bluuebunny/crossref_metadata_2025_split huggingface dataset:
EARLY HYPERTENSION: EXPLORING THE VASCULAR PHENOTYPE
Authors: Murray Eleanor , Guzik Tomasz , Delles Christian 
Published: April 2021

Objective:
Despite well-established demographic and lifestyle risk factors for hypertension, the early phenotypic features remain elusive. Understanding these characteristics could allow for early identification of disease phenotypes and tailoring of management.

Design and method:
Primary hypertension in treatment-naïve patients without co-morbidities (‘HTN’; n = 48) were comprehensively phenotyped. Blood pressure (BP) was analysed using ambulatory monitoring. Vascular assessment included flow mediated dilatation (FMD), pulse wave velocity (PWV); pulse wave analysis (PWA)-derived heart-rate-adjusted augmentation index (AI75), and central BP; and peripheral arterial tonometry (EndoPAT-2000) index (LnRH) and AI75. Data were entered into Principal Component Analysis, generating phenotypic clusters.

Results:
Mean 24hr SBP was 143 ± 15.6; mean age 37 ± 8.6; 69% were male, and BMI was 28.2 ± 5.4 kg/m2. Analysis revealed 3 distinct phenotypic subgroups (see Figure). Age and BMI did not differ between the groups; other parameters are outlined below; statistically significant difference (P < 0.005) is indicated by ∗:
A) ‘Vascular HTN’, n = 19: Mean office BP 151/96 mmHg∗, though 24 hr mean 141/90 mmHg, with loss of nocturnal dip∗ (systolic 7.5%/ diastolic 11.6%); 53% were male∗, 84% were Caucasian; endothelial dysfunction by FMD and EndoPAT AI@75∗ (mean 16.1%); CIMT∗ was greater (0.67 mm); greater vascular stiffness by PWA (15.8), and elevated central pressures∗ (136.6/97.9 mmHg).
B) ‘Early HTN’, n = 15: Mean office BP 136/84 mmHg, 24hr BP similarly 135/82 mmHg, with intermediate nocturnal dip (mean 11.8/17.1%), but high variability in diastolic readings∗ (SD 10.6) and in HR overnight∗; 71% male, 93% Caucasian; endothelial function was normal (EndoPAT AI@75∗ –15.9%, FMD∗ 8%); central pressures were borderline, PWA was healthy range (-6.9).
C) ‘Physically Fit Dippers, HTN driver unknown’, n = 15: Mean office 140/90 mmHg, 24hr 139/85 mmHg, but pronounced nocturnal dip∗ (mean 14.0/18.4%) and variability in SBP∗ (SD 13.8 mmHg) and daytime HR∗ (mean range 33 bpm), though lower resting pulse∗ (61 bpm); intermediate PWV (mean 7.3m/s) and EndoPAT AI75 (mean 8.3%), and lowest central pressures∗ (122/84 mmHg). Physical activity scores higher∗.

Conclusions:
We identify different phenotypes in drug-naïve, incident patients with primary hypertension, with different vascular techniques associated, and potentially differing pathophysiology. This warrants further examination of these phenotypes in a larger population.
RELATIONSHIP BETWEEN DIURETIC RELATED HYPERURICEMIA AND CARDIOVASCULAR EVENTS: DATA FROM THE URRAH (URIC ACID RIGHT FOR HEART HEALTH) STUDY
Authors: Maloberti Alessandro , Bombelli M. , Facchetti R. , Virdis A. , Casiglia E. , Tikhonoff V. , Barbagallo C.m. , Cirillo M. , Desideri G. , Ferri C. , Galletti F. , Iaccarino G. , Mallamaci F. , Masi S. , Mazza A. , Muiesan M.l. , Salvetti M. , Palatini P. , Pontremoli R. , Verdecchia P. , Volpe M. , Grassi G. , Giannattasio C. , Borghi C. 
Published: April 2021

Objective:
Hyperuricemia can be both determined by overproduction (due to xanthine oxidase hyperactivity) or renal hypoexcretion. In this latter case, also diuretic use (particularly hydrochlorotiazhide) can be involved. While the relationship between hyperuricemia and CardioVascular (CV) events has been definitively linked in many studies, data on diuretic related hyperuricemia are still lacking. The objective of this analysis is to assess the relationship between diuretic induced hyperuricemia and CV events.

Design and method:
The URic acid Right for heArt Health study is a nationwide, multicentre, observational cohort study involving data on individuals aged 18–95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 122 ± 66.9 months. Patients were classified into four groups accordingly to the diuretic use (yes vs no) and Uric Acid (UA) levels (higher or lower than the median value of 4.9 mg/dL). All cause death, CV deaths and CV events were consiedered as outcomes.

Results:
A total of 17747 individuals were included in the analysis. Mean age was 57.1 ± 15.2 years, males were 45.3%, SBP/DBP were 144.1/85.2 ± 24.6/13.2. 17.2% of the subjects use diuretic of whom 58% presents UA higher than median values. As showed in figure 1, patients with Hpeuricemia without diuretic use served as reference group. In multivariate adjusted analysis (for sex, age, SBP, BMI, glycemia, total cholesterol and creatinine) subjects without hyperuricemia and without diuretic show a significant lower risk for the three outcomes. Subjects without hyperuricemia with diuretic use have lower risk of all cause death but similar risk of CV death and events. Finally subjects with hyperuricemia and diuretic use exhibit a similar risk for the three outcomes as compared with the reference group.

Conclusions:
Our study showed that diuretic related hyperuricemia is related to CV events similarly to the subjects that present hyperuricemia without diuretics.
REFERENCE RANGES AND CUT-OFF VALUES FOR SIMULTANEOUS MONITORING OF RAS BLOCKER EFFICACY AND SCREENING FOR SECONDARY HYPERTENSION USING RAAS TRIPLE-A PROFILING
Authors: Poglitsch Marko , Foco Luisa , Gögele Martin , Pramstaller Peter Paul , Pattaro Cristian 
Published: April 2021

Objective:
Uncontrolled hypertension is caused by various factors including compliance issues, patient specific drug uptake and elimination profiles or secondary forms of hypertension, resulting in blood pressure control rates of less that 50%. RAAS Triple-A profiling is based on a high-throughput mass-spectrometry assay for Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone in serum samples. Quantified hormone levels are used to calculate markers for plasma-renin-activity (PRA-S), plasma angiotensin-converting-enzyme activity (ACE-S) and adrenal aldosterone secretion (AA2-Ratio). The integrated analysis of these molecular markers together with drug prescription information allows to identify the underlying cause of uncontrolled hypertension, including primary aldosteronism and insufficiency in drug adherence or dosing for ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs).

Design and method:
500 participants with prescribed antihypertensive drugs were selected from the “Cooperative Health Research in South Tyrol” (CHRIS) study, a population-based study from an Alpine rural environment. Five age- and sex-matched groups (N = 100 each) selected were individuals on single therapy with ARBs, ACEi or beta blockers, and on single pill dual therapy of ACEi or ARBs in combination with diuretics. Three age and sex-matched control groups of 100 participants each were included, being normotensive, hypertensive (treated with non-antihypertensive drugs) and hypertensive participants without any prescribed medication.

Results:
RAAS Triple-A analysis was performed in all individuals and reference values for Ang I, Ang II, Aldosterone, PRA-S, ACE-S and AA2-Ratio were established in appropriate sub-populations. Drug monitoring by LC-MS/MS based quantification of anti-hypertensive drugs in serum was used as a gold standard to determine cut-off values for compliance with ARB and ACEi therapy and ROC analysis was performed using angiotensin-based biomarkers.

Conclusions:
RAAS Triple-A profiling for the first time provides an interpretation of blood pressure regulating effector hormone levels under consideration of individual drug prescriptions and its dynamic molecular impact on a patient's physiology. The resulting model for patient stratification paves the way for personalized treatment of hypertension, simultaneously screening for secondary hypertension and drug adherence/dosing based on a single high throughput routine blood test applied to patients while being on their standard therapy.
F-18 FDG PET/CT CAN BE USED AS AN IMAGING BIOMARKER FOR REFLECTING SYNTHETIC VASCULAR SMOOTH MUSCLE CELL ACTIVITY IN THE ANIMAL MODEL OF VASCULAR REMODELING DISORDER
Authors: Pahk Kisoo , Joung Chanmin , Kim Sungeun , Kim Won-Ki 
Published: April 2021

Objective:
Synthetic vascular smooth muscle cells (VSMCs) play important roles in vascular remodeling disorders including atherosclerosis, restenosis, and transplant vasculopathy. 18F-fluorodeoxyglucose positron emission tomography (F-18 FDG PET/CT) is a non-invasive molecular imaging modality widely used in clinical practice for reflecting glucose metabolism. The aim of this study was to demonstrate the feasibility of measuring the activity of synthetic VSMCs using F-18 FDG PET/CT in an atherosclerotic rat model of partial carotid artery ligation.

Design and method:
Using Sprague-Dawley rats, neointimal hyperplasia was made by right partial carotid ligation method. After 1 month, all animal models undertook F-18 FDG PET/CT images. Then the vessels were harvested and analyzed with autoradiography and histomolecular approaches.

Results:
The affected carotid artery exhibited prominent neointinal hyperplasia region with a narrowed lumen. Known surrogate marker of synthetic VSMCs including matrix metallopeptidase-9, cyclophilin A, and collagen type III were increased in neointimal hyperplasia region. There were no immune cells such as macrophages or neutrophils. F-18 FDG PET/CT and autoradiography showed increased tracer uptake along the same affected arteries. Glucose transporter-1 was also increased in neointimal hyperplasia region.

Conclusions:
It is feasible to use F-18 FDG PET/CT as an imaging surrogate-marker for reflecting synthetic VSMC activities in vascular remodeling disorders.
ISOLATED SYSTOLIC HYPERTENSION VERSUS COMBINED SYSTOLIC-DIASTOLIC HYPERTENSION AS PREDICTOR OF ATRIAL FIBRILATION: DATA FROM AN 8-YEAR-FOLLOW-UP STUDY
Authors: Konstantinidis D. , Tsioufis K. , Liatakis I. , Koutra E. , Leontsinis I. , Kouremeti M. , Iliakis P. , Karaminas N. , Tatakis F. , Papakonstantinou P. , Anastasiou A. , Mourtzoukou D. , Siafi E. , Kakouri N. , Dimitriadi M. , Tousoulis D. 
Published: April 2021

Objective:
Isolated systolic hypertension (ISH) and combined systolic-diastolic hypertension (CH) are related with increased cardiovascular risk. To compare the predictive role of ISH and CH for the incidence of atrial fibrillation (AF) in a cohort of essential hypertensive patients.

Design and method:
We followed up 1605 essential hypertensives with office systolic blood pressure (BP)> or = 140 mmHg (mean age 58.1 years, 842 males, office BP = 153/92 mmHg) for a mean period of 8 years. All subjects had at least one annual visit and at baseline underwent echocardiographic study and blood sampling for estimation of metabolic profile. Patients with baseline ISH exhibited office systolic BP > or = 140 mmHg and office diastolic BP <90 mmHg, while those with CH had office systolic BP > or = 140 mmHg and office diastolic BP > or = 90 mmHg. Moreover, new-onset AF was defined as hospitalization for AF or compatible electrocardiographic tracings.

Results:
The incidence of new-onset AF over the follow-up period was 3.4% (n = 55). Patients with ISH (n = 510) compared to those with CH (n = 1095) were older (65 ± 10 vs 55 ± 11 years, p < 0.0001), had at baseline lower waist circumference (95.5 ± 12 vs 98 ± 12 cm, p < 0.0001), office systolic BP (149 ± 10 vs 155 ± 13 mmHg, p < 0.0001), office diastolic BP (80 ± 5 vs 98 ± 7 mmHg, p < 0.0001), while did not differ regarding left ventricular mass index and lipid levels (p = NS for all). Univariate Cox regression analysis revealed that baseline ISH (hazard ratio = 4.612, p = 0.013) and CH (hazard ratio = 1.794, p = 0.036) predicted new-onset AF. However, in multivariate Cox regression model, age (hazard ratio = 1.078, p < 0.001), left ventricular mass index (hazard ratio 1.012, p = 0.014), left atrium diameter (hazard ratio = 1.102, p < 0.001) and ISH (hazard ratio = 1.551, p = 0.035) but not CH turned out to be independent predictors of new-onset AF episodes.

Conclusions:
In essential hypertensive patients, ISH but not CH exhibits independent prognostic value for AF. These findings support that ISH constitutes a hypertensive phenotype of particularly increased arrhythmia risk needing careful evaluation and treatment.
OBSTRUCTIVE SLEEP APNEA IS AN INDEPENDENT PREDICTOR OF ARTERIAL STIFFNESS IN HYPERTENSIVE PATIENTS
Authors: Rietz Hermine , Hellqvist Henrik , Kahan Thomas , Sommermeyer Dirk , Hedner Jan , Grote Ludger , Spaak Jonas 
Published: April 2021

Objective:
Studies have suggested an association between obstructive sleep apnea (OSA) and arterial stiffness. We aimed to further assess this relationship in hypertensive patients.

Design and method:
In all, 199 patients with hypertension (mean age 57 ± 11 years, 73 females, body mass index 27.9 ± 4.4 kg/m2, office blood pressure (BP) 147 ± 19/89 ± 11 mm Hg) referred for 24-h ambulatory blood pressure monitoring (ABPM, recordings every 20 min throughout) underwent simultaneous over-night polygraphic sleep recording (nasal airflow and finger pulse-oximetry). The number of apneas and hypopneas during sleep per hour were measured (apnea hypopnea index, AHI) as well as the burden of desaturation (oxygen desaturation index, ODI). From ABPM the ambulatory arterial stiffness index (AASI) was calculated as 1 - the regression slope of diastolic on systolic BP. Patients were divided into three groups according to their AHI; AHI <5 (no OSA, n = 75), AHI 5<15 (mild OSA, n = 69) and AHI >15 (moderate/severe OSA, n = 44/11). Also 24-h pulse pressure (PP) was assessed as an indirect marker of arterial stiffness.

Results:
AASI increased with AHI severity: 0.39 ± 0.14, 0.44 ± 0.13, and 0.46 ± 0.13 in AHI<5, 5<15, and AHI >15, respectively (p = 0.011, by ANOVA). In a multivariate regression model including age, sex, triglycerides (TG), AHI, 24-h systolic BP, 24-h mean heart rate (HR) and diabetes, all but sex, HR and diabetes remained independent predictors for AASI (age p < 0.001, sex p = 0.086, TG p = 0.029, AHI p = 0.015, 24-h systolic BP p = 0.003, 24-h mean HR p = 0.064, diabetes p = 0.070 with R = 0.52, p < 0.001 for full model). Using ODI instead of AHI yielded similar results, though HR was significant (p = 0.022), not TG (p = 0.057). In a similar regression model for describing 24-h PP (replacing 24-h systolic BP with 24-h mean arterial BP), neither AHI, nor ODI, remained independent predictors for 24-h PP.

Conclusions:
AASI, but not 24-h PP, is independently associated with both AHI and ODI in hypertensive patients together with 24-h systolic BP and age. TG also seems to be of importance in predicting AASI, probably through its association to glucose control. Ongoing work aims to further reveal the potential influence of OSA on arterial function in hypertensive patients.
ARTERIAL STIFFNESS AND WAVE REFLECTIONS IN PATIENTS WITH SERONEGATIVE SPONDYLOARTHROPATHIES TREATED WITH TUMOR NECROSIS ALPHA BLOCKERS
Authors: Bozzao Francesco , Colapietro Nina , Xodo Carlotta , Grillo Andrea , Rovina Matteo , Magazzino Olga , Smitova Kristina Giraldi , Carretta Renzo , Bernardi Stella , Tomietto Paola , Fischetti Fabio , Fabris Bruno 
Published: April 2021

Objective:
The seronegative spondyloarthropathies (SpA) are a group of rheumatic disorders characterized by oligoarticular arthritis, enthesitis and axial involvement. Cardiovascular manifestations play a pivotal role in determining the excess mortality in SpA, owing to the linkage between systemic inflammation and accelerated atherogenesis. Arterial stiffness measured as carotid-femoral pulse-wave velocity (PWV) and wave reflections are validated markers of cardiovascular disease. Anti-inflammatory therapy with anti-tumor necrosis factor-α (TNFα) agents may have a role in reducing arterial stiffening in some disease models but data in patients with SpA are inconclusive.

Design and method:
Twenty-three patients with a short duration and high disease activity SpA (8 males, 15 females, mean age 53.9 ± 11.5 years) and without overt cardiovascular disease were enrolled. PWV and augmentation index (AIx, as a measure of wave reflections) were measured by a validated arterial tonometer (PulsePen, DiaTecne, Milan). Patients were compared with 23 controls matched for age, gender, blood pressure and heart rate. Arterial tonometry was repeated in 10 patients after 16 weeks of treatment with an anti-TNFα agent (Adalimumab, in 9 patients; Certolizumab, in 1 patient).

Results:
Of the patients enrolled, 14 had ankylosing spondylitis, 8 psoriatic SpA, 1 Crohn's disease-associated SpA. The median duration of the disease from diagnosis was 2 years (2–11 years). In the comparison with matched controls, no significant differences in PWV or AIx were found (PWV: SpA 8.9 ± 2.0 m/s, controls 9.2 ± 3.8m/s, p = 0.80; AIx: SpA 18.3 ± 14.7, controls 19.5 ± 12.0, P = 0.77). During the 16-weeks follow-up of patients treated with anti-TNFα therapy, despite significant improvement in disease activity parameters (ASDAS-CRP: 2.75 ± 0.8 to 1.67 ± 0.4, P < 0.01; BASDAI: 5.05 ± 1.9 to 3,0 ± 1.2, P 0.05), no significant change was found in the hemodynamic parameters (PWV: 8.5 ± 1.8 to 9.7 ± 3.5 m/s, p = 0.11; AIx 16.6 ± 15.5 to 13.7 ± 10.0, p = 0.47).

Conclusions:
In patients with a short duration SpA, arterial stiffness and wave reflections are not significantly impaired. Anti-TNFα agents have no effects on arterial stiffness parameters in the short term, despite control of clinical and inflammatory burden. Forthcoming studies should explore the cardiovascular effects of novel therapeutics opportunities (anti-IL12/23 and anti-IL17) in patients with SpA.
RELATIONSHIPS BETWEEN ANTI-HYPERTENSIVE DRUGS AND NOCTURIA: A SYSTEMATIC REVIEW
Authors: Akasaki Yuichi , Kubozono Takuro , Higuchi Koji , Ohishi Mitsuru 
Published: April 2021

Objective:
Nocturia frequently occurs with age in both men and women, and it is the worst symptom among the lower urinary tract symptoms which deteriorate the quality of life. The cause is an increase in urine volume at night or day and night, and a decrease in bladder capacity.
Hypertension is one of the diseases to cause nocturia. However, no systematic review has been performed to collate the evidence on the relationships between antihypertensive drugs and nocturia.
The objective of this systematic review is to synthesize the research evidence on relationships between antihypertensive drugs and nocturia.

Design and method:
A comprehensive search was conducted of the following electronic databases in English and Japanese: PubMed, MEDLINE, The Cochrane Central Register Controlled Trials (CENTRAL), NPO Japan Medical Abstracts Society's Ichushi - Web database, in March 2019. The title and abstracts of the studies were reviewed by two independent reviewers against the inclusion/exclusion criteria. The keywords were as follows: [hypertensive medications], [calcium channel blockers], [angiotensin converting enzyme inhibitors], [angiotensin receptor blockers], [diuretics], [beta blockers] AND [nocturia].

Results:
132 studies were screened (46 articles were about calcium channel blockers. 6 articles were about angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. 70 articles were about diuretics. 10 articles were about beta blockers), 24 (14 retrospective studies, 8 case control studies, and 2 reviews) were included in the systematic review. Hypertensive drugs had showed close relationships with nocturia. Calcium channel blockers worsened symptoms of nocturia. Lower urinary tract symptoms(LUTS) should be evaluated before and after calcium channel blockers administration. While thiazide diuretics worsened urination symptoms, loop diuretics worsened nocturia. People without gender, the use of diuretics was significantly correlated with the number of urinations at least 3 times / night and the rate of increased urinations was especially high in women.

Conclusions:
Hypertension is a risk factor of nocturia. When we treat hypertensive patients with nocturia, we need to consider antihypertensive drugs may worsen the symptoms of LUTS and select drugs which can improve those symptoms.
RENALASE PROTECTS AGAINST SALT-INDUCED KIDNEY INJURY AND INFLAMMATION BY INHIBITING THE ACTIVATION OF THE AKT-1 SIGNALING PATHWAYS
Authors: Wang Keke , Wang Yang , Yuan Yue , Ma Qiong , Yan Yu , Liao Yueyuan , Mu Jianjun 
Published: April 2021

Objective:
An excess of dietary salt is the most common environmental factor that contributes to the development of hypertension leading to renal pathologies. Renalase (RNLS), a novel secreted flavoprotein with oxidoreductase activity, functions as a survival factor and promotes cell and organ survival. Previous evidence showed that recombinant renalase exerts powerful hypotensive effects and ameliorates renal interstitial fibrosis in rodents. In this study, we evaluated the potential protective role of renalase and underlying mechanisms in salt-induced kidney injury and inflammation.

Design and method:
In vitro, human proximal renal tubular epithelial (HK-2) cells were treated with normal salt or high salt (40 mM NaCl) for 24 hours, receiving recombinant renalase (25ug/mL) or vehicle. In vivo, Dahl salt-sensitive (DS) rats and renalase knockout mice were placed on normal (0.8% NaCl) or high salt (8% NaCl) diet with or without renalase (1 mg/kg) for 4 weeks.

Results:
In vitro, renalase decreased the phosphorylation levels of protein kinase B (Akt-1), leading to a reduction in the mRNA expression of pro-inflammatory cytokines and oxidative stress induced by high salt. And when knockdown the channel plasma membrane calcium ATPase (PMCA4b) in HK-2 cells, the inflammation and oxidative stress levels induced by high-salt decreased.
In DS rats, high salt diet significantly increased the blood pressure and the 24 h urinary sodium excretion. Furthermore, renal inflammation and fibrosis of high salt group were more severe compared to normal salt diet group. Administration of recombinant human renalase reduced kidney inflammation through inhibition of Akt-1 pathway.
Similarly, genetic depletion of renalase in mice (renalase knockout) exacerbated kidney injury in animals with high salt diet. Treatment with recombinant renalase significantly decreased the kidney inflammation through inhibition Akt-1 expression.

Conclusions:
Our study provides the first evidence that renalase can ameliorate kidney injury and inflammation through inhibition of the Akt-1 pathway. These results suggest that renalase has potential renoprotective effects in renal injury and inflammation and may be an effective agent for slowing kidney damage.