yet its molecular determinants are poorly understood. Concomitant hypertension and diabetes can synergistically increase damage to the vasculature, with increasing evidence suggesting that resulting immune dysregulation may contribute to endothelial injury. Neutrophil extracellular traps (NETs), networks of chromatin and protein-containing extracellular fibers released to fight infection, are generated from neutrophils following activation of the citrullinating enzyme peptidylarginine deiminase 4 (PAD4). PAD4 has been shown to be upregulated in atherosclerosis, vasculitis, and various inflammatory autoimmune diseases, leading to NET-induced endothelial injury. Whether NETs could contribute to hypertension- and diabetes-induced ED has not been established. The objective of the present study is to investigate the impact of hypertension and diabetes on PAD4 activity and the contribution of NETs to resulting vascular injury.

Design and Methods:
Promyelocytic HL-60 cells were differentiated to neutrophil-like cells and treated with angiotensin II (10−7 M) and/or high glucose (25 mM) for 24 hours, with or without subsequent NET-inducing PMA stimulation (500 nM). NETs were isolated from the culture medium by differential centrifugation and assessed by Western blot analysis of citrullinated histone H3 (citH3, a primary NET component). Isolated NETs were used to treat Human Umbilical Vein Endothelial Cells (HUVECs) at 0.5–500 ng/ml for 24 hours, after which cell viability (XTT cell assay) and proliferation (BrdU assay) were measured. We also assessed NETosis in mice expressing human renin in the liver (TTRhRen) intercrossed with OVE26 diabetic mice [i.e. hypertensive-diabetic, HD mice], compared with wild-type (WT) FVBN/J mice. We examined kidney levels of citH3, neutrophil elastase (NE), and PAD4 expression by immunohistochemistry.

Results:
Treatment with high glucose, but not angiotensin II, increased citH3 levels in neutrophil-like cells. NETs isolated from PMA-stimulated cells decreased HUVEC viability by ∼2-fold at 5 ng/ml (P = < 0.0001), and dose dependently decreased proliferation from 0.5–500 ng/ml, with a ∼80% decrease at 500 ng/ml. In HD mice, we observed a significant increase in kidney levels of citH3 (P < 0.0001), NE (P < 0.0001), and PAD4 (P < 0.0001), which was associated with the presence of albuminuria and increased blood pressure levels.

Conclusion:
These results suggest that NETs are upregulated in hypertension and diabetes and may contribute to endothelial damage and microvascular injury.
S-09-1: HIGH BLOOD PRESSURE AND ALBUMINURIA, BOTH THERAPEUTIC TARGETS FOR CARDIOVASCULAR DISEASE PROTECTION?
Authors: Zeeuw Dick de 
Published: January 2023

High blood pressure is associated with high cardiovascular (CV) risk, and lowering it is associated with risk reduction. Recently, albuminuria has been associated with increased CV risk. This association was explained by albuminuria being the consequence of CV disease rather than the cause. Thus, efforts to explain CV protective effects of new drugs by their ability to lower albuminuria were largely discarded. However, throughout the recent decades many new therapeutic approaches showed that the individual degree of reduction of albuminuria predicts the individual degree of CV protection irrespective of the intervention used (low protein diet, ACE-inhibitors, AII-antagonists, endothelin antagonist or even SGLT2-inhibitors) and irrespective of the underlying disease (healthy population, CV risk population, diabetes, chronic kidney disease of varying origin).
Should one conclude that albuminuria should be aggressively reduced under the motto ‘the lower the better’ (just like blood pressure). Further studies showed the issue to be much more complex. Both blood pressure lowering as well as albuminuria lowering by itself showed to be beneficial in one individual and had no or even bad effects in other individuals. This led to discovery and creation of a therapy response score as a better CV protection predictor. It showed a picture that was similar to the discovery of CV risk scores: a combination of the different risk markers gives a much better CV risk prediction than any risk factor by itself. Logically, drugs targeted to lower a single risk factor may not effectively predict CV protection, since it depends on the composite effect of the drug on all risk factors (be it a fall in one but a rise in another).
Today we are dealing with a new world in which CV risk is determined not only by high blood pressure or albuminuria, but by a host of different risk factors. CV protection thus needs a multiparameter approach improving all of them. This is best shown by the very recent studies with SGLT-2 inhibitors, which have glucose lowering as their registered target, but may also lower blood pressure, albuminuria, and even body weight! Interestingly, CV protection of this class appears overwhelming in all kinds of different diseases. Thus, drugs or combinations of drugs should not have single targets but should be tailored to the risk profile and response profile of each individual person. The time for true Personalized Medicine in cardiovascular disease treatment has clearly arrived.
S-10-2: OPTIMAL BLOOD PRESSURE TARGET TO PREVENT SEVERE HYPERTENSION IN PREGNANCY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Abe Makiko , Arima Hisatomi , Yoshida Yuichi , Fukami Ako , Sakima Atsushi , Metoki Hirohito , Tada Kazuhiro , Mito Asako , Morimoto Satoshi , Shibata Hirotaka , Mukoyama Masashi 
Published: January 2023

Objective:
Severe hypertension in pregnancy is a hypertensive crisis that requires urgent and intensive care due to its high maternal and fetal mortality. However, there still remain some discrepancies between guidelines in a target blood pressure to prevent severe hypertension in pregnancy. This study aimed to find the optimal blood pressure (BP) levels to prevent severe hypertension in pregnant women with nonsevere hypertension.

Design and method:
We searched Ovid MEDLINE and the Cochrane Library to identify all randomized controlled trials, which compared effects of antihypertensive drugs and placebo/no treatment or more intensive and less intensive BP-lowering treatments on adverse maternal and fetal pregnancy outcomes among pregnant women with nonsevere hypertension. A random effects model meta-analysis was performed to estimate the pooled risk ratio (RR) and 95% confidence interval (CI) for the outcomes.

Results:
Forty RCTs with 6355 patients were included in this study. BP lowering treatment significantly prevented severe hypertension (RR, 0.46; 95% CI, 0.37 to 0.56), preeclampsia (RR, 0.82; 95% CI, 0.69 to 0.98), severe preeclampsia (RR, 0.38; 95% CI, 0.17 to 0.84), placental abruption (RR, 0.52; 95% CI, 0.32 to 0.86), and preterm birth (before 37 weeks; RR, 0.81; 95% CI, 0.71 to 0.93), while the risk of small for gestational age infants was increased (RR, 1.25; 95% CI, 1.02 to 1.54). An achieved systolic blood pressure (SBP) of lower than 130 mmHg reduced the risk of severe hypertension to nearly one-third compared with an achieved SBP of 140 mmHg or higher, with a significant interaction of the BP levels achieved with BP lowering therapy. There was no significant interaction between BP lowering treatment and the subtypes of hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and chronic hypertension.

Conclusions:
BP lowering treatment aimed at a SBP of lower than 130 mmHg and accompanied by careful monitoring of fetal growth might be recommended to prevent severe hypertension among pregnant women with nonsevere hypertension.
S-12-5: IMPAIRMENT OF RENAL BLOOD FLOW AUTOREGULATION AND PRESSURE-NATRIURESIS: ROLE IN THE DEVELOPMENT OF HEART FAILURE IN REN-2 TRANSGENIC HYPERTENSIVE RATS
Authors: Honetschlagerova Zuzana , Sadowski Janusz , Jezierska Elzbieta Kompanowska , Cervenka Ludek 
Published: January 2023

Objective:
The prognosis of patients with heart failure (HF), particularly those who were hypertensive before the onset of HF, remains poor and new therapeutic strategies are needed, based on understanding the pathophysiology of the progression of HF. We hypothesized that the kidney is here not simply a victim but also a culprit of the progression. Specifically, we hypothesized that the impairment of renal blood flow (RBF) autoregulation and pressure-natriuresis relationship is present in the very early HF phase, and precedes HF decompensation.

Design and method:
In Ren-2 transgenic rats (TGR), a model of hypertension with increased endogenous activity of the renin-angiotensin system (RAS), HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). One week after ACF creation or sham-operation animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and pressure-natriuresis relationship after stepwise changes in renal arterial pressure (RAP) that were induced by aortic clamps. Sham-operated TGR were evaluated at physiological level of RAP, then at RAP reduced to 125, 100, 90 and 80 mmHg. In ACF TGR RAP was reduced to 100, 90 and 80 mmHg, followed by period of RAP increased to 125 mmHg.

Results:
In sham-operated TGR as compared with ACF TGR the basal mean arterial pressure (156 ± 3 vs. 98 ± 3 mmHg), RBF (11.45 ± 0.6 vs. 8.13 ± 0.3 ml.min-1.g-1), urine flow (UF) (38.3 ± 3.1 vs. 8.7 ± 1.0 μl.min-1.g-1) and absolute sodium excretion (UNaV) (4.77 ± 0.54 vs. 0.46 ± 0.11 μmol.min-1.g-1) were all significantly lower. In sham-operated TGR reductions in RAP resulted in significant decreases in RBF whereas in ACF TGR it did not change in response to RAP alterations. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former.

Conclusions:
Our data show that at the physiological RAP level ACF TGR displayed marked reduction in RBF, UF and UNaV as compared with sham-operated TGR. However, in contrast to sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and better slope of pressure-natriuresis relationship. Thus, even in the very early HF stage the renal dysfunction is demonstrable but such dysfunction and the subsequent onset of HF decompensation cannot be simply ascribed to impaired RBF autoregulation and pressure-natriuresis relationship, at least not in the high-output HF model of originally RAS-dependent hypertensive rat.
S-13-2: PATHOLOGY UPDATE OF CUSHING'S SYNDROME AND PRIMARY ALDOSTERONISM ACCORDING TO WHO 2022
Authors: Sasano Hironobu , Yamazaki Yuto , Satoh Fumitoshi 
Published: January 2023

New pathology classification of endocrine and neuroendocrine tumours is currently being updated as one of WHO classification of tumours version 5. Not only pathologists but also clinicians involved in the clinical management of those patients should be familiar with novel classification including their new concepts. Therefore in this presentation, we will introduce newly updated concepts of adrenocortical diseases associated with Cushing's syndrome and primary aldosteronism.
In Cushing's syndrome, primary bilateral nodular adrenal cortical disease has turned out to harbor multiple independent clonal proliferations and the term hyperplasia should not be used in these adrenocortical disorders. Hyperplasia should be only reserved for those associated with ACTH overproduction from pituitary or others. Various somatic and/or genomic mutations of the genes involved in intracellular signaling pathways have been reported in almost all bilateral micronodular adrenal cortical disease and the great majority of bilateral macronodular adrenal cortical disease associated with Cushing's syndrome.
For instance, bilateral micronodular adrenocortical disease harbors pathogenic germline mutations resulting in the activation of the protein kinase A or PKA pathway including PRKAR1A, PRKAR1A, PRKACA, PDE11A, PDE8B and 2p16 CNC2 locus alterations. On the other hand, bilateral macronodular adrenal cortical disease has been linked to several germline alterations including ARMC5, MEN1, FH, APC and others.Clinical significance of those genetic abnormalities above including potential therapeutic manipulation is being studied at this juncture.
In primary aldosteronism, the introduction of CYP11B2 has enormously contributed to the establishment of new concept of adrenocortical pathology. Primary aldosteronism can be generally classified into two categories. The one in which aldosterone production diffusely occurs in the hyperplastic zona glomerulosa and the other harboring localized aldosterone production. The former is generally bilateral and the latter unilateral or bilateral. The latter category also includes both nodule and adenoma, which could be differentiated according to the status of intra-lesional distribution of CYP11B2. CYP11B2 positive localized proliferation of the zona glomerulosa cells is frequently detected in non hypertensive subject and should be termed aldosterone producing nodules (APN) rather than aldosterone producing cell clusters (APCC). The potential cascade from these aldosterone producing nodules in normal subject to those associated with clinically overt primary aldosteronism is being investigated including the possible concept of pre- or subclinical primary aldosteronism.
S-13-3: AN APPROACH TO IDENTIFY THE UNDETERMINED ADIPOCYTE-DERIVED FACTOR(S) THAT STIMULATE ALDOSTERONE SYNTHASE GENE (CYP11B2) EXPRESSION
Authors: SHIMADA HIROKI , Sato Ikuko , Yokoyama Atsushi , Nakmura Yasuhiro , Sugawara Akira 
Published: January 2023

Objectives:
Hypertension is a frequently observed complication among obese patients. Recently, undetermined adipocyte-derived factor(s) have been recognized as one of the causes of the obesity-related hypertension independent of angiotensin (A) II. In this study, we aim to identify the undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression aldosterone secretion that may induce hypertension.

Methods:
We first differentiated mouse fibroblast 3T3-L1 cells into adipocytes and collected their supernatants. The supernatants were incubated with human adrenocortical carcinoma H295R cells, and their CYP11B2 mRNA expression was measured by quantitative PCR with reverse transcription (qRT-PCR). Thereafter, the supernatants were fractionated by ammonium sulfate precipitation to purify adipocyte-derived factor(s) that stimulate CYP11B2 expression. The precipitates were collected in 30%, 60% and 90% saturated concentration of ammonium sulfate. Each of precipitates was concentrated using 100 kDa ultrafiltration membrane and incubated with H295R cells. CYP11B2 mRNA expression in H295R cells was measured by qRT-PCR. Then, we purified the precipitation of the supernatants that obtained in 60% ammonium sulfate by anion-exchange chromatography. Each of the fractions was incubated with human adrenocortical carcinoma H295R cells, and their CYP11B2 mRNA expression was measured by qRT-PCR.

Results:
The supernatants obtained from 3T3-L1 adipocytes were demonstrated to stimulate CYP11B2 expression. Fractionation of the supernatants by ammonium sulfate precipitation demonstrated that the ability to stimulate CYP11B2 expression was detected in fractions precipitated in 60% saturated concentration. Fractionation of the supernatants by anion-exchange chromatography demonstrated that the ability to stimulate CYP11B2 expression was detected in two specific fractions. Specific fractions were analyzed by mass spectrometry, resulting in the identification of 39 specific proteins. We are now investigating that the relationship between CYP11B2 gene expression and 39 proteins.
S-14-3: WHICH IS THE OPTIMAL BP TARGET TO ACHIEVE? SHOULD GUIDELINES BE UPDATED?
Authors: Verdecchia Paolo , Angeli Fabio , Reboldi Giampaolo 
Published: January 2023

Hypertension Guidelines disagree on the definition of the more appropriate blood pressure (BP) target to achieve. A shared feature of Guidelines was the definition of precise (albeit differing across Guidelines) BP targets in different patient categories (Table).
Does the evidence support the definition of precise BP targets overall and in different patient categories?

Evidence from observational studies. A direct relation between BP and risk of cardiovascular disease emerged from observational studies including a large meta-analysis (Lancet 2002). Most studies showed that after correction for several confounders (cancer; heart failure etc) the lowest cardiovascular risk occurred at low values of achieved BP (<120/80 or even < 100/60 mmHg).

Evidence from intervention studies. Meta-analyses of randomized studies between different drugs or BP targets showed two main findings:
(a) The larger the BP difference between randomized groups in the achieved BP the greater the benefit (particularly on stroke and heart failure) in the group with the lower achieved BP.
(b) When comparing a more intensive with a less intensive BP target (i.e. 120 vs 140 mmHg) the risk of major cardiovascular disease was lower with the more intensive strategy. In a meta-analysis a more intensive strategy reduced stroke by 20%; myocardial infarction by 15%; heart failure by 25%; cardiovascular death by 18% and all-cause death by 11% (Hypertension 2016) when compared to a less intensive strategy. BP targets considerably differed across the studies.

Evidence regarding tolerability of treatment. Some Guidelines suggest that a more intensive BP target could be achieved at condition that the treatment is well tolerated. However the concept of good treatment tolerability holds at any level of achieved BP (not only below 140/90 mmHg) irrespective of the BP target. There is no evidence supporting safety thresholds not to be exceeded when the treatment is well tolerated.

Conclusion:
The lowest well tolerated BP is a reasonable and evidence-based BP target irrespective of the cardiovascular risk status of the patient.
Table: BP targets according to major hypertension Guidelines.
S-18-3: SGLT2 INHIBITOR CANAGLIFLOZIN ANTAGONIZES SALT-SENSITIVE HYPERTENSION THROUGH MODIFYING TRPC3 MEDIATED VASCULAR CALCIUM HANDLING
Authors: Zhao Yu , Li Li , Lu Zongshi , Hu Yingru , Zhang Hexuan , Sun Fang , Li Qiang , He Chengkang , Shu Wentao , Wang Lijuan , Cao Tingbing , Yan Zhencheng , Liu Daoyan , Gao Peng , Zhu Zhiming 
Published: January 2023

Objectiv:
Salt-sensitive hypertension is highly prevalent and associated with cardiorenal damage. Large clinical trials have demonstrated that Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypotensive effect and cardiorenal protective benefits in hypertensive patients with and without diabetes. However, the underlying mechanism remains elusive.

Methods:
Dahl salt-sensitive (SS) rats and salt-insensitive controls were fed with 8% high salt diet to establish salt-sensitive hypertensive model, some of them were treated with canagliflozin. The blood pressure, urinary sodium excretion, vascular function and remodeling were detected. Rat aortic proteomics and TRPC3 knockout mice were used to explain the mechanism of the effect of canagliflozin on salt-sensitive hypertension.

Results:
Canagliflozin treatment significantly reduced high salt induced hypertension and this effect was not totally dependent on urinary sodium excretion in SS hypertensive rats. Assay of vascular function and proteomics showed that canagliflozin significantly inhibited vascular cytoplasmic calcium increase and vasoconstriction in response to high salt diet. High salt intake increased vascular expression of TRPC3 in salt-sensitive rats, which could be alleviated by canagliflozin treatment. Overexpression of TRPC3 mimicked salt-induced vascular cytosolic calcium increase in vitro and knockout of TRPC3 erased the anti-hypertensive effect of canagliflozin. Mechanistically, high-salt-induced activation of sodium/calcium exchanger 1 (NCX1) reverse mode increased cytoplasmic calcium level and vasoconstriction, which required TRPC3, and this process could be blocked by canagliflozin.

Conclusions:
We define a previously unrecognized role of TRPC3/NCX1 mediated vascular calcium dysfunction in the development of high salt induced hypertension, which can be improved by canagliflozin treatment. This pathway is potentially a novel therapeutic target to antagonize salt sensitive hypertension.
S-21-3: EFFECTIVENESS AND ACCEPTABILITY OF MOBILE PHONE TEXT MESSAGING INTERVENTION TO IMPROVE BLOOD PRESSURE CONTROL (TEXT4BP) AMONG HYPERTENSIVE PATIENTS IN NEPAL
Authors: Bhattarai Buna Bhandari , Narasimhan Padmanesan , Jayasuriya Rohan , Vaidya Abhinav , Schutte Aletta E 
Published: January 2023

Objectives:
In LMICs, the rapid uptake and availability of mobile phones provide excellent opportunities for host of an intervention. However, research on the effectiveness and acceptability of mHealth in these settings remains limited. The main objective of this feasibility study was to assess the effectiveness and acceptability of a mobile phone text messaging intervention (TEXT4BP) to improve blood pressure control and treatment adherence among hypertensive patients in Nepal.

Design and Methods:
The TEXT4BP study was a two-arm, parallel-group, unblinded, randomized controlled pilot trial that recruited 200 clinically diagnosed hypertensive patients aged 18–69 years visiting at a tertiary referral hospital in Kathmandu, Nepal. We co-designed the contextual text messages informed by the formative qualitative studies that used COM-B (capability, opportunity, motivation, and behavior) model and Technology Acceptance Model (TAM) model. Patients in the intervention arm (n = 100) received text messages containing information on hypertension, diet, medication, and physical activity three times per week for three months. The control arm (n = 100) received standard care. Primary outcomes were changes in blood pressure and medication adherence at three months. Secondary outcomes included blood pressure control, medication adherence self-efficacy, and hypertension knowledge. Feasibility measures, such as attrition rate, was calculated. A nested qualitative study assessed the acceptability of the intervention.

Results:
Over the 12 weeks of follow-up, the retention rate was 77%. The intervention group had a greater reduction in systolic and diastolic BP vs usual care [-7.09/-5.86 (p = 0.003) vs -0.77/-1.35 (p = 0.28) mmHg] [adjusted difference: systolic B = -6.50 (95% CI, -12.6; -0.33) and diastolic BP B = -4.60 (95% CI, -8.16; -1.04)] (fig 1), coupled with a greater proportion achieving target BP (70% vs 48%, p = 0.006) at three months. The intervention arm showed an improvement in compliance to antihypertensive therapy (p < 0.001), medication adherence (p < 0.001), medication adherence self-efficacy (p = 0.023), and knowledge on hypertension and its treatment (p = 0.013). In addition, intervention participants expressed a high rate of acceptability and desire to continue the TEXT4BP intervention in the future too.

Conclusion:
The TEXT4BP study has generated promising evidence that text messaging intervention is feasible, acceptable, and effective in improving blood pressure control in low-resource settings like Nepal. The findings will inform further large-scale mHealth research and contribute to clinical practice with evidence-based hypertension guidelines in Nepal.
Trial reg: ACTRN12619001213134